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Immunocompromised individuals are at risk for developing lymphocryptovirus-associated lymphoproliferative diseases, such as Epstein Barr virus (EBV)-associated B cell lymphomas and post-transplant lymphoproliferative disorder (PTLD). We previously reported development of cynomolgus lymphocryptovirus (CyLCV)-associated PTLD in Mauritian cynomolgus macaques (MCMs) undergoing hematopoietic stem cell transplantation (HSCT), which mirrored EBV-PTLD in transplant patients. Here, we sought to develop a MCM model of lymphocryptovirus-associated lymphoproliferative disease in immunosuppressed MCMs without HSCT. Five simian immunodeficiency virus (SIV)-infected, CD8α+ cell-depleted MCMs received an infusion of autologous B-lymphoblastoid cells transformed with CyLCV, followed by varying degrees of immunosuppression. Four of five infused macaques developed masses coincident with increasing CyLCV plasma viremia, and necropsies confirmed the presence of multicentric lymphomas, which most commonly manifested in lymph nodes, gastrointestinal tract, adrenal glands, and pancreas. Affected tissues harbored neoplastic lymphocytes double-positive for CD20 and CyLCV EBNA2 antigen, large frequencies of proliferating B cells, and high levels of cell-associated CyLCV DNA. In addition, longitudinal 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) of one MCM successfully detected lymphoproliferative disease in the adrenal glands prior to clinical signs of disease. These data demonstrate successful induction of lymphocryptovirus-associated PTLD-like disease in 4 of 5 MCMs, and thus support the use of MCMs as a preclinical NHP model of EBV-associated lymphoproliferative disease that could be employed to test novel diagnostic and therapeutic modalities. Author summary: Post-transplant lymphoproliferative disorder (PTLD) is a significant transplant-related complication that typically results from uncontrolled proliferation of lymphocryptovirus-infected B cells in the absence of sufficient immune surveillance. We sought to develop a nonhuman primate model of PTLD-like disease by infusing lymphocryptovirus-infected B cells into immunosuppressed Mauritian cynomolgus macaques. This strategy successfully induced lymphocryptovirus-associated lymphoproliferative disease in 4 of 5 studied macaques, who developed LCV+ B cell lymphomas. While further studies are needed to determine the optimal immunosuppressive regimen to universally trigger disease, our findings lay the foundation for a physiologically relevant macaque model of lymphocryptovirus-associated PTLD that can be employed to test new therapies. [ABSTRACT FROM AUTHOR]

Background: Methotrexate-associated lymphoproliferative disease (MTX–LPD) is a rare and life-threatening complication of MTX administration. MTX–LPD features more extranodal lesions than malignant lymphoma; however, the liver is an extremely rare organ that develops LPD. Herein, we present a case of hepatic MTX–LPD treated with surgical resection. We also reviewed the literature on hepatic MTX–LPD. Case presentation: A 66-year-old man with a history of rheumatoid arthritis (RA) was admitted to our department for the treatment of hepatic solitary liver tumor. The patient had been receiving MTX (14 mg/week) for RA for 6 years. MTX was withdrawn and salazosulfapyridine was prescribed 3 weeks prior to admission because of mediastinal MTX–LPD. Abdominal contrast-enhanced computed tomography showed a slightly ring-like enhanced hypovascularized mass (80 mm) in the lateral section of the liver. Carbohydrate antigen 19-9 (78.1 U/mL) level was elevated. No evidence was observed on esophagogastroduodenoscopy or colonoscopy. The tumor was suspected to be an intrahepatic cholangiocarcinoma. The patient underwent hepatic lateral sectionectomy and lymphadenectomy. Pathological examination revealed that the hepatic mass was coagulative necrosis of the CD20-positive B-cell lymphocytes. These histological findings were similar to those of rapid necrotic lymphoma. MTX–LPD is known to spontaneously regress after withdrawing MTX, and the patient was diagnosed with hepatic MTX–LPD. Conclusions: MTX–LPD can occur in the liver. Clinician should suspect hepatic MTX–LPD when a liver mass is detected in patient who had been treating with MTX for RA. [ABSTRACT FROM AUTHOR]

