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Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with POT1 pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in POT1 and four other telomere-maintenance genes associated with familial cancer underlie PTC susceptibility. Among 470 individuals, we identified pathogenic or likely pathogenic variants in three genes encoding telomere-binding proteins: POT1 , TINF2 , and ACD. They were found in 4.5% and 1.5% of familial and unselected cases, respectively. Individuals harboring these variants had ultra-long telomere length, and 15 of 18 (83%) developed other cancers, of which melanoma, lymphoma, and sarcoma were most common. Among individuals with PTC and melanoma, 22% carried a deleterious germline variant, suggesting that a long telomere syndrome might be clinically recognizable. Successive generations had longer telomere length than their parents and, at times, developed more cancers at younger ages. Tumor sequencing identified a single oncogenic driver, BRAF p.Val600Glu, in 10 of 10 tumors studied, but no telomere-maintenance mechanism, including at the TERT promoter. These data identify a syndromic subset of PTCs with locus heterogeneity and telomere lengthening as a convergent mechanism. They suggest these germline variants lower the threshold to cancer by obviating the need for an acquired telomere-maintenance mechanism in addition to sustaining the longevity of oncogenic mutations. DeBoy et al. identify telomere-lengthening variants in genes encoding three telomere-binding proteins as monogenic risk factors for papillary thyroid cancers, the most common of endocrine malignancies. Eighty-three percent of individuals had second cancers, of which melanoma, sarcoma, and lymphoid malignancies were most common. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has emerged recently as a standard of care treatment for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and several subtypes of B-cell non-Hodgkin lymphoma (NHL). However, its use remains limited to highly specialized centers, given the complexity of its administration and its associated toxicities. We previously reported our experience in using a novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy in the peri-transplant setting, where it exhibited an excellent safety profile with encouraging survival outcomes. We have since modified the SB CD19 CAR construct to improve its efficacy and shorten its manufacturing time. We report here the phase 1 clinical trial safety results. Fourteen heavily treated patients with relapsed/ refractory ALL and NHL were infused. Overall, no serious adverse events were directly attributed to the study treatment. Three patients developed grades 1-2 cytokine release syndrome and none of the study patients experienced neurotoxicity. All dose levels were well tolerated and no dose-limiting toxicities were reported. For efficacy, 3 of 8 (38%) patients with ALL achieved CR/CRi (complete remission with incomplete count recovery) and 1 (13%) patient had sustained molecular disease positivity. Of the 4 patients with DLBCL, 2 (50%) achieved CR. The SB-based CAR constructs allow manufacturing of targeted CAR T-cell therapies that are safe, cost-effective and with encouraging antitumor activity. [ABSTRACT FROM AUTHOR]

Objectives: Epstein-Barr virus (EBV) causes different clinical presentations in immunocompetent and immunocompromised persons, and thus indications for testing vary between these populations. We reviewed our institution's EBV DNA testing across these populations to understand its clinical utility and appropriateness., Methods: We conducted a retrospective chart review of adult patients with positive EBV nucleic acid amplification (NAAT) testing from November 2022 to 2023. We recorded demographics, indications for testing, EBV-related diagnosis, laboratory results, and whether testing influenced patient treatment., Results: Of 3560 EBV NAAT tests, 187 (5.3%) were positive, representing 124 unique adult patients (51 immunocompetent and 73 immunocompromised). Reactivation of EBV was the most common diagnosis in both populations, followed by acute EBV infection in the immunocompetent and non-posttransplant lymphoproliferative disorder malignancies in the immunocompromised. In immunocompromised patients, positive tests led to treatment changes more frequently than in immunocompetent patients (27.4% vs 11.7%, P = .06). Testing affected clinical management in 0% to 2% of cases when sent for sepsis/shock and nonspecific viral syndromes compared to 37% to 49% of cases when sent for posttransplant and malignancy screening/monitoring., Discussion: EBV NAAT testing infrequently influenced clinical management in immunocompetent individuals but had a notable impact in immunocompromised patients, particularly those undergoing posttransplant or malignancy screening. This underscores the need for targeted testing to optimize resource utilization and cost-effectiveness., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Chimeric antigen receptor (CAR) T-cell therapy has emerged recently as a standard of care treatment for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and several subtypes of B-cell non-Hodgkin lymphoma (NHL). However, its use remains limited to highly specialized centers, given the complexity of its administration and its associated toxicities. We previously reported our experience in using a novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy in the peri-transplant setting, where it exhibited an excellent safety profile with encouraging survival outcomes. We have since modified the SB CD19 CAR construct to improve its efficacy and shorten its manufacturing time. We report here the phase 1 clinical trial safety results. Fourteen heavily treated patients with relapsed/refractory ALL and NHL were infused. Overall, no serious adverse events were directly attributed to the study treatment. Three patients developed grades 1-2 cytokine release syndrome and none of the study patients experienced neurotoxicity. All dose levels were well tolerated and no dose-limiting toxicities were reported. For efficacy, 3 of 8 (38%) patients with ALL achieved CR/CRi (complete remission with incomplete count recovery) and 1 (13%) patient had sustained molecular disease positivity. Of the 4 patients with DLBCL, 2 (50%) achieved CR. The SB-based CAR constructs allow manufacturing of targeted CAR T-cell therapies that are safe, cost-effective and with encouraging antitumor activity.

