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Summary: Background: Castleman disease (CD) comprises a group of rare and heterogeneous haematological disorders, including unicentric (UCD) and multicentric (MCD) forms, the latter further subdivided into HHV8‐MCD, POEMS‐MCD and idiopathic‐MCD (iMCD). However, according to the Castleman Disease Collaborative Network guidelines, the diagnosis of CD can only be achieved through collaboration between clinicians and pathologists. Methods: We applied these clinical and pathological criteria and implement with clonality testing to a retrospective cohort of 48 adult and paediatric Italian patients diagnosed with reactive lymphadenitis with CD‐like histological features. Results: We confirmed the diagnosis of CD in 60% (29/48) of the cases, including 12 (41%) UCD and 17 (59%; five HHV8‐MCD, three POEMS‐MCD and nine iMCD) MCD. Of the remaining 19 cases (40%) with multiple lymphadenopathy, 5 (26%) were classified as autoimmune diseases, 1 (5%) as autoimmune lymphoproliferative disorder, 1 (5%) as IgG4‐related disease, 11 (83%) as reactive lymphadenitis and 1 (5%) as nodal marginal zone lymphoma. Conclusions: Our study emphasizes the importance of the multidisciplinary approach to reactive lymphadenitis with CD‐like features in order to achieve a definitive diagnosis and choose the appropriate treatment. [ABSTRACT FROM AUTHOR]

Background: Early in the history of kidney transplantation, short-term graft survival was low. Yet some have had excellent long-term survival. Herein, we describe characteristics of pediatric recipients with > 40 years of graft survival currently alive with a functioning first graft. Methods: We reviewed all pediatric (age < 18 years) kidney transplants performed at the University of Minnesota between January 1, 1970, and December 31, 1979 (n = 148), to identify all recipients currently alive with a functioning first graft. Data are presented as medians with interquartile ranges (IQR) and proportions. Results: We identified 10 recipients with > 40-year graft survival (median follow-up: 45.0 years (IQR: 43.1, 48.1)). The median age at transplant was 13.8 years (IQR: 5.1, 16.3). All recipients were white; half were male. Of the 10, 4 had glomerulonephritis, 2 had congenital anomalies of the kidney and the urinary tract, 2 had congenital nephrotic syndrome, 1 had Alport syndrome, and 1 had cystic kidney disease as kidney failure cause. Nine patients received a living-related donor transplant, and 1 patient received a deceased-donor transplant. The median estimated glomerular filtration rate at 20 years post-transplant was 79.9 (IQR: 72.3, 98.4); at 30 years, 67.7 (IQR: 63.2, 91.8); and at 40 years, 80.3 ml/min/1.73 m2 (IQR: 73.7, 86.0). None developed rejection, 5 developed hypertension, 2 developed dyslipidemia, 1 developed diabetes, and 7 patients developed malignancy (4 skin cancer, 2 breast cancer, and 1 post-transplant lymphoproliferative disease). Conclusion: Pediatric kidney transplant recipients may achieve > 4 decades of graft survival. Cancer is a common complication warranting vigilant screening. [ABSTRACT FROM AUTHOR]

Purpose: To assess the effect of kaempferol on the growth, apoptosis, and motility of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) cells, and to elucidate its mechanism of action. Methods: Human DLBCL cells were used to generate EBV-positive (EBV +) cell line Pfeiffer. CCK-8, colony formation, flow cytometry (FCM), and immunoblot assays were employed to determine the effects of kaempferol on the growth and apoptosis of EBV + DLBCL cells. Cell motility was evaluated by Transwell and immunoblot assays. Immunoblot assay was further conducted to unravel the mechanism of action. Results: Kaempferol inhibited the growth of EBV + DLBCL cells. It also enhanced the apoptosis of EBV + DLBCL cells, but inhibited the motility of the cells. Furthermore, kaempferol inhibited PI3K/AKT axis, thereby suppressing DLBCL. Conclusion: Kaempferol inhibits the growth and motility of EBV + DLBCL cells via PI3K/AKT axis. It is therefore a potential drug for the treatment of DLBCL. [ABSTRACT FROM AUTHOR]

Lymphoproliferative disorders comprise of a group of heterogenous diseases characterised by uncontrolled production of lymphocytes.Castleman disease (CD) is one such disease and comprises of a group of rare disorders that involve enlarged lymph nodes and a broad range of inflammatory symptoms and laboratory abnormalities [1]. We came across young girl who presented to us in the out patient department with this disease After ruling out other pathologies and confirming the diagnosis by doing a tissue biopsy the girl was treated surgically and is disease free till date. [ABSTRACT FROM AUTHOR]

Castleman disease (CD) is a lymphoproliferative disorder classified into two categories as unicentric Castleman disease (UCD) or localized type and multicentric Castleman disease (MCD). A rare case of hyaline vascular variant of tonsil has been presented in which a 14 years old male presented with symptomatic unilateral hypertrophy of right tonsil. A right tonsillectomy was done and surgical pathology report was concluded as hyaline vascular variant of Castleman's disease.Castleman disease (CD) is a rare lymphoproliferative disorder also called as giant lymph node hyperplasia, angiofollicular lymph node hyperplasia (AFH), angiomatous lymphoid hematoma and follicular lymphoreticuloma. The treatment of symptomatic patients with UCD is complete surgical excision (as in present case). In cases with incomplete resection, adjuvant radiotherapy can be given. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre‐emptive strategies. While the group made a strong recommendation for pre‐emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre‐emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein‐Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre‐emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre‐emptive interventions in patients who are EBV seronegative pre‐transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre‐transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre‐emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association (IPTA) Consensus Conference on Practice Guidelines for the Diagnosis, Prevention, and Management of Post‐Transplant Lymphoproliferative Disorders after Solid Organ Transplantation in Children took place on March 12–13, 2019, and the work of conference members continued until the end of December 2021. The goal was to produce evidence‐based consensus guidelines on the definitions, diagnosis, prevention, and management of PTLD and related disorders based on the critical review of the literature and consensus of experts. This report describes the goals, organization, and methodology of the consensus conference and follow‐up activities. The results of each working group (Definitions, Prevention, Management, and Epstein–Barr viral [EBV] load/Biomarker Monitoring) are presented in separate manuscripts within this volume of Pediatric Transplantation. [ABSTRACT FROM AUTHOR]