Background: Kidney transplantation (KT) is the best treatment for patients with end-stage renal disease. However, postoperative complications remain the main issues faced during KT recovery period. Posttransplant lymphoproliferative disorders (PTLD) are one of the severe and life-threatening complications that occur after KT while the recipient is undergoing immunosuppressive therapy. PTLD risk factors include Epstein-Barr virus (EBV) infection, the cumulative degree of immunosuppression, as well as genetic aspects. PTLD is more common in the transplanted organ itself and its surroundings, and the central nervous system, while PTLD involving the pharyngeal soft tissue is relatively rare, with only a few reported case reports. Therefore, systematic experience is scarce regarding whether the treatment or the care. Case presentation: Herein, we report a 41-year-old male, underwent a reproductive KT due to chronic renal insufficiency. Recurrent fever, pharyngeal pain, and bilateral cervical lymph node enlargement were recurred during five years' follow-up after KT surgery. In this inpatient experience, the patient vomited a large amount of blood from the oropharynx, then the tonsil artery was ligated by emergency operation. EBV-associated T/NK cell monomorphic PTLD was eventually diagnosed by blood EBV DNA test, pharyngeal biopsy, and corresponding pathological examination. After six cycles of R-CHOP chemotherapy, the clinical symptoms and laboratory tests changed into normal. Subsequent three years' follow-up shows no tumor recurrence and good transplant kidney function. Conclusion: This rare case report describes a manifestation of PTLD with pharyngeal involvement. Early diagnosis using histopathological examination is crucial to prevent damage to the throat and airway, and even life-threatening conditions. Discontinuing immunosuppression and starting systemic treatment can help in disease regression. Since the low incidence of this disease, limited clinical experience, and limited data, our experience with a smooth recovery through efficacy treatment and nursing can provide a reference for the development of new clinical drugs and diagnostic and treatment plans of patients with PTLD in the future. [ABSTRACT FROM AUTHOR]

ABSTRACT Castleman Disease (CD) is a rare lymphoproliferative disorder that can be separated into two primary forms: Unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD). UCD is localized, while MCD is systemic. Though UCD generally has a favorable prognosis following surgical resection, more aggressive forms of this disease have been identified, including cases associated with dendritic and spindle cell proliferation. Genetic analysis has deepened our understanding of UCD. Despite advancements in better understanding the pathophysiology of UCD, challenges persist in the diagnosis, management, and treatment due to its rarity and heterogeneity. Here, we review current knowledge on UCD, highlighting the epidemiology, clinical presentation, diagnostic criteria, and treatment options while emphasizing the need for further research and innovation in therapeutic strategies. [ABSTRACT FROM AUTHOR]

Alemtuzumab is a potent lymphocyte-depleting immunotherapy used in solid organ transplan-tation (SOT), that is increasingly being applied in diverse lymphoproliferative disorders (LPDs). However, a significant toxicity limiting expanded usage is cytomegalovirus (CMV) infection, for which standardized preventive strategies exist in SOT but not in LPDs due to a poor understanding of infection risk in this population, with early LPD studies largely limited to stem cell transplantation. Using one of the most diverse arrays of LPDs studied to date, our retrospective cohort study of non-transplant patients receiving alemtuzumab over a ten-year period at a large regional cancer center examines the incidence and clinical profile of infected patients. Among 24 patients, we identified a composite CMV infection rate of 42% with a symptomatic rate of 21%. We also noted significant variations in preventive strategies, which alongside a high infection rate presents an opportunity to improve outcomes through further work in standardization. [ABSTRACT FROM AUTHOR]

Simple Summary: Kaposi sarcoma-associated herpesvirus (KSHV) is associated with lymphoproliferative disorders, including primary effusion lymphoma and multicentric Castleman disease. KSHV expresses viral proteins that aid in the evasion of antiviral immune responses and manipulate host factors and signaling to promote cell survival. By altering the cell environment, KSHV contributes to lymphomagenesis. Approximately 15–20% of cancers are caused by viruses. Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is an oncogenic virus that is the etiologic agent of not only Kaposi sarcoma but also the lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KSHV can infect a broad tropism of cells, including B lymphocytes, wherein KSHV encodes specific viral proteins that can transform the cell. KSHV infection precedes the progression of PEL and MCD. KSHV establishes lifelong infection and has two phases of its lifecycle: latent and lytic. During the latent phase, viral genomes are maintained episomally with limited gene expression. Upon sporadic reactivation, the virus enters its replicative lytic phase to produce infectious virions. KSHV relies on its viral products to modulate host factors to evade immune detection or to co-opt their function for KSHV persistence. These manipulations dysregulate normal cell pathways to ensure cell survival and inhibit antiviral immune responses, which in turn, contribute to KSHV-associated malignancies. Here, we highlight the known molecular mechanisms of KSHV that promote lymphomagenesis and how these findings identify potential therapeutic targets for KSHV-associated lymphomas. [ABSTRACT FROM AUTHOR]