Vaccines having aided in escaping the majority of the population from immunological naïvety, our strategies are now shifting towards an increased focus on identifying and protecting the extremely vulnerable. We here describe the results of testing 12 patients, those with lymphoid malignancies having been targeted their B-cells for therapy with rituximab-containing regimens or a Bruton tyrosine kinase inhibitor, for anti-SARS-CoV-2 spike antibodies after receiving the BNT162b2 mRNA vaccine doses. The interval from last dosing of B-cell depletion therapy to SARS-CoV-2 vaccination was at median 5.3 (range 3.1–6.6) months. Using the 'seroprotection' threshold of 775 [BAU/mL] for the anti-spike antibody titer, our finding points out the crucial unresponsiveness of the targeted population with 0/12 (0%) achieving 'seroprotection'. Although IgG seroconversion was observed in 4/12 (33%), supporting the overall benefit of vaccination, the figures still point out a potential need for optimization of practice. IgA was further less responsive (unsuccessful 'seroconversion' in 11/12 (92%)), implicating an underlying class switch defect. Those with depletion on B-cells are caught at a dilemma between, being too early and too late on receiving SARS-CoV-2 vaccines. They wish to get over their immunological naïvety at the earliest, while, in order to assure quality immune memory, are also required to hold the patience for their B-cells to repopulate. Although it remains an issue whether intensified vaccine schedules and/or regimens will lead to stronger immunogenicity or more effective boosters for non-responders, we shall take advantage of every increasing evidence in order to optimize current options. [ABSTRACT FROM AUTHOR]

Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.

Severe haematological diseases and lymphoid malignancies require bone marrow (BM)-suppressive treatments. Knowledge regarding the impact of BM-suppressive treatments on children's memory T cells is very limited. Memory T cells play a crucial role in defending against herpesviruses, which is particularly relevant in paediatric cancer care. We studied 53 children in total; 34 with cancer and 2 with severe haematological disorders, with some receiving BM-suppressive treatment with or without allogeneic-haematopoietic stem cell transplantation (allo-HSCT), alongside 17 healthy controls. We focused on peripheral blood proportions of memory T-cell subsets using flow cytometry and analysed cytokine-secreting T cells with a four-parameter FluoroSpot assay in response to T-cell mitogen and varicella zoster virus (VZV) peptides. Patients on BM-suppressive treatment showed increased clusters of differentiation (CD)4 + and CD8 + effector memory (TEM)/terminally differentiated effector (TEFF) T cells compared to the healthy controls. They also exhibited, amongst other things, when compared to the healthy controls, a reduced total number of cytokine-secreting cells, by means of interferon (IFN)-γ, interleukin (IL)-17A, IL-10, and IL-22, following mitogen activation. A diminished IFN-γ response among the children with BM-suppressive treatment was observed upon VZV-peptide stimulation, compared to the healthy children. Collectively, the findings herein indicate that the children who are undergoing or have finished BM-suppressive treatment display qualitative differences in their T-cell memory compartment, potentially increasing their susceptibility to severe viral infections and impacting their immunotherapy, which relies on the functional ability of autologous T cells.

