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Experimental Cell Research Apr 2024A major obstacle in improving survival in pediatric T-cell acute lymphoblastic leukemia is understanding how to predict and treat leukemia relapse in the CNS. Leukemia...
A major obstacle in improving survival in pediatric T-cell acute lymphoblastic leukemia is understanding how to predict and treat leukemia relapse in the CNS. Leukemia cells are capable of infiltrating and residing within the CNS, primarily the leptomeninges, where they interact with the microenvironment and remain sheltered from systemic treatment. These cells can survive in the CNS, by hijacking the microenvironment and disrupting normal functions, thus promoting malignant transformation. While the protective effects of the bone marrow niche have been widely studied, the mechanisms behind leukemia infiltration into the CNS and the role of the CNS niche in leukemia cell survival remain unknown. We identified a dysregulated gene expression profile in CNS infiltrated T-ALL and CNS relapse, promoting cell survival, chemoresistance, and disease progression. Furthermore, we discovered that interactions between leukemia cells and human meningeal cells induced epigenetic alterations, such as changes in histone modifications, including H3K36me3 levels. These findings are a step towards understanding the molecular mechanisms promoting leukemia cell survival in the CNS microenvironment. Our results highlight genetic and epigenetic alterations induced by interactions between leukemia cells and the CNS niche, which could potentially be utilized as biomarkers to predict CNS infiltration and CNS relapse.
Topics: Child; Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Cell Survival; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Recurrence; Cell Cycle; Tumor Microenvironment
PubMed: 38561062
DOI: 10.1016/j.yexcr.2024.114015 -
Journal of Hematopathology Mar 2024A 22-year-old man presented at the emergency department with progressive headache, vomiting and horizontal diplopia over 2-month period. He also developed blurred vision...
A 22-year-old man presented at the emergency department with progressive headache, vomiting and horizontal diplopia over 2-month period. He also developed blurred vision in his left eye. He complained of loss of appetite for the past 2 months, resulting in a 5-kg weight loss. Examination upon arrival revealed papilledema and bilateral abducens nerve palsy. Motor and sensory functions were intact. Magnetic resonance imaging (MRI) of the brain revealed multiple extra-axial nodular enhancing lesions with size of 5-10 mm mainly along with both sides of falx cerebri and vasogenic brain oedema (Fig. 1). Stereotactic brain biopsy was performed to obtain tissue diagnosis. Histologic examination revealed brain infiltration by few atypical cells hidden amongst abundant and mixed population of inflammatory cells including lymphocytes and histiocytes. The atypical cells are large cells with horseshoe nuclei (red arrow; Fig. 2A ×100 and Fig. 2B ×400). Immunohistochemistry showed strong, uniform CD30 expression (Fig. 2C ×400) and cytoplasmic ALK staining (Fig. 2D ×400), as well as for CD3 (Fig. 2E ×400) and CD68 (Fig. 2F ×400). B-cell markers (CD20) were negative (Fig. 2G ×400).
Topics: Humans; Male; Young Adult; Brain; Brain Edema; Central Nervous System; Dura Mater; Lymphoma, Large-Cell, Anaplastic
PubMed: 38376722
DOI: 10.1007/s12308-023-00570-7 -
Current Cancer Drug Targets Jan 2024Leptomeningeal metastasis (LM) is a serious and often fatal complication in patients with advanced lung cancer, resulting in significant neurological deficits, decreased...
Leptomeningeal metastasis (LM) is a serious and often fatal complication in patients with advanced lung cancer, resulting in significant neurological deficits, decreased quality of life, and a poor prognosis. This article summarizes current research advances in treating lung cancer with meningeal metastases, discusses clinical challenges, and explores treatment strategies. Through an extensive review of relevant clinical trial reports and screening of recent conference abstracts, we collected clinical data on treating patients with lung cancer with meningeal metastases to provide an overview of the current research progress. Exciting progress has been made by focusing on specific mutations within lung cancer, including the use of EGFR tyrosine kinase inhibitors or inhibitors for anaplastic lymphoma kinase gene rearrangement, such as osimertinib, alectinib, and lorlatinib. These targeted therapies have shown impressive results in penetrating the central nervous system (CNS). Regarding whole-brain radiotherapy, there is currently some controversy among investigators regarding its effect on survival. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated reliable clinical benefits due to their ability to retain anticancer activity in CNS metastases. Moreover, combination therapy shows promise in providing further treatment possibilities. Considerable progress has been made in the clinical research of lung cancer with LM. However, the sample size of prospective clinical trials investigating LM for lung cancer is still limited, with most reports being retrospective. Developing more effective management protocols for metastatic LM in lung cancer remains an ongoing challenge for the future.