Lymphadenopathy in an immunosuppressed patient raises the quintessential diagnostic dilemma: infection or malignancy? We present the case of a transplant recipient on anti-rejection prophylaxis admitted with acute fever, malaise and a swollen right axillary node. The patient had pancytopenia and tested positive for Epstein–Barr virus; nodal core biopsy demonstrated atypical plasma cell infiltration, immediately raising suspicion for post-transplant lymphoproliferative disorder. However, excisional biopsy and Bartonella henselae serology clarified a final diagnosis of cat-scratch disease—a potentially fatal zoonosis requiring a disparate treatment regimen. Here, we explore this patient's investigations, hospital course and recovery, with an emphasis on recognizing and differentiating these diagnostic mimics in post-transplant practice. [ABSTRACT FROM AUTHOR]

Autoimmune haemolytic anaemia (AIHA) is an acquired heterogenous clinical entity with variable presentations like acute haemolysis or mild, chronic haemolysis compounded with acute exacerbation in winters or fatal uncompensated haemolysis. A step-wise approach to the diagnosis and characterisation of AIHA should be undertaken, firstly the diagnosis of haemolysis followed by the establishment of immune nature with the aid of direct agglutination tests (DAT). Simultaneously the other causes of immune haemolysis need to be excluded too. In light of advancements in diagnostics, a wide array of investigations can be used like absolute reticulocyte count, bone marrow responsiveness index to establish the evidence of haemolysis, sensitive gel technology, enhanced DAT assays, e.g., modified DAT with low ionic strength saline solution (LISS) at 4°C, DAT assays utilizing reagents such as anti-IgA and anti-IgM and DAT by flowcytometry, to detect RBC bound autoantibodies (Abs) and monospecific DAT to establish immune causes of haemolysis and characterisation of the autoantibodies. The compensatory role of bone marrow and synchronous pathologies like clonal lymphoproliferation, dyserythropoiesis, fibrosis are important factors in the evolution of the disease and aid in the customisation of treatment modalities. The laboratory work up should aim to diagnose underlying diseases like chronic lymphoproliferative disorders, autoimmune disorders and infectious diseases. Also, tests like autoimmune lymphoproliferative syndromes (ALPS) screening panel and Next-generation sequencing (NGS) panel for RBC membrane disorders, RBC enzymopathies, and congenital dyserythropoietic aneamia have found their place. It is incumbent upon the clinicians to use the all-available diagnostic modalities for the accurate diagnosis, prognostication and customisation of the therapy. [ABSTRACT FROM AUTHOR]

Epstein-Barr Virus (EBV) diseases, including EBV-associated post-transplant lymphoproliferative disorder (PTLD) remain important causes of morbidity and mortality in children undergoing solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Despite progress in the prevention of EBV disease including PTLD (EBV/PTLD) in HCT, key questions in the prevention, and management of these infectious complications remain unanswered. The goal of this manuscript is to highlight key points and recommendations derived from the consensus guidelines published by the International Pediatric Transplant Association and the European Conference on Infections in Leukemia for children undergoing SOT and HCT, respectively. Additionally, we provide background and guidance on the use of EBV viral load measurement in the prevention and management of these children. [ABSTRACT FROM AUTHOR]

Primary cutaneous CD4+ small or medium T‐cell lymphoproliferative disorder (PCSM‐LPD) is a clonal T‐cell proliferation disease confined to the skin. PCSM‐LPD shares expression of T follicular helper (Tfh) cell markers with various mature T‐cell lymphomas. However, the benign presentation of PCSM‐LPD contrasts the clinical behavior of other Tfh‐lymphomas. The aim of our study was to delineate the molecular similarities and differences between PCSM‐LPD and other Tfh‐derived lymphomas to explain the clinical behavior and unravel possible pathological mechanisms. We performed targeted next‐generation sequencing of 19 genes recurrently mutated in T‐cell neoplasms in n = 17 PCSM‐LPD with high and in n = 21 PCSM‐LPD with low tumor cell content. Furthermore, gene expression profiling was used to identify genes potentially expressed in the PD1‐positive (PD1+) neoplastic cells. Expression of some of these genes was confirmed in situ using multistain immunofluorescence. We found that PCSM‐LPD rarely harbored mutations recurrently detected in other T‐cell neoplasms. PCSM‐LPD is characterized by the invariable expression of the T‐cell‐receptor‐associated LCK protein. CD70 and its ligand CD27 are co‐expressed on PD1+ PCSM‐LPD cells, suggestive of autoactivation of the CD70 pathway. In conclusion, PCSM‐LPD differs from disseminated lymphomas of Tfh origin by their mutation profile. Activation of CD70 signaling also found in cutaneous T‐cell lymphoma represents a potential driver of neoplastic proliferation of this benign neoplasia of Tfh. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

EBV+ lymphomas constitute a significant cause of morbidity and mortality in recipients of allogeneic hematopoietic cell (HCT) and solid organ transplants (SOT). Phase I and II trials have shown that in HCT recipients, adoptive transfer of EBV-specific T-cells from the HCT donor can safely induce durable remissions of EBV+ lymphomas including 70->90% of patients who have failed to respond to treatment with Rituximab. More recently, EBV-specific T-cells generated from allogeneic 3rd party donors have also been shown to induce durable remission of EBV+ lymphomas in Rituximab refractory HCT and SOT recipients. In this review, we compare results of phase I and II trials of 3rd party and donor derived EBVspecific T-cells. We focus on the attributes and limitations of each product in terms of access, safety, responses achieved and durability. The limited data available regarding donor and host factors contributing to T cell persistence is also described. We examine factors contributing to treatment failures and approaches to prevent or salvage relapse. Lastly, we summarize strategies to further improve results for virus-specific immunotherapies for post-transplant EBV lymphomas. [ABSTRACT FROM AUTHOR]