Objectives: To investigate concordance in survival time among first‐degree relatives with lymphoid malignancies. Methods: By linkage of national Swedish registers, we identified 66 430 patients diagnosed with a lymphoid malignancy 1958‐2016 with information on first‐degree relationships and follow‐up until 2017. Among these, we identified pairs of first‐degree relatives with any (N = 3326) or a similar (N = 690) lymphoid malignancy subtype. We defined survival in the first‐degree relative as good, expected, or poor based on tertiles of deviance residuals from a multivariable Cox regression model. Next, we used Cox regression to estimate hazard ratios (HR) of death with 95% confidence intervals (CI) among patients, using the survival of their first‐degree relative as exposure and adjusting for confounders. Results: There was no concordance in survival among first‐degree relatives with any lymphoid malignancy (HRgood = 1.00 (reference), HRExpected = 1.02, 95% CI: 0.89‐1.17, HRPoor = 1.12, 95% CI: 0.98‐1.27, Ptrend =.08). Among first‐degree relatives with indolent lymphoma, including chronic lymphocytic leukemia, those with a first‐degree relative to an expected or poor survival had worse outcome compared to those with a first‐degree relative with good survival (HRExpected = 1.44, 95% CI: 0.82‐2.53, HRPoor = 1.79, 95% CI: 1.07‐3.00, Ptrend =.03). Conclusion: Our results support a role of inherited factors in the outcome of indolent lymphoma, including chronic lymphocytic leukemia. [ABSTRACT FROM AUTHOR]

Hyperglycemia and glucose test abnormalities are problems during the treatment of patients with lymphoid malignancy, caused by corticosteroid therapy. However, its long-term complications or risk of developing diabetes are not available. Two hundred patients with lymphoid hematologic malignancy were recruited and followed up for median of 47 months. The underlying hematologic malignancy includes Hodgkin's disease (HD), Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia(CLL), Multiple Myeloma (MM) and Acute Lymphocytic Leukemia (ALL). Fasting blood sugar, glucose tolerance test and lipid profiles were measured before each chemotherapy cycle and every 3 months after. This study was designed to evaluate patients for long-term follow up of glucose tests abnormalities. The mean age of the non-diabetic patients was significantly lower than that of diabetics and patients with fasting glucose disorder (p < 0.001). The prevalence of diabetes and impaired FBS and GTT was higher in NHL (9%), CLL (6.5%) and MM (1.5%), respectively. For lipid profiles, the highest levels of cholesterol and triglycerides were observed in multiple myeloma and the lowest in Hodgkin's lymphoma (P:0.004). The most important factor for steroid-induced diabetes is age, which was more prevalent with age increase (P < 0.001). Glucocorticoid-induced diabetes is common in multiple myeloma and then in chronic lymphocytic leukemia and non-Hodgkin's lymphoma in comparison with Hodgkin's lymphoma and acute lymphoblastic leukemia. • The most important risk factor for diabetes associated with glucocorticoids is aging. • Glucocorticoid-related diabetes is more common in non-Hodgkin lymphoma. • The highest levels of cholesterol and triglycerides are in multiple myeloma. [ABSTRACT FROM AUTHOR]

The cytokine interleukin-7 (IL-7) and its receptor are critical for lymphoid cell development. The loss of IL-7 signaling causes severe combined immunodeficiency, whereas gain-of-function alterations in the pathway contribute to malignant transformation of lymphocytes. Binding of IL-7 to the IL-7 receptor results in the activation of the JAK-STAT, PI3K-AKT and Ras-MAPK pathways, each contributing to survival, cell cycle progression, proliferation and differentiation. Here, we discuss the role of deregulated IL-7 signaling in lymphoid malignancies of B- and T-cell origin. Especially in T-cell leukemia, more specifically in T-cell acute lymphoblastic leukemia and T-cell prolymphocytic leukemia, a high frequency of mutations in components of the IL-7 signaling pathway are found, including alterations in IL7R, IL2RG, JAK1, JAK3, STAT5B, PTPN2, PTPRC and DNM2 genes.