Introduction: Endobronchial ultrasound-guided transbronchial needle aspiration remains the gold standard for the diagnosis of mediastinal pathologies. Its greatest limitation has been the low diagnostic yield in lymphoproliferative disorders as well as insufficient samples for molecular testing. Transesophageal examinations using an EBUS scope have helped increase the diagnostic yield by allowing for additional biopsies of paraesophageal and intra-abdominal lesions. Similarly, the novel approach of transbronchial mediastinal cryobiopsy has further increased the yield by providing larger and better-preserved biopsies. Both complimentary techniques have shown great individual feasibility and safety. However, the feasibility of transesophageal cryobiopsies in the evaluation of mediastinal pathologies remains a subject of debate. Aim: The aim of the study was to investigate the safety and feasibility of transesophageal EBUS-guided mediastinal cryobiopsies performed at our center. Methods: We conducted a retrospective review of 30 patients who underwent mediastinal cryobiopsy through the esophagus at our institution between October 2023 and March 2024. Data on patient demographics, diagnostic yield, and complications were collected and analyzed. Results: The mean patient age was 43 years, with a gender distribution of 60% male and 40% female. The primary indications included suspicion of lymphoproliferative disorders, suspected sarcoidosis, and malignancies with paraesophageal lesions. The overall diagnostic yield was 93%. No major complications were noted in any of the patients. Conclusion: Transesophageal mediastinal cryobiopsy appears to be a promising complimentary technique for mediastinal evaluation with a relatively high diagnostic yield and favorable safety profile. However, further studies with larger cohorts are warranted to validate the findings at our institution. [ABSTRACT FROM AUTHOR]

Background: Immunosuppressive medications play a crucial role in determining both organ and patient survival following liver transplantation (LT). Typically, immunosuppressive protocols for pediatric LT patients rely on calcineurin inhibitors (CNIs). While inhibitors of mammalian target of rapamycin (mTOR) have demonstrated beneficial outcomes in adult recipients of liver allografts, such as improved renal function post-LT, their application in pediatric liver transplant recipients is a subject of debate due to uncertain efficacy and potential adverse effects. Objectives: This review evaluates the potential roles of mTOR inhibitors in the context of pediatric LT patients. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for conduct and reporting. Databases until 31 August 2023 were searched using specific terms and keywords. All clinical studies focusing on mTOR inhibitors in pediatric LT were included. Results: Out of 888 identified articles, 30 studies, involving 386 children who had undergone liver transplantation and received mTOR-inhibitor-based immunosuppressive regimens, met the inclusion criteria. The beneficial impacts of switching from a CNI to an mTOR inhibitor or adding an mTOR inhibitor to CNI-reduced immunosuppression in LT pediatric patients with impaired kidney function are controversial, and high-powered clinical studies are need. It appears that enhancing immunosuppression by adding an mTOR inhibitor to CNI is helpful for pediatric LT recipients who are experiencing refractory acute rejection or chronic rejection. mTOR-inhibitor-containing regimens failed to reduce the occurrence of post-transplant lymphoproliferative disorders (PTLD) among children with LT that may be due to concomitant high CNI concentration among studied patients. The effectiveness of mTOR inhibitors in treating PTLD remains uncertain; however, in patients with PTLD who are at high risk of rejection, mTOR inhibitors may be administered. Conversion to or the addition of mTOR inhibitors to maintenance immunosuppression seems to be suitable for pediatric patients who received a transplant due to hepatic malignancies such as hepatoblastoma or hepatocellular carcinoma or for those with post-transplant primary or recurrent malignancies. Switching to an mTOR inhibitor may improve some CNI-related adverse effects such as gingival hyperplasia, neurotoxicity, nephropathy, hypertrophic cardiomyopathy, or thrombotic microangiopathy. Conclusion: Although the exact role of mTOR inhibitors among pediatric patients who have received a liver transplant needs further study, two algorithms are presented in this review to guide conversion from CNIs to mTOR inhibitors or the addition of mTOR inhibitor to a CNI-minimization immunosuppressive regimen for pediatric patients who may benefit from this class of drugs. This review mainly consisted of retrospective studies with inadequate sample sizes and lacked a control group, which represents the main limitation of this study. [ABSTRACT FROM AUTHOR]

Background Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) is a rare and indolent lymphoma entity. Although TLPD was first identified many years ago, the molecular pathogenesis is still not fully understood. Objectives In order to better understand the molecular pathogenesis of cutaneous acral CD8+ TLPD and to identify further discriminatory markers to differentiate this lymphoma subtype from other CD8+ cutaneous lymphomas, we analysed five cases of cutaneous acral CD8+ TLPD for putative molecular alterations. Methods Somatic alterations were assessed using whole-exome and targeted sequencing of paraffin-embedded tissue. Results were evaluated using immunohistochemical staining of respective relevant proteins. CD8+ cutaneous T-cell lymphomas (n = 12) served as control for KIR3DL1 staining. Results Copy number variation analysis revealed a homozygous deletion of the KIR3DL1 gene in two of the analysed cases. This resulted in loss of KIR3DL1 protein expression, which was observed in all cases of cutaneous acral CD8+ TLPD. In contrast, KIR3DL1 expression was more variable in other CD8+ cutaneous T-cell lymphomas with 50% of analysed cases (n = 12) found to be positive. In addition, one further case of acral CD8+ TLPD harboured a loss-of-function mutation in the PIK3R1 gene, presumably activating the phosphoinositide 3-kinase-AKT pathway. Conclusions Alterations of the KIR3DL1 gene may be of pathogenetic relevance for acral CD8+ TLPD. Loss of KIR3DL1 protein expression may support the diagnosis of this indolent lymphoma entity; however, this is not a subtype-specific discriminative feature. [ABSTRACT FROM AUTHOR]