Background. Immunosuppression in solid organ transplantation (SOT) increases the risk of Epstein–Barr virus (EBV) DNAemia, which may herald development of posttransplant lymphoproliferative disease (PTLD). Few studies have characterized the incidence, risk factors, and clinical impact of EBV DNAemia in adult SOT recipients (SOTR). Methods. A single-center, retrospective review of adult (≥18 years) SOTR between 01 January 2015 and 31 December 2019 was conducted. Patients were stratified by the primary study endpoint of development of EBV DNAemia (whole blood EBV DNA PCR > 200 copies/mL). Secondary endpoints included development of PTLD, reduction in immunosuppression (RIS), use of pre-emptive therapy, and all-cause mortality. Results. Among 442 adult SOTR, the predominant transplant organs were the kidney (258, 58%) and liver (141, 31.9%). EBV serostatus in most subjects (430, 97%) was classified as intermediate risk (R+). Eight subjects (2%) were high risk (donor (D+/R−), and 4 (1%) were low risk (D−/R−). The overall incidence of EBV DNAemia was 4.1% (18/442) with a median time to detection of 14 months (range 3–60). The highest proportion of DNAemia was observed in D+/R− subjects (37.5%; p < 0.001). Development of PTLD was significantly associated with EBV DNAemia and occurred in 3/18 patients with DNAemia (16.7%) vs. 3/424 (0.7%) without DNAemia (p < 0.001). All patients with PTLD were managed with RIS and rituximab. Conclusion. We observed that EBV D+/R− serostatus and development of sustained EBV DNAemia were high risk features associated with subsequent development of PTLD in our cohort of adult SOTR. [ABSTRACT FROM AUTHOR]

Simple Summary: Marek's disease (MD) is caused by herpesvirus and is a common disease of chickens, usually characterized by tumors in various tissues. Lately, numerous studies have also shown an increasing incidence of the disease in turkeys. This report describes various clinical signs and pathological changes in three different flocks of commercial turkeys in Slovenia. Molecular analysis confirmed the presence of identical Marek's disease virus (MDV) strains in all three cases and showed that the MDV detected is most similar to the MDV detected in chickens in Tunisia. Marek's disease (MD), caused by Mardivirus gallidalpha 2 (GaAHV-2), also known as MD virus (MDV), is a lymphoproliferative disease that primarily affects chickens. Recently, MDV has been detected in lymphomatous tumors in turkeys in various countries. Between 2021 and 2023, three cases ranging from no to severe clinical disorders (depression, lameness, and increased mortality) occurred in commercial turkey flocks in Slovenia. In all cases, MDV was detected by PCR in DNA samples extracted from organs developing tumor infiltrations. Sequencing and phylogenetic analysis of the meq gene revealed that the GaAHV-2 detected has molecular features of a very virulent pathotype and genetic similarity with GaAHV-2 detected in chickens in Tunisia. This is the first report of MDV in commercial turkeys in Slovenia. [ABSTRACT FROM AUTHOR]

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients. [ABSTRACT FROM AUTHOR]

Epstein Barr Virus (EBV) is associated both solid (nasopharyngeal carcinoma, non-nasopharyngeal lymphoepithelioma-like carcinoma, gastric carcinoma, leiomyosarcoma) and hematolymphoid malignancies, some of the latter, however, spanning over a spectrum ranging from reactive and self-limiting to severe and life-threatening conditions. This review will focus on the disorder most commonly involving the skin, namely: EBVpositive mucocutaneous ulcer; lymphomatoid granulomatosis; EBV-positive diffuse large B cell lymphoma; plasmablastic lymphoma; post-transplant lymphoproliferative disorder; extranodal NK/T cell lymphoma, nasal type; angoimmunoblastic T cell lymphoma; severe mosquito bite allergy; hydroa vacciniformelike lymphoproliferative disorder. Given the uncommon occurrence of all these infiltrates in the skin, multidisciplinary approach, as well as referral to tertiary care centers are always advisable. [ABSTRACT FROM AUTHOR]

Rare subtypes of cutaneous T-cell lymphomas (CTCL) include four entities, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders, primary cutaneous acral CD8+ T-cell lymphoma, which were previously considered provisional and are now included in the new 5th World Health Organization classification of hematolymphoid tumors as distinct entities. An updated summary of the clinical, histological, and genomic characteristics of these uncommon CTCL subtypes is given in this review, with a focus on the growing body of knowledge regarding their classification and possible treatment strategies. [ABSTRACT FROM AUTHOR]

The epithelial and lymphoid compartments of the thymus can give rise to a wide variety of tumours, including thymomas, thymic carcinomas, lymphoreticular proliferations, germ cell tumours, and sarcomas. While some of these have close similarity to their counterparts in other organs, both in terms of histology and immunohistochemistry, as well as molecular features, others are unique to the thymus. The epithelial tumours, which can develop in the thymus, will be discussed in this review, with a particular emphasis on resolving differential diagnosis by means of morphology, immunohistochemical profiles, and molecular diagnostics. [ABSTRACT FROM AUTHOR]

Lymphomatoid papulosis (LYP) is a chronic CD 30 + lymphoproliferative disorder (LPD) which is characterized by chronic, recurrent, and self-healing papulonecrotic or papulonodular skin eruptions, which are clinically benign and histopathologically malignant. It can resolve spontaneously; however, long-term follow-up is essential as it can progress to malignant lymphoma in 10-20% of the patients. We hereby report a case of a 42-year-old male presenting with recurrent papulonecrotic lesions over the face, trunk, and extremities from the last 3 years which heal with post-inflammatory hyperpigmentation and atrophic scars with a history of treated pulmonary tuberculosis one year back. There was no systemic involvement. LYP, involving cosmetically sensitive area like face, is an infrequent finding. [ABSTRACT FROM AUTHOR]

A 3-year-old male with X-linked lymphoproliferative syndrome type 1 underwent an unrelated umbilical cord blood transplant (UUCBT). The week prior to transplant the patient tested positive for adenovirus (HAdV) with a viral load of <190 copies/mL and was started on cidofovir. UUCBT proceeded as scheduled, and the patient engrafted on day +19. The patient's HAdV load in serum continued to rise with resulting hepatic dysfunction, despite ongoing therapy with cidofovir and HAdV specific T-cell infusions. The patient died 6 months after transplantation having never cleared the virus. Next generation whole genome sequencing and sequence data analyses identified an intertypic recombinant HAdV-C P1H2F2 closely related (99.6% similarity) to genotype C108 in the isolates from three blood specimens obtained during the last week of life. Incidentally, the de novo assembly strategy enabled the detection of an adeno-associated virus type 2 (AAV2) genome in the DNA purified from the plasma isolates. Proteotyping analysis revealed minor differences in the predicted amino acid sequences for E1A, E1B 19K, E1B 55K, DNA polymerase, penton base, and fiber. None of the mutations previously described for HAdV-C5 variants resistant to cidofovir were identified. In silico restriction enzyme analysis revealed a distinct Sac I profile for the identified virus, supporting its designation as a C108 variant. [ABSTRACT FROM AUTHOR]