Purpose: Globally, cancer is a critical illness which seriously threatens human health. T-cell-based cancer immunotherapy for some patients has demonstrated impressive achievements including chimeric antigen receptor T cells, immune checkpoint inhibitors and T cell-redirecting bispecific antibodies (TRBAs). TRBAs recruit T cells to lyse cancer cells bypassing the antigen presentation through the major histocompatibility complex pathways. In this review we summarized the TRBAs formats, biophysical characteristics, the preclinical and clinical trial results, as well as the challenges faced by TRBAs in tumour therapy. Methods: Herein the relevant literature and clinical trials from the PubMed and ClinicalTrials.gov database. Results: The advances in protein engineering technology have generated diverse TRBAs format which can be classified into two categories: IgG-like TRBAs and non-IgG-like TRBAs. Multiple applications of TRBAs showed encouraging curative effect and entered clinical trials for lymphoid malignancy and solid tumour. Conclusions: TRBA is a powerful tool for the cancer treatment and the clinical studies showed potent anti-tumour efficacy in hematologic malignancies. Although the clinical outcomes of TRBAs in solid tumours are less satisfied than hematologic malignancies, many preclinical antibodies and combination therapies are being evaluated [ABSTRACT FROM AUTHOR]

The role of HLA system in allogeneic haematopoietic stem cell transplantation (allo-HSCT) outcome is unarguable. In this study we investigated association of HLA-A,-B and-DRB1 alleles with overall survival (OS) in 186 patients undergoing allo-HSCT for lymphoid malignancies. Analyses confirmed significantly better OS for HLA-DRB1∗04 carriers compared with non-carriers (p = 0.01). Survival benefit was confined to male patients (in multivariate analyses p = 0.034, hazard ratio 0.35, 95% confidence interval 0.13–0.92), whereas in females no difference was noted (p = 0.82). Furthermore, donor gender also affected outcome and transplantation from female HLA-DRB1∗04 carrier donors resulted in superior survival compared with female non-carrier donors (p = 0.01). Combined analyses including recipient/donor gender and HLA-DRB1∗04 showed that survival of male patients varied significantly according to donor gender and HLA-DRB1∗04 carriership (p = 0.04) with best survival among HLA-DRB1∗04 carriers transplanted from female donors. Of relevance to our results, HLA-DRB1∗04 has been documented as risk allele group for lymphoid malignancies, and studies described a male-specific risk. We believe that our findings provide further supporting evidence for sex-specific alterations secondary to HLA-DRB1∗04 or related genes. Further studies are warranted to evaluate whether in contrast to general favour of male donors HLA-DRB1∗04 carrier patients with lymphoid malignancies could benefit from transplantation from female donors. [ABSTRACT FROM AUTHOR]

The phagocytic clearance of host cells is important for eliminating dying cells and for the therapeutic clearance of antibody-targeted cells. As ubiquitous, motile and highly phagocytic immune cells, macrophages are principal players in the phagocytic removal of host cells throughout the body. In recent years, great strides have been made in identifying the molecular mechanisms that control the recognition and phagocytosis of cells by macrophages. However, much less is known about the physical and metabolic constraints that govern the amount of cellular material macrophages can ingest and how these limitations affect the overall efficiency of host cell clearance in health and disease. In this review we will discuss, in the contexts of apoptotic cells and antibody-targeted malignant cells, how physical and metabolic factors associated with the internalization of host cells are relayed to the phagocytic machinery and how these signals can impact the overall efficiency of cell clearance. We also discuss how this information can be leveraged to increase cell clearance for beneficial therapeutic outcomes. [ABSTRACT FROM AUTHOR]