Background: Primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous CD4+ small/medium T‐cell lymphoproliferative disease (CD4+ TLPD) are two distinct entities with excellent prognosis; however, they show profound clinical and histopathological similarities, leading to differential diagnostic uncertainty. Aims: Our aim was to review and reanalyze cases of primary cutaneous lymphoproliferations diagnosed at Semmelweis University, featuring characteristics of PCMZL and CD4+ TLPD. Materials and Methods: Cutaneous lymphoma biopsy specimens between 2018 and 2022 were collected and re‐evaluated. Medical history, clinical picture, imaging, and laboratory findings were collected. Immunohistochemical staining for CD20, CD3, BCL6, CD10, PD1, CD3, CD4, CD8, and PCR tests for IGH, IGK, TCRB, and TCRG were repeated in selected cases. Results: Among 55 cases diagnosed as PCMZL (16) or CD4+ TLPD (39), 3 patients had been diagnosed with both LPDs at different time points of their disease course. Four additional patients were identified with single lesions featuring overlapping histopathological characteristics of both LPDs and both monoclonal IGH and TCR rearrangements. All patients are currently in complete remission with local treatment. Conclusion: We propose that besides the overlapping histopathological, molecular, and clinical features, the subsequent appearance of PCMZL and CD4+ TLPD in a short timeframe in the same patients may suggest a common pathogenic background. [ABSTRACT FROM AUTHOR]

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Introduction: Inborn errors of immunity (IEI) are a group of genetically heterogeneous disorders with a wide-ranging clinical phenotype, varying from increased predisposition to infections to dysregulation of the immune system, including autoimmune phenomena, autoinflammatory disorders, lymphoproliferation, and malignancy. Lymphoproliferative disorder (LPD) in IEI refers to the nodal or extra-nodal and persistent or recurrent clonal or non-clonal proliferation of lymphoid cells in the clinical context of an inherited immunodeficiency or immune dysregulation. The Epstein-Barr virus (EBV) plays a significant role in the etiopathogenesis of LPD in IEIs. In patients with specific IEIs, lack of immune surveillance can lead to an uninhibited proliferation of EBV-infected cells that may result in chronic active EBV infection, hemophagocytic lymphohistiocytosis, and LPD, particularly lymphomas. Areas covered: We intend to discuss the pathogenesis, diagnosis, and treatment modalities directed toward EBV-associated LPD in patients with distinct IEIs. Expert opinion: EBV-driven lymphoproliferation in IEIs presents a diagnostic and therapeutic problem that necessitates a comprehensive understanding of host–pathogen interactions, immune dysregulation, and personalized treatment approaches. A multidisciplinary approach involving immunologists, hematologists, infectious disease specialists, and geneticists is paramount to addressing the diagnostic and therapeutic challenges posed by this intriguing yet formidable clinical entity. [ABSTRACT FROM AUTHOR]

Background: Common Variable Immunodeficiency (CVID) represents a heterogenic group of primary immunodeficiencies (PID) characterized by impaired antibody production and susceptibility to infections. Non-infectious complications, such as autoimmune diseases, lymphoproliferative disorders, and malignancies, now significantly impact prognosis. Moreover, both hematologic and solid organ malignancies are more frequently observed in CVID patients compared to other PIDs. The risk factors for carcinogenesis in CVID remain largely unknown. Objective: This multicenter study aims to characterize the clinical profile of cancer in CVID patients in Spain and to identify independent risk factors associated with malignancy development, focusing on the role of immune dysregulation. Methods: A nationwide, cross-sectional study was conducted from November 2019 to May 2022, involving 17 hospitals treating PID patients in Spain. Data were collected systematically on demographics, infectious and non-infectious comorbidities, immunological parameters, and treatment. Statistical analysis, including multivariate logistic regression, was performed to identify risk factors associated to malignancy. Results: Of 250 CVID patients, 38 (15.26%) were diagnosed with cancer, predominantly non-Hodgkin lymphoma, gastric cancer, and lung adenocarcinoma. Cancer patients were significantly older (mean age 60.70 vs. 49.36 years, p<0.001) and had higher rates of immune dysregulation (81.58% vs. 59.7%, p=0.01). Immune dysregulation was an independent risk factor for cancer (OR 2.19, p=0.04), alongside previous immunosuppressant therapy (OR 2, p=0.031), higher IgM levels (OR 1.008 per SD, p=0.012), older age (OR 1.04, p<0.001), and lower CD4 cell counts at diagnosis (OR 0.997, p<0.001). Conclusions: This study highlights the increased cancer risk in CVID patients, with immune dysregulation, prior immunosuppressant use, elevated IgM levels, and lower CD4 cell counts as conjointly associated. These findings underscore the need for vigilant cancer screening and tailored management strategies in CVID patients to improve outcomes. Future research should focus on elucidating the molecular mechanisms linking immune dysregulation and malignancy in CVID. [ABSTRACT FROM AUTHOR]

UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced. [ABSTRACT FROM AUTHOR]

Introduction: Lichen planus (LP) is a chronic inflammatory dermatosis that causes plaques and itchy papules on the skin, as well as erosion and ulcers in the mucous membranes. LP is characterized by a dense dermal T-cell infiltration. Perieccrine inflammation can be seen in a variety of dermatoses, but genuine lymphocyte permeation of the secretory coil or lymphocytic syringotropism is a rare sign that is typically seen in mycosis fungoides. Case Presentation: In this study, we present 2 uncommon instances of lymphocytic syringotropism in LP. Histopathological examination revealed dense T-cell infiltration and lymphocytic involvement of eccrine glands, confirming syringotropism. Conclusion: Lymphocytic syringotropism is an uncommon finding in LP. Its presence broadens the histopathological spectrum of LP and highlights the need to differentiate it from lymphoproliferative disorders like mycosis fungoides. [ABSTRACT FROM AUTHOR]

Distinguishing between primary (PID) and secondary (SID) immunodeficiencies, particularly in relation to hematological B-cell lymphoproliferative disorders (B-CLPD), poses a major clinical challenge. We aimed to analyze and define the clinical and laboratory variables in SID patients associated with B-CLPD, identifying overlaps with late-onset PIDs, which could potentially improve diagnostic precision and prognostic assessment. We studied 37 clinical/laboratory variables in 151 SID patients with B-CLPD. Patients were classified as "Suspected PID Group" when having recurrent-severe infections prior to the B-CLPD and/or hypogammaglobulinemia according to key ESID criteria for PID. Bivariate association analyses showed significant statistical differences between "Suspected PID"- and "SID"-groups in 10 out of 37 variables analyzed, with "Suspected PID" showing higher frequencies of childhood recurrent-severe infections, family history of B-CLPD, significantly lower serum Free Light Chain (sFLC), immunoglobulin concentrations, lower total leukocyte, and switch-memory B-cell counts at baseline. Rpart machine learning algorithm was performed to potentially create a model to differentiate both groups. The model developed a decision tree with two major variables in order of relevance: sum κ + λ and history of severe-recurrent infections in childhood, with high sensitivity 89.5%, specificity 100%, and accuracy 91.8% for PID prediction. Identifying significant clinical and immunological variables can aid in the difficult task of recognizing late-onset PIDs among SID patients, emphasizing the value of a comprehensive immunological evaluation. The differences between "Suspected PID" and SID groups, highlight the need of early, tailored diagnostic and treatment strategies for personalized patient management and follow up. [ABSTRACT FROM AUTHOR]

Immune deficiency and dysregulation‐associated lymphoproliferative disorders and lymphomas (IDD‐LPDs) encompass a heterogeneous clinical and pathological spectrum of disorders that range from indolent lymphoproliferations to aggressive lymphomas. They arise in a variety of clinical settings and are associated with oncogenic viruses such as the Epstein–Barr virus (EBV) and Kaposi sarcoma‐associated herpesvirus/human herpes virus (KSHV/HHV8) in some, but not all, cases. The recognition of IDD‐LPDs as distinct from LPDs in immune competent patients is essential to tailor clinical management options for affected patients. The 5th edition of the World Health Organisation classification has introduced an integrated classification of IDD‐LPDs with the goal of standardising diagnoses among different settings to enhance clinical decision support. In parallel, new knowledge in the field, particularly surrounding the role of oncogenic viruses and the tumour microenvironment, has led to clearer understanding of the complex pathogenesis of IDD‐LPDs and how these features can be precisely harnessed for therapeutic purposes. In this perspective, we highlight the need for multidisciplinary decision‐making to augment patient care as well as key areas where evolving concepts offer challenges and opportunities for clinical management, research and future iterations of the classification. [ABSTRACT FROM AUTHOR]