PubMed: 38279718
DOI: 10.2174/0115680096276133231201061114 -
The International Journal of... Jan 2024Primary leptomeningeal lymphoma (PLML) without brain parenchymal involvement or systemic disease is very rare, comprising of approximately 7% of all primary central...
BACKGROUND
Primary leptomeningeal lymphoma (PLML) without brain parenchymal involvement or systemic disease is very rare, comprising of approximately 7% of all primary central nervous system lymphomas (PCNSL). PLML is a diagnosis of exclusion which should be confirmed on biopsy after ruling out metastasis from systemic lymphomas and dissemination from PCNSL.
CASE DESCRIPTION
A 21-year-old patient presented with the chief complaints of headache, diplopia, decreased vision for five months, and a swelling on the left side of the forehead for four months. On radiology, a large, lobulated, extra-axial mass lesion along the left frontal region with its base towards dura noted. No parenchymal or subependymal CNS lesions were found on CT/MRI. Histopathology was reported as primary leptomeningeal CD30 positive diffuse large B cell lymphoma.
CONCLUSIONS
PLML is a very rare meningeal tumor that requires a very high index of suspicion and is always a diagnosis of exclusion.
PubMed: 38217364
DOI: 10.1080/00207454.2024.2306300 -
Enfermedades Infecciosas Y... Jan 2024The use of systemic corticosteroids during Epstein-Barr virus (EBV)-induced infectious mononucleosis is a controversial but widespread practice. We aimed to investigate...
BACKGROUND AND AIM
The use of systemic corticosteroids during Epstein-Barr virus (EBV)-induced infectious mononucleosis is a controversial but widespread practice. We aimed to investigate the frequency of complications in adolescents and adults with infectious mononucleosis in relation to the use of corticosteroids.
METHODS
We reviewed the clinical records of 396 patients admitted to the hospital with infectious mononucleosis (52.0% male; median age, 19 years; range, 15-87 years), with a focus on both short-term (infectious and non-infectious) and long-term (hematological malignancies) complications in relation to corticosteroid use.
RESULTS
A total of 155 (38.6%) patients received corticosteroids at some point during infectious mononucleosis. Corticosteroid use was significantly (P≤0.002) associated with sore throat, lymphadenopathy, leukocytosis, and with antibiotics use (mainly indicated after suspicion of tonsillar bacterial superinfection). Overall, 139/155 (89.7%) patients who were treated with corticosteroids also received antibiotics either before or during hospitalization, compared with 168/241 (69.7%) patients who did not. The frequency of short-term severe complications, either infectious (peritonsillar-parapharyngeal abscess or bacteremia) or non-infectious (splenic rupture, severe thrombocytopenia, myopericarditis, or lymphocytic meningitis) were similar in patients receiving and not receiving corticosteroids. After a median of 15 years of follow-up, only one Hodgkin's lymphoma was diagnosed, in a patient who was not treated with corticosteroids during infectious mononucleosis.
CONCLUSIONS
The use of systemic corticosteroids during EBV-induced infectious mononucleosis is generally safe, at least with concomitant antibiotic therapy. However, this should not encourage the use of corticosteroids in this context, given that their efficacy has yet to be demonstrated.
PubMed: 38216421
DOI: 10.1016/j.eimce.2023.10.005 -
International Journal of Molecular... Dec 2023C-X-C-motif chemokine ligand 13 (CXCL13) in cerebrospinal fluid (CSF) is increasingly used in clinical routines, although its diagnostic specificity and divergent...
C-X-C-motif chemokine ligand 13 (CXCL13) in cerebrospinal fluid (CSF) is increasingly used in clinical routines, although its diagnostic specificity and divergent cut-off values have been defined so far mainly for neuroborreliosis. Our aim was to evaluate the value of CSF-CXCL13 as a diagnostic and treatment response marker and its role as an activity marker in a larger disease spectrum, including neuroborreliosis and other neuroinflammatory and malignant CNS-disorders. Patients who received a diagnostic lumbar puncture (LP) ( = 1234) between July 2009 and January 2023 were included in our retrospective cross-sectional study. The diagnostic performance of CSF-CXCL13 for acute neuroborreliosis was highest at a cut-off of 428.92 pg/mL (sensitivity: 92.1%; specificity: 96.5%). In addition, CXCL13 levels in CSF were significantly elevated in multiple sclerosis with clinical ( = 0.001) and radiographic disease activity ( < 0.001). The clinical utility of CSF-CXCL13 appears to be multifaceted. CSF-CXCL13 is significantly elevated in patients with neuroborreliosis and shows a rapid and sharp decline with antibiotic therapy, but it is not specific for this disease and is also highly elevated in less common subacute neuroinfectious diseases, such as neurosyphilis and cryptococcal meningitis or in primary/secondary B-cell lymphoma.