High.dose methotrexate is the backbone of various regimens for treating lymphoid malignancies. Mucositis is a well.known, dose.related side effect of methotrexate. Prophylactic measures such as folinic acid rescue are useful but do not prevent mucositis in all the cases. Once severe mucositis (WHO Grade IV) sets in, mortality is very high. The index case highlights the natural course of methotrexate.induced mucositis and the need for swift and preemptive intervention. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a cause of increased morbidity and mortality in cancer patients. VTE is the second leading cause of death in cancer patients. Risk assessment models have been developed to identify patients at risk of VTE for thromboprophylaxis. Risk scores of patients in our environment have not been adequately investigated., Objective: The study evaluates the association of thrombotic risk assessment scores (using the modified Khorana risk assessment tool) and soluble P-selectin levels with thrombotic events in patients with lymphoid cancer., Methods: This is a comparative cross-sectional study conducted at Nnamdi Azikiwe University Teaching Hospital (NAUTH, Nnewi, Anambra State). Forty-five patients with lymphoid malignancy and 45 apparently healthy subjects participated in the study. The modified Khorana risk assessment score was used to assess cancer-associated thrombotic risk. Blood sample was collected for soluble P-selectin estimation. Data were analyzed with SPSS version 23., Results: The age of subjects with lymphoid neoplasm and controls were 49.1±15.8 years, and 49.6±11.1 years respectively (p = 0.548). Subjects with lymphoid neoplasm consist of 26 (57.8%) males and 19 (42.2%) females while the controls consist of 25 (55.6%) males and 20 (44.4%) females. Non-Hodgkin's lymphoma was the most frequent of lymphoid neoplasm (18, 40.0%), followed by multiple myeloma (10, 22%), CLL (9, 20%), ALL (6, 13.0%) and Hodgkin's lymphoma (2, 4.0%). Thirty-five (77.8%) subjects with lymphoid neoplasm had intermediate risk scores and 10 (22.2%) had high-risk scores. Nineteen (42.2%) of the controls had intermediate risk and 26 (57.8%) low risk. The differences in proportion were statistically significant (p < 0.001). The median (IQR) levels of soluble P-selectin were significantly higher in patients with lymphoid neoplasm (12.2 vs. 7.0ng/mL, p <0.001). Three (6.6%) patients with lymphoid malignancies had deep vein thrombosis confirmed by a Doppler ultrasound scan., Conclusion: Lymphoid malignancy is associated with relatively higher thrombotic risk scores, sP-selectin levels, and venous thromboembolic events., Contexte: La thromboembolie veineuse (TEV) est une cause de morbidité et de mortalité accrues chez les patients atteints de cancer. La TEV est la deuxième cause de décès chez les patients atteints de cancer. Des modèles d’évaluation des risques ont été mis au point pour identifier les patients présentant un risque de TEV en vue d’une thromboprophylaxie. Les scores de risque des patients dans notre environnement n’ont pas été étudiés de manière adéquate., Objectif: L’étude évalue l’association des scores d’évaluation du risque thrombotique (en utilisant l’outil modifié d’évaluation du risque de Khorana) et des niveaux de P-sélectine soluble avec les événements thrombotiques chez les patients atteints d’un cancer lymphoïde., Méthodes: Il s’agit d’une étude transversale comparative menée au Nnamdi Azikiwe University Teaching Hospital (NAUTH, Nnewi, État d’Anambra). Quarante-cinq patients atteints d’un cancer lymphoïde et 45 sujets apparemment sains ont participé à l’étude. Le score modifié d’évaluation du risque de Khorana a été utilisé pour évaluer le risque thrombotique associé au cancer. Un échantillon de sang a été prélevé pour l’estimation de la P-sélectine soluble. Les données ont été analysées avec SPSS version 23., Résultats: L’âge des sujets atteints de néoplasme lymphoïde et des témoins était respectivement de 49,1±15,8 ans et 49,6±11,1 ans (p = 0,548). Les sujets atteints de néoplasme lymphoïde sont 26 (57,8 %) hommes et 19 (42,2 %) femmes, tandis que les témoins sont 25 (55,6 %) hommes et 20 (44,4 %) femmes. Le lymphome non hodgkinien était le néoplasme lymphoïde le plus fréquent (18, 40 %), suivi du myélome multiple (10, 22 %), de la LLC (9, 20 %), de la LAL (6, 13 %) et du lymphome hodgkinien (2, 4 %). Trente-cinq (77,8 %) sujets atteints de néoplasmes lymphoïdes présentaient un score de risque intermédiaire et 10 (22,2 %) un score de risque élevé. Dix-neuf (42,2 %) des témoins présentaient un risque intermédiaire et 26 (57,8 %) un risque faible. Les différences de proportion étaient statistiquement significatives (p < 0,001). Les niveaux médians (IQR) de P-sélectine soluble étaient significativement plus élevés chez les patients atteints de néoplasme lymphoïde (12,2 vs. 7,0 ng/mL, p <0,001). Trois (6,6 %) patients atteints de tumeurs lymphoïdes ont présenté une thrombose veineuse profonde confirmée par une échographie Doppler., Conclusion: Les tumeurs malignes lymphoïdes sont associées à des scores de risque thrombotique, des taux de sP-sélectine et des événements thromboemboliques veineux relativement plus élevés., Mots-Clés: Malignité lymphoïde, Thrombose, P-sélectine soluble, Scores d’évaluation du risqué., Competing Interests: The Authors declare that no competing interest exists, (Copyright © 2023 by West African Journal of Medicine.)