Simple Summary: Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of various B-cell lymphoid malignancies. However, acquisition of resistance to BTKi has emerged as an important clinical challenge. Herein, we provide a detailed review, describing the clinical trials that led to the FDA approval of the BTK inhibitors for management of Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma, Marginal Zone Lymphoma (MZL), Follicular Lymphoma (FL) and Waldenstrom Macroglobulinemia (WM). We describe the mechanism of intrinsic and extrinsic resistance to the BTKi with main emphasis on the functional description of BTK mutations in CLL. Finally, we review the latest updates of the PROTACs BTK degraders, an evolving treatment modality for the management of the BTKi refractory B-cell malignancies. B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTKi. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies. [ABSTRACT FROM AUTHOR]

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome that can occur either in genetically predisposed individuals (primary HLH) or in particular conditions in immunocompromised patients (secondary HLH). Secondary HLH is very rare among solid organ transplant recipients, especially in lung transplant recipients, for whom its prognosis is dismal. Case Report: We report an exceptional case of HLH occurring unusually late following lung transplantation. At 11 years after transplantation, the patient, aged 67 years, presented with pancytopenia, fever, hyperferritinemia, and hypertriglyceridemia, along with splenomegaly. Exhaustive serological and PCR tests ruled out active infection. Bone marrow aspirates showed signs of hemophagocytosis, and bone marrow biopsy was suggestive of posttransplant lymphoproliferative disorder (PTLD). Timely treatment with etoposide and corticosteroids led to a transient improvement in the patient's clinical condition, and rituximab was initiated as a treatment for PTLD. Unfortunately, pancytopenia persisted for weeks, and the patient died from refractory septic shock, despite appropriate intravenous antibiotics. Autopsy revealed lymphoid infiltration of the mediastinal lymph nodes, liver and bone marrow, with some lymphocytes expressing CD3. A final diagnosis of Ann-Arbor stage IV non-EBVmediated monomorphic T-cell PTLD was established. Conclusions: This case report highlights a very unusual and fatal presentation of HLH in a lung transplant recipient, secondary to a T-cell PTLD. Indeed, HLH is typically seen as infection-related and reported to occur in the initial months following transplantation. To date, no guidelines or consensus exist regarding the management of immunosuppression regimen in solid organ transplantation. [ABSTRACT FROM AUTHOR]

Summary Idiopathic multicentric Castleman disease (iMCD) is a rare and heterogeneous lymphoproliferative disorder that lacks standardised treatment options for patients with refractory or relapsed (r/r) disease. Blocking Bruton's tyrosine kinase (BTK) has emerged as a promising therapeutic approach for iMCD without depleting B cells. This single‐centre, retrospective study enrolled 10 patients with r/r iMCD who were treated with orelabrutinib, a novel, next‐generation BTK inhibitor. The median age at orelabrutinib initiation was 48 (range: 31–58) years. The overall response rate was 70% (7/10 patients, 95% CI: 34.8–93.3), with 20% (n = 2) achieving complete response and 50% (n = 5) achieving partial response. The median time to response was 9.8 (range: 5.9–20.5) months. Patients in the non‐responder group also demonstrated a continuous improvement in haemoglobin (91–105 g/L) and albumin (32–38 g/L) levels at month 12 of treatment despite not fulfilling response criteria. No grade 3 or higher adverse events occurred during the median time to the next treatment of 29.0 (range: 15.0–36.2) months. No patient mortality was recorded during the median follow‐up duration of 32.8 (range: 15.0–36.9) months. In conclusion, orelabrutinib is a safe and effective regimen for r/r iMCD. [ABSTRACT FROM AUTHOR]

