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Case Reports in Oncology 2022Chronic lymphocytic leukemia (CLL) involves the proliferation of a clonal population of B cells within the bone marrow that classically spreads to the blood and...
Chronic lymphocytic leukemia (CLL) involves the proliferation of a clonal population of B cells within the bone marrow that classically spreads to the blood and lymphatic system. Central nervous system (CNS) manifestations of CLL occur rarely, and no gold standard treatment regimen has been designated to date. We report a case of CLL with CNS involvement in a 68-year-old woman who presented with a severe headache 4 years after initial diagnosis. She was started on ibrutinib, which failed to clear her CSF of malignancy. Venetoclax was then added, and this was successful in clearing her CSF. For its CNS penetration and efficacy in achieving CSF remission of CLL, we propose that venetoclax be considered as a treatment option for CLL meningitis.
PubMed: 35529288
DOI: 10.1159/000523858 -
Pathology Oncology Research : POR 2022Central nervous system (CNS) involvement is a leading cause of therapy-refractory pediatric acute lymphoblastic leukemia (pALL), which is aggravated by underdiagnosing...
Central nervous system (CNS) involvement is a leading cause of therapy-refractory pediatric acute lymphoblastic leukemia (pALL), which is aggravated by underdiagnosing CNS disease with the currently used cell-based approach of cerebrospinal fluid (CSF) diagnostics. Our study focused on developing novel subcellular CNS leukemia indicators in the CSF and the bone marrow (BM) of patients with pALL. Serial liquid biopsy samples ( = 65) were analyzed by Elisas to measure the level of essential proteins associated with blast cell CNS trafficking, vascular endothelial growth factor A (VEGF-A) and integrin alpha 6 (ITGA6). In CSF samples from early induction chemotherapy, VEGF-A concentration were uniformly elevated in the CNS-positive group compared to those patients without unambiguous meningeal infiltration (9 vs Nine patients, Δc = 17.2 pg/ml, = 0.016). Expression of miR-181a, a -regulating microRNA which showed increased level in CNS leukemia in our previous experiments, was then paralleled with VEGF-A concentration. A slight correlation between the levels of miR-181a and VEGF-A indicators in CSF and BM samples was revealed ( = 46, Pearson's = 0.36, = 0.015). After validating in international cohorts, the joint quantification of miR-181a and VEGF-A might provide a novel tool to precisely diagnose CNS involvement and adjust CNS-directed therapy in pALL.
Topics: Central Nervous System; Central Nervous System Neoplasms; Child; Humans; MicroRNAs; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vascular Endothelial Growth Factor A
PubMed: 35449729
DOI: 10.3389/pore.2022.1610096 -
Journal of Neuro-ophthalmology : the... Jun 2022A 75-year-old man presented with 3 days of progressive left retro-orbital pain, eyelid swelling, tearing, and pain with extraocular movement. His medical history was...
A 75-year-old man presented with 3 days of progressive left retro-orbital pain, eyelid swelling, tearing, and pain with extraocular movement. His medical history was significant for type II diabetes mellitus and chronic lymphocytic leukemia, stable on no therapy since diagnosis 8 years prior. The initial examination was significant for diffuse restriction of left ocular motility, marked lid edema, and mild dyschromatopsia. Computed tomography demonstrated asymmetric left periorbital soft tissue swelling and intraconal fat stranding with an irregular left optic nerve sheath complex and clear paranasal sinuses. He was hospitalized for orbital cellulitis and treated empirically with broad-spectrum intravenous antibiotics, but his visual acuity declined over the ensuing 2 days. Subsequent MRI demonstrated left-greater-than-right circumferential optic nerve sheath enhancement, and leptomeningeal enhancement. An orbital biopsy demonstrated monoclonal B-cell lymphocyte aggregation, whereas a lumbar puncture was positive for Cryptococcus antigen with subsequent demonstration of abundant Cryptococcus by Papanicolaou stain. The final diagnosis was optic perineuritis secondary to cryptococcal meningitis presenting with orbital inflammation. Although his clinical course was complicated by immune reconstitution inflammatory syndrome, symptoms and signs of optic neuropathy ultimately resolved after 1 month of intensive antifungal therapy.