With the worldwide approval of the oral covalent Bruton tyrosine kinase (BTK) inhibitors ibrutinib and zanubrutinib for treating patients with Waldenström macroglobulinemia (WM), targeted agents have certainly taken center stage in the therapeutic landscape of WM. This review discusses the biological and clinical data supporting current and up-and-coming targeted agents in WM. Bruton tyrosine kinase inhibitors induce fast, deep, and durable responses in patients with WM, comparable to chemoimmunotherapy; however, there is a glaring absence of comparative studies between these regimens. The high response and progression-free survival rate and the ease of administration of BTK inhibitors must be balanced against their specific adverse-event profile with unique toxicity (e.g., bleeding and cardiac arrhythmia) and the indefinite duration of the therapy. Novel targeted agents of interest include BCL2 antagonists (e.g., venetoclax and sonrotoclax) and non-covalent BTK inhibitors (e.g., pirtobrutinib and nemtabrutinib), among others. The therapeutic landscape of patients with WM will benefit from the robust participation of patients in clinical trials. [ABSTRACT FROM AUTHOR]

Castleman disease is non-clonal lymphoproliferative disorders defined by hypertrophy of lymph nodes. The multicentric form (MCD), in which multiple lymph node stations are involved, is not associated with HHV8 infection, but considered idiopathic, although IL-6 appears to play a central role in its pathogenesis. Here, we report the case of a patient who presented with mixed autoimmune hemolytic anemia (AIHA) and adenopathy that was very challenging to diagnose due to very low values of hemoglobin and refractoriness of obtaining any improvement of AIHA with standard first and second lines of therapy (steroids, rituximab, immunoglobulin, erythropoietin, and cyclosporine). When we safely proceeded to lymph node biopsy, a diagnosis of MCD was established. This permitted the treatment with siltuximab, an anti-IL-6 monoclonal antibody. After only 1 week, hemoglobin raised and he was discharged. After 1 year, he was still in remission. This case underlines the challenges in diagnosis of MCD, and the first case of response to siltuximab after the failure of rituximab to relieve mixed AIHA. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is an gamma of herpes virus affecting exclusively humans, was the first oncogenic virus described and is associated with over seven different cancers. Curiously, the exchange of genes during viral infections has enabled the evolution of other cellular organisms, favoring new functions and the survival of the host. EBV has been co-evolving with mammals for hundreds of millions of years, and more than 95% of adults have been infected in one moment of their life. The infection is acquired primarily during childhood, in most cases as an asymptomatic infection. However, during adolescence or young adulthood, around 10 to 30% develop infectious mononucleosis. The NK and CD8+ T cells are the cytotoxic cells of the immune system that focus on antiviral responses. Importantly, an essential role of NK and CD8+ T cells has been demonstrated during the control and elimination of EBV-infected cells. Nonetheless, when the cytotoxic function of these cells is compromised, the infection increases the risk of developing lymphoproliferative diseases and cancer, often fatal. In this review, we delineate EBV infection and the importance of cytotoxic responses by NK and CD8+ T cells during the control and elimination of EBV-infected cells. Furthermore, we briefly discuss the main inborn errors of immunity that compromise cytotoxic responses by NK and CD8+ T cells, and how this scenario affects the antiviral response during EBV infection. Finally, we conclude the review by underlying the need for an effective EBV vaccine capable of preventing infection and the consequent development of malignancies and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Purpose Post-transplantation lymphoproliferative disorders (PTLDs) after hematopoietic stem transplantation (HCT) or solid organ transplantation (SOT) result in poorer outcomes, including death. There are limited large cohort data on the incidence and natural course of PTLD in Asians. Materials and Methods We investigated PTLD using Korean national health insurance claims data of 47,518 patients who underwent HCT or SOT in 2008-2020. Patient demographics, time and type of PTLD diagnosis, type of PTLD treatment, and death data were collected. We used Fine and Gray subdistribution hazard models to calculate the cumulative incidence and risk factors for PTLD. Results During median follow-up of 5.32 years, PTLD occurred in 294 of 36,945 SOT patients (0.79%) and 235 of 10,573 HCT patients (2.22%). Cumulative incidence of PTLD were 0.49% at 1 year, 1.02% at 5 years, and 1.50% at 10 years post-transplantation. Age < 20 years (subdistribution hazard ratio [SHR] of 1.67 in age 10-19, SHR 1.51 in age 0-9), HCT (SHR 3.02), heart transplantation (SHR 2.27), and liver transplantation (SHR 1.47) were significant risk factors for PTLD. The presence of PTLD was associated with an increased risk of death (hazard ratio of 2.84). Overall, 5-year survival of PTLD patients was 68.9% (95% confidence interval, 64.9 to 73.2). Conclusion We observed a steady increase in PTLD over 10 years after HCT or SOT in this large cohort study. Pediatric age group, HCT, liver transplantation, and heart transplantation were suggested to be risk factors for PTLD, and PTLD was associated with a higher risk of death. [ABSTRACT FROM AUTHOR]

Individual reports described lymphoproliferative disorders (LPDs) after COVID-19 vaccination; however, the relationship between cases is unexamined. We aim to determine if there are cases of cutaneous LPDs associated with COVID-19 vaccination and their outcomes. We present a review of world literature, vaccine registries, and two unreported cases of LPDs after COVID-19 vaccination. Review of the medical literature, VAERS, and our two cases reveal predominance of Pfizer-BioNTech vaccine, younger patients, and males. All cases resulted in favorable outcomes. Approximately 84% of cases demonstrated CD30+ positivity in their skin biopsies, suggesting that an antigenic trigger may lead to a type IV adaptive immune response, with clonal expansion of CD30+ T-cells and subsequent oncogenic mutational hits eventuating in transient LPDs. LPDs after COVID-19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self-limited character. [ABSTRACT FROM AUTHOR]