Introduction. Non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating from B, T or natural killer (NK) lymphocytes. Clinical scoring systems have been developed to better stratify the patients' risk and help select therapeutic strategies. Materials and methods. Clinical and prognostic stratification scores were applied to 99 patients with extranodal aggressive NHL. The diagnosis was confirmed morphologically by tumor biopsy and immunohistochemistry. Results. IPI is an independent prognostic factor for progression-free survival. In addition, it facilitates the investigation of the independent impact of other prognostic biomarkers through adjusted analyses. Calculating International Prognostic Index (IPI), we obtained the following results: IPI 0 - 25% and IPI1 - 23.2% with a low risk and 5-year survival of 73%, IPI2 - 18.1% with low intermediate risk and 5-year survival of 51%, IPI3 - 17.1% with high intermediate risk and 5-year survival of 43%, IPI4 - 12.1% and IPI 5 - 4.5% with high risk and 5-year survival of 26%. Conclusions. Clinical scoring systems allow better risk stratification of patients and selection of appropriate therapeutic strategies. The IPI is a clinical tool developed to help predict the prognosis of patients with aggressive NHL. RIPI is a clinically useful prognostic index that allows guiding treatment planning in patients with DLBCL. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma and is characterized by heterogeneity in biology and clinical behavior. Mutations in the myeloid differentiation primary response 88 (MYD88) are found in different lymphoproliferative disorders and are associated with variable clinical and prognostic impact. Aim: To investigate the frequency of MYD88 L265P mutation and its clinical impact in a cohort of Egyptian DLBCL patients. Methods: FFPE lymph node samples from 87 DLBCL patients (46 males / 41 females; median age, 58 years) were included and analyzed for MYD88 L265P by an allele-specific PCR. Results: MYD88 L265P mutations were found in 52 patients (59.8%) out of 87 DLBCL cases. Patients with L265 mutation were significantly younger than non-mutated patients (p = 0.022). None of the patients with the L265P mutation showed a significant association with the clinical parameters of DLBCL. Interestingly, MYD88 L265 mutated patients were found to be significantly correlated with HCV infection (p = 0.037). The median follow-up time across the entire cohort was 26 months. Univariate analysis showed that overall survival (OS) was affected by gender, LDH level, and CNS-IPI scoring (p = 0.048, 0.008, and 0.046, respectively), while disease-free survival (DFS) was affected by B symptoms and LDH level (p = < 0.000 and 0.02, respectively). However, the MYD88 mutation status and other prognostic factors showed no association with OS or DFS. Conclusions: Our findings indicate a high frequency of MYD88 L265P mutations in our study population and not associated with prognostic markers or the outcome of the disease. [ABSTRACT FROM AUTHOR]

Posttransplantation primary cutaneous T‐cell lymphomas (PT‐CTCL) are a rare complication of sustained immunosuppression in the posttransplant setting. When present, PT‐CTCLs are typically EBV− and exhibit features of mycosis fungoides/Sézary syndrome or CD30+ lymphoproliferative disorders. We present a case of a 75‐year‐old individual who developed skin lesions 30 years after liver transplantation. Pathologic evaluation of the skin biopsy revealed involvement by a clonal, EBV+ T‐cell population of gamma/delta lineage with no evidence of systemic disease. Comprehensive genomic profiling was performed, confirming focal one‐copy loss of 6q23.3, altogether consistent with the extremely rare and unusual diagnosis of primary cutaneous EBV+ extranodal NK/T‐cell lymphoma of gamma/delta T‐cell lineage in the posttransplantation setting. [ABSTRACT FROM AUTHOR]

A 42-year-old male was referred to the internal medicine department because of renal failure and persistent malaise after a recent SARS-CoV-2 infection. Blood results showed anemia and severe renal insufficiency (hemoglobin of 10.3 g/dL and a creatinine of 2.19 mg/dL). Additional tests revealed a type I cryoglobulinemia with a cryoprecipitate composed of dual IgM (kappa and lambda). Further investigations on the cryoprecipitate revealed that the immunoglobulins were directed against SARS-CoV-2 antigens. In the meanwhile, our patient noticed improvement of his symptoms accompanied by resolution of laboratory abnormalities. Three months later, the cryoglobulin could no longer be detected. Type 1 cryoglobulinemia is usually associated with lymphoproliferative disorders and is characterized by various symptoms caused by cryoprecipitates occluding small blood vessels. This is, to our knowledge, the first case of type I cryoglobulinemia with proven precipitation of SARS-CoV-19 antibodies. COVID-19 induced cryoglobulinemia appears to have a mild disease course and to be self-limiting upon viral clearance. [ABSTRACT FROM AUTHOR]

Evans syndrome (ES) is rare and mostly treated on a "case‐by‐case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP‐NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work‐up and management. Thirty clinicians who had followed a median of 5 patients (1–45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p <.001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti‐platelets and anti‐neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization. [ABSTRACT FROM AUTHOR]

Purpose: To describe a case of bilateral panuveitis in an 11-year-old girl with autoimmune lymphoproliferative syndrome (ALPS) due to CTLA4 haploinsufficiency. Case Description: A 5-year-old girl developed cervical adenopathy, and autoimmune hemolytic anemia and thrombocytopenia consistent with Evan's Syndrome. She was subsequently diagnosed with autosomal dominant CTLA4 haploinsuffciency and treated with immunosuppressants. Ocular symptoms developed 6 years later when she complained of blurry vision and photophobia. There were 3+ anterior chamber cells and 1+ flare, stellate keratic precipitates, and 3+ vitreous cells in both eyes. On fluorescein angiography, there was staining along the arcades and peripheral perivascular leakage in both eyes. On indocyanine green angiography, there were hypofluorescent spots throughout the posterior pole. The inflammation was partially responsive to topical and oral corticosteroids. Conclusion: Panuveitis may be associated with ALPS due to CTLA4 haploinsufficiency. Retinal and choroidal involvement should be assessed when anterior chamber inflammation is the presenting sign. [ABSTRACT FROM AUTHOR]