Topics: Aged; Diabetes Mellitus, Type 2; Edema; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Meningitis, Cryptococcal; Orbit; Pain; Vision Disorders
PubMed: 35421041
DOI: 10.1097/WNO.0000000000001538 -
BMC Infectious Diseases Apr 2022To analyse clinical characteristics, antibiotic susceptibility, and risk factors for mortality in paediatric invasive pneumococcal disease (IPD) in Beijing.
BACKGROUND
To analyse clinical characteristics, antibiotic susceptibility, and risk factors for mortality in paediatric invasive pneumococcal disease (IPD) in Beijing.
METHODS
Paediatric IPD patients in our hospital were retrospectively collected from 2012 to 2017. Clinical manifestations, laboratory tests, antimicrobial susceptibility and serotype of isolates, and risk factors for mortality of IPD were analysed.
RESULTS
Overall, 186 IPD cases were enrolled. The major manifestations were meningitis (76), pneumonia with bacteraemia (60), bacteraemia without focus (21), and pneumonia with empyaema (22). Of 72 cases with underlying diseases, leukaemia (18.0%), congenital heart disease (15.3%), primary immunodeficiency disease (12.5%), nephrotic syndrome (12.5%), and cerebrospinal fluid leakage (12.5%) were most common. In total 96.9% of isolates would have been covered by the pneumococcal conjugate vaccine (PCV13), including 19F (32.8%), 19A (23.4%), 4 (17.2%), and 23F (9.4%). Nonsusceptibility rates of penicillin, cefotaxime, and cefepime among nonmeningitis patients increased between 2012 and 2017; The mortality rate was 21.5%. Meningitis, respiratory failure, multiple organ failure, and white blood cell count < 4000 cells/μL were independent risk factors for mortality.
CONCLUSION
Meningitis was the most common clinical manifestation of IPD, and was frequently associated with death. Strains in the PCV13 vaccine would cover most of the cases, and so wider use of PCV13 should be considered.
Topics: Anti-Bacterial Agents; Beijing; Child; Drug Resistance, Bacterial; Humans; Infant; Pneumococcal Infections; Pneumococcal Vaccines; Retrospective Studies; Risk Factors; Serogroup; Serotyping; Streptococcus pneumoniae
PubMed: 35382757
DOI: 10.1186/s12879-022-07179-8 -
Journal of Pediatric Hematology/oncology Apr 2022Extramedullary infiltration (EMI) is a rare condition defined by the accumulation of myeloid tumor cells beyond the bone marrow. The clinical significance is still...
PURPOSE
Extramedullary infiltration (EMI) is a rare condition defined by the accumulation of myeloid tumor cells beyond the bone marrow. The clinical significance is still controversial. This study was aimed to evaluate the incidence, characteristics, and prognostic significance of EMI on complete magnetic resonance imaging (MRI) investigation in newly diagnosed pediatric acute myeloid leukemia (AML) patients who are asymptomatic without clinical evidence to suspect EMI.
MATERIALS AND METHODS
Retrospective clinical and radiologic review of 121 patients with MRI examination at the time of initial diagnosis of AML without any clinical evidence suggestive of EMI was performed. Patients were divided into 2 groups according to the presence or absence of EMI, and the relationship between EMI and established risk factors was analyzed. Initial white blood cell count, the occurrence of an event (including relapse, death, and primary refractory disease), survival status, and detailed information on cytogenetic/molecular status was performed by a thorough review of electronic medical records system. All patients underwent full imaging evaluation with the contrast-enhanced whole body and some regional MRI at the time of initial diagnosis.