Rituximab, anti-CD20 monoclonal antibody, has broad clinical application. The aim of this study is to compare the safety and cost of the original reference rituximab (MabThera) and its biosimilar (Riximyo). This retrospective analysis of 262 patients receiving Riximyo in the Department of Hematology of Wroclaw Medical University in Poland from the period of 1 October 2020 to 21 June 2021 focused on infusion-related reactions (IRRs), which occurred in 4,96% of patients (N = 13). 109 patients (41,6%) had previously been treated with the reference drug and 2 IRRs were reported after switching therapy. During the study period, after biosimilar introduction, the cost of rituximab decreased by 41%. Rixmyo while maintaining similar safety profile is much more cost-effective. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) associated T-cell and NK-cell lymphoproliferative diseases are lethal and extremely rare in Caucasians. We expand on the clinical, immunological and histogenetic characteristics associated with this second European case (19 years old, previously healthy, Caucasian boy) of systemic EBV positive T-cell lymphoma of childhood. We report, as novel findings, severe lympho-depletion and abrogation of thymopoiesis secondary to severe EBV activation and excessive immune activation. Similar to the first European case, we also detected a somatic missense variant in the proto-oncogene FYN. In the first European patient however, the FYN variant allele frequency (VAF) was 10% and the patient only experienced moderate leukopenia, whereas in our case, the VAF was 48% and the patient experienced severe leukopenia and lymphopenia. This could suggest a pathogenic role of these FYN variants in driving excessive T cell activation. If confirmed, FYN might become target in future treatments of this fatal disorder. [ABSTRACT FROM AUTHOR]

Introduction: Primary splenic lymphoma is a rare lymphoproliferative disorder that involves the spleen, exhibits diverse clinical presentations, and lacks a clear consensus in terms of management strategies. Case Presentation: We present the case of a 52-year-old patient with a complex medical history marked by multiple chronic medical conditions. The patient was diagnosed with primary splenic lymphoma, specifically the diffuse large B-cell subtype. Treatment for our patient involved a shortened course of chemotherapy (4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] followed by two doses of rituximab) due to issues related to compliance and treatment-related complications. This was followed by consolidative radiotherapy without resorting to splenectomy. Conclusion: Remarkably, despite using a shortened course of R-CHOP, the patient achieved complete resolution, and a positron emission tomography scan conducted at the end of the 6-month posttreatment period confirmed sustained complete remission. [ABSTRACT FROM AUTHOR]

Introduction: Acquired angioedema due to C1 esterase inhibitor deficiency (C1INH-AAE) is most associated with lymphoproliferative disorders (LPDs), particularly low-grade B-cell subtypes. The condition remains under-recognized with long diagnostic delays due to various challenges including a lack of awareness of the condition. Case Presentation: We discuss 4 cases of C1INH-AAE associated with low-grade B-cell LPDs, including various diagnostic and management challenges. As our cases illustrate, constitutional symptoms or overt manifestations of LPD at diagnosis are often absent. Hence, a comprehensive multimodal approach to screening for an underlying B-LPD is important when a diagnosis of acquired angioedema is made. Levels of complement C4, C1q, and C1INH are useful for diagnosing C1INH-AAE and for monitoring disease activity. Changes in these parameters may also indicate relapse of the underlying hematological malignancy. Treating the underlying disorder is important as this commonly leads to clinical improvement with decreased episodes of angioedema and normalization of complement studies. Conclusion: Awareness of C1INH-AAE can lead to an early diagnosis of hematological malignancies. The absence of constitutional symptoms emphasizes the need for a comprehensive multimodal approach to screening for LPD in C1INH-AAE. C4, C1INH level, and function are useful for monitoring disease activity. [ABSTRACT FROM AUTHOR]

Tropical spastic paraparesis is a lymphoproliferative disease associated with human T-lymphotropic virus type 1 (HTLV-1), which can have multiple systemic manifestations, with neurological and cutaneous progression. The case of a male patient with tropical spastic paraparesis, with positive HTLV-1 in the course of infective dermatitis, confirmed by histology, is presented. [ABSTRACT FROM AUTHOR]

Primary cutaneous anaplastic large-cell lymphoma (C-ALCL) is a rare subtype of non-Hodgkin lymphoma, CD30 positive that does not exhibit extracutaneous manifestations at the time of diagnosis. The emergence of solitary papules or nodules, on the trunk and extremities, characterizes the disease. This case reports a 58-year-old female who presented with a rapidly enlarging nodule on her right calf. The biopsy revealed a malignant neoplasm of large cells. The morphological features, combined with the immunohistochemical profile, revealed a CD30-positive and anaplastic lymphoma kinase-negative lymphoproliferative disorder, consistent with C-ALCL. Shortly after the first excision, new lesions manifested in violaceous papules and nodules, and a new biopsy was performed, confirming the initial diagnosis. The patient underwent radiotherapy for 4 weeks and the lesions regressed but recurred about a year after. The patient is currently under treatment. The main goal is to emphasize the importance of considering this diagnosis as a possibility in large-cell cutaneous lymphomas. [ABSTRACT FROM AUTHOR]

Background: Lymphoproliferative diseases encompass a spectrum of heterogeneous conditions, necessitating a comprehensive understanding for effective management. This study aimed to analyze lymphoma subtypes, demographic variations, and their clinical implications. Introduction: The study focuses on a cohort of 57 subjects diagnosed with lymphoproliferative diseases between November 2008 and December 2011. The investigation aimed to characterize lymphoma subtypes, elucidate age-gender variations, and analyse organ and extra-nodal site involvements. Methodology: This retrospective study involved 57 subjects diagnosed with various lymphoproliferative diseases within a multi-specialty oncology hospital between November 2008 and December 2011. Detailed clinical records, including morphological, immune-phenotyping, and cytogenetic data, were meticulously reviewed and analysed. Morphological evaluations comprised peripheral blood and bone marrow smear analyses, stained with Leishman and May-Grunwald Giemsa stains, respectively. Immunophenotyping was conducted using a panel of monoclonal antibodies, and cytogenetic analyses involved short-term unstimulated cultures from fresh bone marrow aspirates, subjected to G-banding and Fluorescent In Situ Hybridization (FISH) assays. Results: Prominent findings included a notable prevalence of T cell non-Hodgkin lymphoma with lymph node involvement in younger individuals. Gender-based variations showcased diverse lymphoma subtypes in females across age brackets. Organ involvement analysis revealed distinct infiltrations in liver, spleen, and bone marrow, with extensive extra-nodal manifestations observed. Conclusion: The study's outcomes underscore the significance of personalized treatment strategies based on specific subtypes and demographic profiles. Clinical implications highlight the need for tailored diagnostic approaches and emphasize the importance of precise staging and disease monitoring for optimized patient care. [ABSTRACT FROM AUTHOR]

