Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with ...high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent. The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus ...reactivation and subsequent onset of autoimmune diseases
. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge
and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases
. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions
, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4
T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.
Diagnosis of Hodgkin lymphoma in the modern era Wang, Hao‐Wei; Balakrishna, Jayalakshmi P.; Pittaluga, Stefania ...
British journal of haematology,
January 2019, Letnik:
184, Številka:
1
Journal Article
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Summary
The Hodgkin lymphomas are a family of unique lymphoma subtypes, in which the nature of the neoplastic cell was enigmatic for many years. Much of the mystery has been solved, with all forms ...now considered to be of B‐cell origin, in most cases of germinal centre derivation. Today we recognize Hodgkin lymphoma as an eponym that encompasses multiple entities. One of the unifying themes is the major contribution from the tumour microenvironment. Both the character of the neoplastic cells and the nature of the immune environment are critical to accurate diagnosis. Moreover, an understanding of the molecular alterations that characterize both the neoplastic cells and their microenvironment have led to therapeutic advances, targeting both neoplastic and reactive components. Other conditions may foster a similar inflammatory milieu and lead to lymphoproliferations that mimic the Hodgkin lymphomas. In this review we provide an update on the diagnostic features of the various subtypes and include additional information relevant for prognostic evaluation and investigation of potential therapeutic targets. Additionally, we also discuss those conditions that often cause confusion in diagnosis and need to be distinguished from the Hodgkin lymphomas.
CD55 prevents convertase enzyme formation in the complement cascade, acting as a brake on complement activation. Inactivating mutations in
CD55
result in hyperactivation of complement, angiopathic ...thrombosis, and protein-losing enteropathy.
A dose-intense infusional chemotherapy program plus rituximab had a high degree of efficacy in patients with primary mediastinal B-cell lymphoma, which is genetically related to Hodgkin's lymphoma ...and predominantly affects young women.
Primary mediastinal B-cell lymphoma is a distinct pathogenetic subtype of diffuse large-B-cell lymphoma that arises in the thymus.
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,
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Although it comprises only 10% of cases of diffuse large-B-cell lymphoma, primary mediastinal B-cell lymphoma, which predominantly affects young women,
3
is aggressive and typically is manifested by a localized, bulky mediastinal mass, often with pleural and pericardial effusions. Less commonly, the disease involves extranodal sites, including the lung, kidneys, gastrointestinal organs, or brain.
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,
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This disease is clinically and biologically related to nodular sclerosing Hodgkin's lymphoma; the putative cell of origin for both conditions is a thymic B cell.
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,
2
The . . .
Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active ...in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.
•Ibrutinib reduced tumor masses in 94% of patients with primary brain lymphoma•Chronic active B cell receptor signaling is a feature of primary brain lymphoma•Ibrutinib promotes fungal infections with Aspergillus fumigatus•TEDDi-R treatment produced durable remissions in refractory primary brain lymphoma
Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor signaling. In a phase 1b study, Lionakis et al. observe promising therapeutic effects of the BTK inhibitor ibrutinib in PCNSL but also increased aspergillosis, which they show is linked to BTK-dependent fungal immunity in a mouse model.
Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in BTK and PLCG2. The rate of ...resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry, TP53 aberration, advanced Rai stage, and high β-2 microglobulin were independently associated with inferior progression-free survival (P < .05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations in BTK (Cys481) and/or PLCG2 (within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying high-sensitivity testing (detection limit ∼1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
•Most cases of ibrutinib-resistant CLL were due to mutations in BTK and/or PLCG2 and often composed of multiple independent subclones.•High sensitivity testing identified resistance mutations up to 15 months before manifestation of clinical progression.
Plerixafor for the Treatment of WHIM Syndrome McDermott, David H; Pastrana, Diana V; Calvo, Katherine R ...
New England journal of medicine/The New England journal of medicine,
01/2019, Letnik:
380, Številka:
2
Journal Article
Recenzirano
Odprti dostop
WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis) results from hyperactivity of the chemokine receptor CXCR4. Plerixafor blocks the receptor. It was used in three patients ...who could not receive granulocyte colony-stimulating factor and was associated with sustained improvement.
Low-Intensity Therapy in Adults with Burkitt's Lymphoma Dunleavy, Kieron; Pittaluga, Stefania; Shovlin, Margaret ...
New England journal of medicine/The New England journal of medicine,
11/2013, Letnik:
369, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Toxic high-dose chemotherapy may not be necessary to cure Burkitt's lymphoma in adults and patients with immunodeficiency. An infusion-based chemotherapy program with modest toxicity administered ...mainly in outpatients resulted in an overall survival rate of 90 to 100%.
Burkitt's lymphoma, first described by Denis Burkitt in African children, is a highly proliferative human cancer.
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Although rare, Burkitt's lymphoma disproportionately affects children, accounting for 30 to 50% of pediatric lymphomas. Three major variants are recognized: endemic, which occurs in equatorial Africa; sporadic, which occurs worldwide; and immunodeficiency-associated, which occurs primarily in persons with human immunodeficiency virus (HIV) infection. Young patients with sporadic Burkitt's lymphoma have a favorable outcome with intense short-cycle treatment, whereas adult patients and those with immunodeficiency have inferior outcomes.
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Burkitt's lymphoma is derived from a germinal-center B cell and has distinct oncogenic pathways.
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A . . .
Objective
Heightened inflammation, dysregulated immunity, and thrombotic events are characteristic of hospitalized COVID‐19 patients. Given that platelets are key regulators of thrombosis, ...inflammation, and immunity they represent prime candidates as mediators of COVID‐19‐associated pathogenesis. The objective of this study was to understand the contribution of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) to the platelet phenotype via phenotypic (activation, aggregation) and transcriptomic characterization.
Approach and Results
In a cohort of 3915 hospitalized COVID‐19 patients, we analyzed blood platelet indices collected at hospital admission. Following adjustment for demographics, clinical risk factors, medication, and biomarkers of inflammation and thrombosis, we find platelet count, size, and immaturity are associated with increased critical illness and all‐cause mortality. Bone marrow, lung tissue, and blood from COVID‐19 patients revealed the presence of SARS‐CoV‐2 virions in megakaryocytes and platelets. Characterization of COVID‐19 platelets found them to be hyperreactive (increased aggregation, and expression of P‐selectin and CD40) and to have a distinct transcriptomic profile characteristic of prothrombotic large and immature platelets. In vitro mechanistic studies highlight that the interaction of SARS‐CoV‐2 with megakaryocytes alters the platelet transcriptome, and its effects are distinct from the coronavirus responsible for the common cold (CoV‐OC43).
Conclusions
Platelet count, size, and maturity associate with increased critical illness and all‐cause mortality among hospitalized COVID‐19 patients. Profiling tissues and blood from COVID‐19 patients revealed that SARS‐CoV‐2 virions enter megakaryocytes and platelets and associate with alterations to the platelet transcriptome and activation profile.
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