Topics: Humans; Cross-Sectional Studies; Retrospective Studies; Spinal Puncture; Multiple Sclerosis; Neurosyphilis; Syndrome; Chemokine CXCL13
PubMed: 38203597
DOI: 10.3390/ijms25010425 -
BioRxiv : the Preprint Server For... Dec 2023Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor...
Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.
PubMed: 38187773
DOI: 10.1101/2023.12.18.572239 -
Zhonghua Bing Li Xue Za Zhi = Chinese... Jan 2024To investigate the clinicopathological characteristics, diagnosis and differential diagnosis of intravascular large B-cell lymphoma (IVLBCL) and its collision tumors....
To investigate the clinicopathological characteristics, diagnosis and differential diagnosis of intravascular large B-cell lymphoma (IVLBCL) and its collision tumors. Five cases of IVLBCL were collected, including 2 cases of collision tumors, and 1 case complicated with liver cirrhosis. The morphology and immunophenotype were analyzed. The related literature was reviewed. There were 2 females and 3 males, aged from 53 to 73 years, with a median age of 65 years. The tumors were located in the lower extremities, right cerebellar hemisphere, left kidney, bilateral nasal cavity, and liver, respectively. Cases 2 and 3 were incidentally found in meningioma and renal cell carcinoma tissues, respectively. Case 5 had a background of liver cirrhosis. Morphologically, atypical large lymphoid cells were located in small blood vessels and capillary lumen, with little cytoplasm, hyperchromasia, prominent nucleoli, and obvious mitotic figures. Immunohistochemically, the IVLBCL tumor cells expressed CD20 and PAX5; 2 cases were CD5 positive. One of the 5 cases was GCB phenotype, and 4 cases were non-GCB phenotype. All cases expressed C-MYC (positive rate was 10%-40%). PD-L1 was positive in 4 cases (positive rate was 60%-90%). Ki-67 proliferation index was 70%-90%. CKpan, CD3, TDT, and CD34 were negative. In case 2, meningioma cells were positive for PR, EMA, and vimentin, but negative for CKpan and PD-L1. In case 3, renal carcinoma cells were positive for CKpan, PAX8, EMA, vimentin, CAⅨ and CD10, while PD-L1 was negative. No EBER expression (by in situ hybridization) or C-MYC gene translocation (FISH, break-apart probe) was detected in any of the 5 cases. Three patients were followed up, and all died within 1-13 months. IVLBCL is a highly aggressive lymphoma, with occult clinical manifestations and poor prognosis. Collision tumors of IVLBCL are extremely rare. A better understanding of IVLBCL would help pathologists avoid misdiagnoses.
Topics: Male; Female; Humans; Aged; B7-H1 Antigen; Vimentin; Meningioma; Lymphoma, Large B-Cell, Diffuse; Carcinoma, Renal Cell; Kidney Neoplasms; Meningeal Neoplasms; Liver Cirrhosis
PubMed: 38178742
DOI: 10.3760/cma.j.cn112151-20230913-00169 -
Iranian Journal of Microbiology Dec 2023Cryptococcosis, a relatively uncommon infection in cancer patients is often associated with delayed diagnosis and high fatality rate due to its highly heterogeneous and...
Cryptococcosis, a relatively uncommon infection in cancer patients is often associated with delayed diagnosis and high fatality rate due to its highly heterogeneous and protean manifestations. Early recognition and initiation of appropriate antifungal therapy might have a favourable outcome in such cases. Here we report three cases of Cryptococcosis among cancer patients in a tertiary care cancer centre in South India. All three patients were males of different ages at presentation with immunosuppression in the form of solid organ or hematologic malignancy and were using immunosuppressive medications like steroids or chemotherapeutic agents. They presented with cryptococcemia and cryptococcal meningitis. Patients with microbiologically proven cryptococcosis had poor outcome in this subgroup of patients.
PubMed: 38156297
DOI: 10.18502/ijm.v15i6.14163 -
Mayo Clinic Proceedings Dec 2023
Topics: Humans; Meningitis; Magnetic Resonance Imaging; Lymphoma, B-Cell
PubMed: 38044004
DOI: 10.1016/j.mayocp.2023.06.014