Primary cutaneous CD4+ small to medium T-cell lymphoproliferative disorder is rare, accounting for only 2-3% of all primary cutaneous lymphomas. Patients usually present in their 50s with a rapidly growing yet asymptomatic nodule on the face or neck. In this report, we describe the case of a 50-year-old man with an asymptomatic, small, round nodule on his temple area appearing in the preceding two months without any systemic involvement. Surgical excision was done, and histopathological and immunohistochemical studies revealed high infiltration of CD4+ lymphocytes in the dermis, confirming the diagnosis of primary cutaneous CD4+ small to medium T-cell lymphoproliferative disorder. An excellent outcome was achieved, with no signs of recurrence after two months of follow-up. As the disease is often overlooked in the differential diagnoses of suddenonset, rapidly growing lesions, this report reminds physicians to keep it in mind and avoid unnecessary aggressive interventions. [ABSTRACT FROM AUTHOR]

Flow cytometry (FCM) has become a method of choice for immunologic characterization of chronic lymphoproliferative disease (CLPD). To reduce the potential subjectivities of FCM data interpretation, we developed a machine learning random forest algorithm (RF) allowing unsupervised analysis. This assay relies on 16 parameters obtained from our FCM screening panel, routinely used in the exploration of peripheral blood (PB) samples (mean fluorescence intensity values (MFI) of CD19, CD45, CD5, CD20, CD200, CD23, HLA‐DR, CD10 in CD19‐gated B cells, ratio of kappa/Lambda, and different ratios of MFI B‐cells/T‐cells [CD20, CD200, CD23]). The RF algorithm was trained and validated on a large cohort of more than 300 annotated different CLPD cases (chronic B‐cell leukemia, mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, splenic red pulp lymphoma, hairy cell leukemia) and non‐tumoral selected from PB samples. The RF algorithm was able to differentiate tumoral from non‐tumoral B‐cells in all cases and to propose a correct CLPD classification in more than 90% of cases. In conclusion the RF algorithm could be proposed as an interesting help to FCM data interpretation allowing a first B‐cells CLPD diagnostic hypothesis and/or to guide the management of complementary analysis (additional immunologic markers and genetic). [ABSTRACT FROM AUTHOR]

Primary cutaneous B‐cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence‐based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple‐step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners. [ABSTRACT FROM AUTHOR]

Background: Waldenstroms macroglobulinemia (WM) or Lymphoplasmacytic lymphoma is a rare B cell lymphoproliferative malignancy characterized by serum monoclonal immunoglobulin M (IgM) protein and lymphoplasmacytic infiltration in the bone marrow. Patients usually present in their seventh decade with symptoms related to the infiltration of the marrow or the effects of monoclonal IgM in the blood. Objective: Was to study the clinical characteristics and treatment outcome of patients diagnosed with WM. Materials and methods: This is a retrospective analysis of 26 cases of WM treated at a tertiary cancer centre. Results: WM constituted 0.68% of our nonHodgkin's lymphoma. The median age at presentation was 67 years with a male to female ratio of 2:1. Four patients had lymphadenopathy, six had splenomegaly and four patients had evidence of hyper viscosity. All patients had IgM paraproteinemia, the M band was IgM-kappa in 19 patients and IgM-lambda in seven patients. All patients had a histopathological confirmation. According to IPSS-WM, 12 patients each were in the intermediate and high risk group and 2 in the low risk group. Among the 26 patients, 20 patients received upfront treatment and four patients were kept under observation. The indications for treatment were cytopenia in ten patients, constitutional symptoms in five, hyper viscosity in four and symptomatic lymphadenopathy in one patient. Sixteen patients received rituximab-based chemotherapy. Four patients with features with hyper viscosity underwent plasmapheresis. The three year progression free survival and overall survival were 69.4% and 78 % respectively. Conclusions: WM is a low grade B cell lymphoproliferative disorder having an indolent course and do not require treatment for prolonged period. Diagnosis is challenging due to lack of distinct diagnostic features. Rituximab containing regimens are the standard of care. Newer targeted treatment options may improve the outcome of this incurable disease. [ABSTRACT FROM AUTHOR]

Double-negative T (DNT) cells are a rare and unconventional T-lymphocyte subpopulation lacking both CD4 and CD8 markers. Their immunopathological roles and clinical relevance have yet to be elucidated. Beyond autoimmune lymphoproliferative syndrome (ALPS), these cells may also play a role in rheumatic disorders, including systemic lupus erythematosus (SLE); indeed, these two diseases share several autoimmune manifestations (including nephritis). Moreover, one of the main experimental murine models used to investigate lupus, namely the MRL/lpr mouse, is characterized by an expansion of DNT cells, which can support the production of pathogenic autoantibodies and/or modulate the immune response in this context. However, lupus murine models are not completely consistent with their human SLE counterpart, of course. In this mini review, we summarize and analyze the most relevant clinical studies investigating the DNT cell population in SLE patients. Overall, based on the present literature review and analysis, DNT cell homeostasis seems to be altered in patients with SLE. Indeed, most of the available clinical studies (which include both adults and children) reported an increased DNT cell percentage in SLE patients, especially during the active phases, even though no clear correlation with disease activity and/or inflammatory parameters has been clearly established. Well-designed, standardized, and longitudinal clinical studies focused on DNT cell population are needed, in order to further elucidate the actual contribution of these cells in SLE pathogenesis and their interactions with other immune cells (also implicated and/or altered in SLE, such as basophils), and clarify whether their expansion and/or immunophenotypic aspects may have any immunopathological relevance (and, then, represent potential disease markers and, in perspective, even therapeutic targets) or are just an unspecific epiphenomenon of autoimmunity. [ABSTRACT FROM AUTHOR]