DNA ligase IV deficiency is a rare primary immunodeficiency, LIG4 syndrome, often associated with other systemic features. DNA ligase IV is part of the non-homologous end joining mechanism, required to repair DNA double stranded breaks. Ubiquitously expressed, it is required to prevent mutagenesis and apoptosis, which can result from DNA double strand breakage caused by intracellular events such as DNA replication and meiosis or extracellular events including damage by reactive oxygen species and ionising radiation. Within developing lymphocytes, DNA ligase IV is required to repair programmed DNA double stranded breaks induced during lymphocyte receptor development. Patients with hypomorphic mutations in LIG4 present with a range of phenotypes, from normal to severe combined immunodeficiency. All, however, manifest sensitivity to ionising radiation. Commonly associated features include primordial growth failure with severe microcephaly and a spectrum of learning difficulties, marrow hypoplasia and a predisposition to lymphoid malignancy. Diagnostic investigations include immunophenotyping, and testing for radiosensitivity. Some patients present with microcephaly as a predominant feature, but seemingly normal immunity. Treatment is mainly supportive, although haematopoietic stem cell transplantation has been used in a few cases. [ABSTRACT FROM AUTHOR]

A 22-year-old Tennessee Walking Horse mare was presented to the Auburn University Large Animal Teaching Hospital with a 3-day history of lethargy, anorexia, and mild signs of colic. The mare had a several-month history of weight loss and refractory cough. Physical examination revealed an increased respiratory rate, and crackles and wheezes were heard on thoracic auscultation. Thoracic ultrasonographic examination showed disseminated, minor, bilateral comet tail-like lesions on the parietal pleural surfaces. Abdominal ultrasonographic examination was unremarkable. Trans-rectal palpation revealed a firm small colon impaction with concomitant diarrhea. Laboratory data were characterized by a very pronounced acute inflammatory leukogram with severe neutropenia and significant left shift, evidence of hepatocellular damage/necrosis, cholestasis, and possibly mixed metabolic alkalosis and acidosis. On cytologic evaluation of a peritoneal fluid sample, there were many large granular lymphocytes ( LGL). Large numbers of LGL were also observed on cytologic examination of a subsequent transtracheal wash. The final cytologic interpretation was disseminated lymphoma with LGL morphology. Due to worsening of the clinical signs and poor prognosis, the mare was euthanized. On necropsy and in histopathologic examination, disseminated lymphoma with LGL morphology was noted in a mesenteric lymph node, lungs, liver, spleen, kidneys, and right dorsal colon. Lymphoma with LGL morphology is rarely diagnosed in the horse. This report provides unique cytologic findings of a case of disseminated lymphoma with LGL morphology in a horse, confirmed with histopathologic evaluation. [ABSTRACT FROM AUTHOR]

Bruton tyrosine kinase ( BTK), a mediator of B-cell receptor ( BCR) signalling, has been implicated in the pathogenesis of chronic lymphocytic leukaemia ( CLL) and other B-cell malignancies. Ibrutinib is an orally bioavailable and highly specific BTK inhibitor that was recently approved for treatment of patients with recurrent CLL and mantle cell lymphoma ( MCL). In addition, ibrutinib has shown efficacy in subsets of patients with diffuse large B cell lymphoma ( DLBCL) and Waldenstrom macroglobulinaemia ( WM). However, despite ibrutinib's activity in multiple B-cell malignancies, cases of primary and secondary resistance have emerged. The overall reported frequency of resistance is low, but follow-up in many trials was short, and we predict that the incidence of observed resistance will increase as clinical use outside clinical trials expands over time. Mutations within BTK have been described and clearly interfere with drug binding; however, there are also emerging alternative mechanisms that bypass BTK entirely and offer new opportunities for other targeted agents. Improved understanding of mechanisms of primary and secondary resistance is essential to developing appropriate therapeutic strategies to both prevent and address resistance. This review provides a comprehensive analysis of ibrutinib resistance in CLL, MCL, DLBCL and WM and considers potential strategies for further study. [ABSTRACT FROM AUTHOR]