RESULTS
The median age at diagnosis was 10.77 years (range, 0.37 to 18.83 y). Based on the risk stratification system of AML, 36, 45, and 40 patients are classified as low-risk, intermediate-risk, and high-risk groups, respectively. MRI at the time of the initial diagnosis of AML revealed 35 of 121 patients (28.9%) with EMI. The most common site of EMI was a skull, followed by the lower extremity bone and meninges of the brain. The median age at diagnosis was significantly younger in patients with EMI (7.87 vs. 11.08 y, P=0.0212). Low incidence of FLT3/ITD mutation, low incidence of AML-ETO gene rearrangement, and the larger extent and more severe degree of bone marrow involvement was related with EMI. However, there was no significant prognostic difference in event-free survival and overall survival regardless of the presence of EMI in the overall patient population and each risk group. The location of EMI occurrence was also not related to prognosis.
CONCLUSIONS
Even if EMI symptoms are not evident, surveillance MRI scans at the initial diagnosis of pediatric AML patients are very helpful in detecting a significant number of EMIs. Younger age, some molecular features, and more severe bone marrow involvement of AML patients were related with EMI. However, there was no significant prognostic difference between patients with or without EMI regardless of risk group. Further prospective investigation is necessary to validate the prognostic effect of EMI in a larger group of patients with different risk groups.
Topics: Child; Humans; Leukemia, Myeloid, Acute; Magnetic Resonance Imaging; Prognosis; Retrospective Studies; Risk Factors
PubMed: 35319510
DOI: 10.1097/MPH.0000000000002353 -
Frontiers in Bioengineering and... 2022Central nervous system leukemia (CNS-L) is caused by leukemic cells infiltrating into the meninges or brain parenchyma and remains the main reason for disease relapse....
Central nervous system leukemia (CNS-L) is caused by leukemic cells infiltrating into the meninges or brain parenchyma and remains the main reason for disease relapse. Currently, it is hard to detect CNS-L accurately by clinically available imaging models due to the relatively low amount of tumor cells, confined blood supply, and the inferior glucose metabolism intensity. Recently, integrin α6-laminin interactions have been identified to mediate CNS-L, which suggests that integrin α6 may be a promising molecular imaging target for the detection of CNS-L. The acute lymphoblastic leukemia (ALL) cell line NALM6 stabled and transfected with luciferase was used to establish the CNS-L mouse model. CNS-L-bearing mice were monitored and confirmed by bioluminescence imaging. Three of our previously developed integrin α6-targeted peptide-based molecular imaging agents, Cy5-S5 for near-infrared fluorescence (NIRF), Gd-S5 for magnetic resonance (MR), and F-S5 for positron emission tomography (PET) imaging, were employed for the molecular imaging of these CNS-L-bearing mice. Bioluminescence imaging showed a local intensive signal in the heads among CNS-L-bearing mice; meanwhile, Cy5-S5/NIRF imaging produced intensive fluorescence intensity in the same head regions. Moreover, Gd-S5/MR imaging generated superior MR signal enhancement at the site of meninges, which were located between the skull bone and brain parenchyma. Comparatively, MR imaging with the clinically available MR enhancer Gd-DTPA did not produce the distinguishable MR signal in the same head regions. Additionally, F-S5/PET imaging also generated focal radio-concentration at the same head regions, which generated nearly 5-times tumor-to-background ratio compared to the clinically available PET radiotracer F-FDG. Finally, pathological examination identified layer-displayed leukemic cells in the superficial part of the brain parenchyma tissue, and immunohistochemical staining confirmed the overexpression of the integrin α6 within the lesion. These findings suggest the potential application of these integrin α6-targeted molecular imaging agents for the accurate detection of CNS-L.
PubMed: 35284414
DOI: 10.3389/fbioe.2022.812277 -
BMJ Case Reports Mar 2022Cryptococcal species endocarditis is infrequently described, carries high mortality and nearly always occurs in immunocompromised states or on prosthetic valves. We...