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS. Editor's summary: Autoimmune lymphoproliferative syndrome (ALPS) has been linked to defective FAS signaling. Patients with ALPS-FAS typically have hypergammaglobulinemia and impaired B cell differentiation, but these defects cannot be explained by apoptosis-inducing functions of FAS. Staniek et al. observed that patients with ALPS-FAS have fewer germinal center (GC) B cells but a greater number of extrafollicular (EF) B cells. They determined that engagement of FAS upon T-dependent B cell activation via CD40L does not cause apoptosis but decreased mTOR activation, a process dependent on caspase-8 and nuclear exclusion of PTEN. By contrast, FASL-mediated mTOR modulation by PTEN nuclear exclusion was defective in B cells from patients with ALPS-FAS. Normal FAS signaling was also linked to expression of genes needed for GC initiation, thus suggesting a role for non-apoptotic FAS signaling as a molecular switch determining GC or EF fates. —Christiana N. Fogg [ABSTRACT FROM AUTHOR]

Introduction: Methotrexate induces lymphoproliferative disorders on rare occasions; however, its pathogenesis remains unknown. A clinical diagnosis based on imaging studies alone is often difficult. Case presentation: A 57-year-old Japanese woman was referred to our department for the evaluation of multiple lung and hepatic nodules that developed during methotrexate treatment for rheumatoid arthritis. Since she had a history of nephrectomy for localized renal cell carcinoma, multiple lung and hepatic metastases were initially considered. However, pathological diagnosis of the lung nodules (needle biopsy) revealed methotrexate-associated polymorphic-type lymphoproliferative disorders. After methotrexate discontinuation, continuous smooth shrinkage of the lung and liver lymphoproliferative disorders was observed. Conclusion: Methotrexate-associated lymphoproliferative disorders should be considered in the event of newly appearing neoplastic lesions, even during follow-up for renal cell carcinoma, if methotrexate is being administered. [ABSTRACT FROM AUTHOR]

Background: Lymphomas involving the gastrointestinal tract may be manifested as anti-inflammatory tract bleeding, abdominal lymph node enlargement, or even perforation of the gastrointestinal tract. After organ transplantation, the likelihood of post-transplant lymphoproliferative disorders increases, and some rare infections may also appear. Case presentation: Herein, we report a living transplant patient with talaromycosis marneffei (TSM) or Talaromyces marneffei (TM) infection with gastrointestinal hemorrhage and systemic lymph node enlargement, which presented clinically as lymphoma. Conclusion: This case is TSM in a kidney transplant patient, confirmed by lymph node biopsy and blood culture. The patient discharged from hospital successfully under the treatment of antifungal therapy and immunosuppressive therapy. Physicians should be aware that TSM can mimic lymphoma, and early diagnosis and treatment can benefit the outcomes. [ABSTRACT FROM AUTHOR]

T-cell large granular lymphocyte leukaemia (T-LGLL) generally has a favourable prognosis, but a small proportion of patients are facing a relatively short survival time. This study aimed to identify clinical factors associated with survival in patients with T-LGLL and develop a predictive model for guiding therapeutic decision-making. We conducted a retrospective study on 120 patients with T-LGLL. Lasso regression was performed for feature selection followed by univariate and multivariate Cox regression analysis. A decision tree algorithm was employed to construct a model for predicting overall survival (OS) in T-LGLL. The median age of diagnosis for the entire cohort was 59 years, and 76.7% of patients reported disease-related symptoms. After a median follow-up of 75 months, the median OS was not reached. The 5-year OS rate was 82.2% and the 10-year OS rate was 63.8%. Multivariate analysis revealed that an Eastern Cooperative Oncology Group performance status over two and a platelet count below 100 × 109/L were independently associated with worse OS, leading to the development of a simplified decision tree model. The model's performance was adequate when internally validated. The median OS of the high- and intermediate-risk- risk groups was 43 and 100 months respectively, whereas the median OS of the low-risk group was not reached. Furthermore, we found that immunosuppressive agent-based conventional treatment was unsatisfactory for our high-risk patients. Our model is an easily applicable clinical scoring system for predicting OS in patients with T-LGLL. However, external validation is essential before implementing it widely. [ABSTRACT FROM AUTHOR]

Background: In the last decade, Ibrutinib has become the standard of care in the treatment of several lymphoproliferative diseases such as chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphoma. Beyond Bruton tyrosine kinase inhibition, Ibrutinib shows broad immunomodulatory effects that may promote the occurrence of infectious complications, including opportunistic infections. The infectious burden has been shown to vary by disease status, neutropenia, and prior therapy but data focusing on severe infections requiring intensive care unit (ICU) admission remain scarce. We sought to investigate features and outcomes of severe infections in a multicenter cohort of 69 patients receiving ibrutinib admitted to 10 French intensive care units (ICU) from 1 January 2015 to 31 December 2020. Results: Median time from ibrutinib initiation was 6.6 [3–18] months. Invasive fungal infections (IFI) accounted for 19% (n = 13/69) of severe infections, including 9 (69%; n = 9/13) invasive aspergillosis, 3 (23%; n = 3/13) Pneumocystis pneumonia, and 1 (8%; n = 1/13) cryptococcosis. Most common organ injury was acute respiratory failure (ARF) (71%; n = 49/69) and 41% (n = 28/69) of patients required mechanical ventilation. Twenty (29%; n = 20/69) patients died in the ICU while day-90 mortality reached 55% (n = 35/64). In comparison with survivors, decedents displayed more severe organ dysfunctions (SOFA 7 [5–11] vs. 4 [3–7], p = 0.004) and were more likely to undergo mechanical ventilation (68% vs. 31%, p = 0.010). Sixty-three ibrutinib-treated patients were matched based on age and underlying malignancy with 63 controls receiving conventional chemotherapy from an historic cohort. Despite a higher median number of prior chemotherapy lines (2 [1–2] vs. 0 [0–2]; p < 0.001) and higher rates of fungal [21% vs. 8%, p = 0.001] and viral [17% vs. 5%, p = 0.027] infections in patients receiving ibrutinib, ICU (27% vs. 38%, p = 0.254) and day-90 mortality (52% vs. 48%, p = 0.785) were similar between the two groups. Conclusion: In ibrutinib-treated patients, severe infections requiring ICU admission were associated with a dismal prognosis, mostly impacted by initial organ failures. Opportunistic agents should be systematically screened by ICU clinicians in this immunocompromised population. [ABSTRACT FROM AUTHOR]