Introduction: Haemoperitoneum due to spontaneous splenic rupture is a rare condition. Methods: We present a case of AL-type amyloidosis and chronic kidney disease (CKD) who is presented with diffuse abdominal pain. A contrast-enhanced CT scan of the abdomen revealed moderate to large amounts of free fluid in the peritoneum, indicating splenic rupture causing haemoperitoneum. Result: The patient underwent emergency exploratory laparotomy and splenectomy. After the operation, the patient was closely monitored in the ICU and was transferred to the ward on postoperative day 3. He was discharged home on day 6. Conclusion: This case report highlights a rare occurrence of haemoperitoneum secondary to spontaneous splenic rupture in a patient with AL amyloidosis. [ABSTRACT FROM AUTHOR]

Kimura's disease, also known as eosinophilic hyperplastic lymphogranuloma, is a benign chronic lymphoproliferative inflammatory disorder with unknown etiology. Due to its rare and high recurrence rate, there is currently no consensus on the optimal treatment approach. Currently, traditional treatment for this condition mainly including glucocorticoids, surgery and radiotherapy. In recent years, the rapid development of biologies and small molecule drugs has provided new options for this disease. This article reviews the treatment of Kimura' s disease and its recent advancements. [ABSTRACT FROM AUTHOR]

Marcus Ground,1 Thijmen Veenendaal,1 Daniel Rexie Chiluzi,1 Geoffrey Nkhonjera,2 Arie C Glas,1 Lisanne Glas-van Dijk1 1Mulanje Mission Hospital, Mulanje, Malawi; 2Oncology Department, Queen Elizabeth Central Hospital, Blantyre, MalawiCorrespondence: Marcus Ground, Email marcus.ground@gmail.comAbstract: We present the case of an HIV-positive man diagnosed with multicentric Castleman disease (MCD) associated with human herpesvirus 8 (HHV8) infection, complicated by renal failure. This subtype of an otherwise rare disease is a complication of HIV and HHV8 infection. The diagnosis and management of HHV8-MCD in the developing world is challenging—in part due to its rarity, but largely due to the limited access to histology and other laboratory services. Our case presented with a confusing constellation of symptoms and was diagnosed with MCD on histology. Here we discuss the epidemiology, pathogenesis, diagnosis, and treatment of HHV8-MCD in the context of HIV infection in a resource-limited setting, in the hope that greater awareness will lead to more prompt recognition.Keywords: Castleman disease, HIV, lymphoproliferative disorders, case report, human herpesvirus 8

Objective To investigate the clinical features and diagnosis and treatment of RAS-associated autoimmune lymphoproliferative disorder (RALD). Methods We reported the clinical data of a case of RALD diagnosed and treated in our hospital in 2019, and reviewed relevant literature on RAS variation retrieved using the keywords “NRAS”, “KRAS”, and “RALD” through PubMed, CNKI, and Wanfang Data between January 2000 and November 2023. Results The patient was hospitalized due to recurrent fevers for 1.5 months with a 1.5 years history of thrombocytopenia. The physical signs included an appearance of mild anemia, an abdominal bulge, a hard liver palpable up to 5 cm below the costal margin, and the spleen edge up to 3 cm below the costal margin. CD4-CD8- cells accounted for 2.3% of lymphocytes. The degranulation of NK cells decreased. Gene sequencing detected a somatic mutation in exon 2 of the NRAS gene c.38G>A(p.G13D). A total of 32 cases of RALD were retrieved, including 13 cases caused by NRAS somatic mutations and 19 cases caused by KRAS somatic mutations. The main clinical features of the 32 patients included splenomegaly, autoimmune anemia, thrombocytopenia, hypergammaglobulinemia, mononuc-leosis, a normal or slightly elevated proportion of double-negative T cells. Conclusion RALD is characterized by hepatosplenomegaly and autoimmunity, and gene testing is helpful for its diagnosis.

Castleman disease (CD), also known as giant lymph node hyperplasia or angiofollicular lymph node hyperplasia, is a rare and indeterminate group of chronic lymphoproliferative disorders. CD is highly heterogeneous, classified into unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD) based on lesion distribution, and further categorized into three pathological types: hyaline vascular type (HV), plasma cell type (PC), and mixed type (Mix). This paper describes a rare case of solitary mediastinal Castleman disease with transparent vessels in the anterior sacrum, presenting as the HV type. Surgical excision of the mass was performed following coccygectomy for treatment. The patient recovered well postoperatively. During a 6-month follow-up period, there were no signs of recurrence, and the patient's quality of life significantly improved. [ABSTRACT FROM AUTHOR]