Cryptococcal species endocarditis is infrequently described, carries high mortality and nearly always occurs in immunocompromised states or on prosthetic valves. We report the case of a man in his 70s with multiple recent hospitalisations for pneumonia, hypercalcaemia and septic tank exposure who presented with intermittent fevers, progressive weakness,and worsening encephalopathy, manifested as confusion and word-finding difficulties for 3 weeks. Workup revealed cryptococcal species on blood serum gram stain, native aortic valve endocarditis and meningitis. Cerebrospinal fluid analysis demonstrated lymphocytosis, ultimately found to be secondary to chronic lymphocytic leukaemia. Surgical valve replacement was deemed medically contraindicated and antifungal therapy was initiated. Though poorly understood with very few documented cases, management of cryptococcal endocarditis relies on prompt diagnosis, early surgery when indicated, long-term antifungal therapy and treatment of underlying immunocompromising states where possible.
Topics: Antifungal Agents; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Endocarditis; Humans; Immunocompromised Host; Meningitis; Meningitis, Cryptococcal
PubMed: 35236688
DOI: 10.1136/bcr-2021-247310 -
Cell Reports. Medicine Dec 2021Acute lymphoblastic leukemia (ALL) dissemination to the central nervous system (CNS) is a challenging clinical problem whose underlying mechanisms are poorly understood....
Acute lymphoblastic leukemia (ALL) dissemination to the central nervous system (CNS) is a challenging clinical problem whose underlying mechanisms are poorly understood. Here, we show that primary human ALL samples injected into the femora of immunodeficient mice migrate to the skull and vertebral bone marrow and provoke bone lesions that enable passage into the subarachnoid space. Treatment of leukemia xenografted mice with a biologic antagonist of receptor activator of nuclear factor κB ligand (RANKL) blocks this entry route. In addition to erosion of cranial and vertebral bone, samples from individuals with B-ALL also penetrate the blood-cerebrospinal fluid barrier of recipient mice. Co-administration of C-X-C chemokine receptor 4 (CXCR4) and RANKL antagonists attenuate both identified routes of entry. Our findings suggest that targeted RANKL and CXCR4 pathway inhibitors could attenuate routes of leukemia blast CNS invasion and provide benefit for B-ALL-affected individuals.
Topics: Animals; Blast Crisis; Cell Line, Tumor; Central Nervous System; Fusion Proteins, bcr-abl; Gene Rearrangement; Histone-Lysine N-Methyltransferase; Humans; Mice, Inbred NOD; Models, Biological; Myeloid-Lymphoid Leukemia Protein; Neoplasm Invasiveness; Osteoprotegerin; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; RANK Ligand; Receptors, CXCR4; Spine; Subarachnoid Space; Xenograft Model Antitumor Assays; Mice
PubMed: 35028611
DOI: 10.1016/j.xcrm.2021.100470 -
Blood Cancer Discovery Jan 2022Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed...
Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing as well as transcriptional and proteomic profiling of paired leukemia-infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS-infiltrating cells, including complement component 3 (C3), and drug targeting of C3 influenced CNS disease in xenografts. CNS-infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies targeting of mRNA translation as a potential therapeutic approach for B-ALL leptomeningeal disease. SIGNIFICANCE: Cancer metastases are often driven by distinct subclones with unique biological properties. Here we show that in B-ALL CNS disease, the leptomeningeal environment selects for cells with unique functional dependencies. Pharmacologic inhibition of mRNA translation signaling treats CNS disease and offers a new therapeutic approach for this condition..
Topics: Central Nervous System; Central Nervous System Diseases; Central Nervous System Neoplasms; Humans; Meningeal Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Biosynthesis; Proteomics
PubMed: 35019858
DOI: 10.1158/2643-3230.BCD-20-0216 -
Frontiers in Cell and Developmental... 2021Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with... (Review)
Review
Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with a significant risk of short- or long-term toxicities. Leukemic cells can metabolically adapt and survive in the microenvironment of the CNS. The supporting role of the CNS microenvironment in leukemia progression and dissemination has not received sufficient attention. Understanding the mechanism by which leukemic cells survive in the nutrient-poor and oxygen-deprived CNS microenvironment will lead to the development of more specific and less toxic therapies. Here, we review the current literature regarding the roles of metabolic reprogramming in leukemic cell adhesion and survival in the CNS.
PubMed: 34957100
DOI: 10.3389/fcell.2021.767510