Background: Dexamethasone (DEX) induces CYP3A activity in a concentration-dependent manner. However, no study has examined changes in the blood concentration of CYP3A substrate drugs when DEX is administered at high doses. Herein, we present a case in which tacrolimus (TAC), a typical CYP3A substrate drug, was co-administered with a chemotherapy regimen that included high-dose DEX. Case presentation: A 71-year-old woman underwent liver transplantation for hepatocellular carcinoma 18 years prior to her inclusion in this case study. She was receiving TAC orally at 2 mg/day and had a stable trough blood concentration of approximately 4 ng/mL and a trough blood concentration/dose (C/D) ratio of approximately 2. The patient was diagnosed with post-transplant lymphoproliferative disease (histological type: Burkitt's lymphoma) after admission. Thereafter, the patient received cyclophosphamide-prednisolone (CP), followed by two courses of R-HyperCVAD (rituximab, cyclophosphamide, doxorubicin, vincristine, and DEX) and R-MA (rituximab, methotrexate, and cytarabine) replacement therapy. DEX (33 mg/day) was administered intravenously on days 1–4 and days 11–14 of R-HyperCVAD treatment, and aprepitant (APR) was administered on days 1–5 in both courses. The TAC C/D ratio decreased to approximately 1 on day 11 during both courses, and then increased. Furthermore, a decreasing trend in the TAC C/D ratio was observed after R-MA therapy. The decrease in the TAC C/D ratio was attributed to APR administration rather than to DEX. Conclusion: The induction of CYP3A activity by a high dose of DEX may not be strong. The pharmacokinetic information on DEX and in vitro enzyme activity induction studies also suggested that CYP3A activity induction is not prominent under high-dose DEX treatment. [ABSTRACT FROM AUTHOR]

Cancer is a leading cause of mortality worldwide. B-cells are a keystone of the adaptive immune response and are essential for the presentation of tumor-associated antigens to various types of T-cells. Approximately 1.5% of global cancer cases, including breast and gastric carcinomas and both Hodgkin's and non-Hodgkin's lymphomas, are linked with prior Epstein–Barr Virus (EBV) infection. Such properties make EBV-infected lymphocytes ideal models for understanding the effect of oxyhydrogen gas on dysfunctional cell cycling. The aim of this study is to assess the effects of the direct infusion of oxyhydrogen gas on the replicative capacity of EBV-immortalised B-lymphocytes. Oxyhydrogen gas was directly infused into cell culture media. Cells were incubated in 95% air and 5% CO2 for up to 72 h. Cell enumeration was assessed with and without the addition of mitogenic growth stimuli, and subsequent cell-cycle analysis was performed. Cell enumeration: An initial trend of replicative inhibition of TK6 cells is noted with a single oxyhydrogen treatment at the 24 and 48 h time points. The daily addition of oxyhydrogen-infused media showed statistically relevant data at 24 and 48 h but not at 72 h. In mitogen-stimulated cells, a non-statistical trend of inhibition was observed at 24, 48 and 72 h. Analysis details a significant increase in DNA in the Sub G1 phase, indicating increased apoptosis. [ABSTRACT FROM AUTHOR]

A 45-year-old man presented with an isolated sciatic mononeuropathy, which then evolved into a lumbosacral radiculoplexus neuropathy. His initial symptoms included lower limb pain, sensory disturbance and later weakness, without autonomic dysfunction. Neurophysiology suggested a postganglionic neuropathy. MR and ultrasound scans of the thighs showed right sciatic nerve thickening, and CSF analysis showed albuminocytological dissociation. Fluorodeoxyglucose positron emission tomography (FDG PET) was unremarkable. He then developed orthostatic symptoms and urinary disturbance, and was found to have an IgM paraprotein. Fat aspirate, cardiac and wholebody imaging found no amyloid deposition, and genetic testing for transthyretin amyloidosis was negative. A bone marrow biopsy was unremarkable. However, neuropathology review of a proximal, fascicular nerve biopsy identified a lambda chain-restricted plasma cell population with positive Congo red staining, leading to a diagnosis of peripheral nerve restricted amyloid light amyloidosis. We discuss the diagnostic approach to this case from the perspectives of neurology, neurophysiology, radiology and neuropathology. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death ligand 1 (PD‐L1) expression on tumor cells engages the PD‐1 receptor on T cells, inhibiting anti‐tumor responses. PD‐L1 has been detected in cases of post‐transplant lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD‐L1 expression and evaluate for clinical correlations. Methods: Twenty‐one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin‐embedded tissue biopsies, we examined 21 primary tumors for expression using PD‐L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD‐L1 on lesional B‐cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review. Results: Applying revised 2017 WHO PTLD classification showed five non‐destructive, nine polymorphic, and seven monomorphic cases. Average PD‐L1 expression based upon PTLD subtype was: non‐destructive 11%, polymorphic 43%, and monomorphic 73% (p =.01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B‐cells expressed PD‐L1. Conclusion: In this case series, significant differences in PD‐L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD‐L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis. [ABSTRACT FROM AUTHOR]

Heuristics are cognitive strategies used to facilitate decision‐making. They can be helpful tools for expediting pathologic diagnoses, however, they can also affect judgment and lead to biases that guide the pathologist astray. We report the case of a 52‐year‐old female who presented with two unusual pigmented lesions on the wrist and thigh that clinically and histopathologically resembled an atypical melanocytic proliferation. A biopsy of the thigh revealed a broad proliferation of large, atypical cells forming nests within a heavily pigmented epidermis. The lesion was initially misdiagnosed as melanoma in situ, despite equivocal staining for melanocytic markers, likely due to anchoring and adjustment as well as availability biases, which restricted the differential diagnosis and limited the selection of immunohistochemical stains. It was later discovered through chart review that the patient had a prior history of a cutaneous CD30+ lymphoproliferative disorder, which eventually led to the appropriate diagnosis in this case. Herein, we highlight a rare and unusual presentation of a pigmented epidermotropic CD30+ lymphoproliferative disorder, along with the biases leading to its misdiagnosis and the steps leading to the revelation of the actual diagnosis. [ABSTRACT FROM AUTHOR]

CD30+ cells are typically part of lymphoproliferative disorders but can also be seen in inflammatory dermatoses. We present a case of 47‐year‐old man with a history of B‐lymphoblastic leukemia (B‐ALL) who presented with fever, leukocytosis, and papulonodular skin lesions, involving the extremities and trunk. A punch biopsy specimen demonstrated papillary dermal edema with a neutrophilic and histiocytic infiltrate extending into the subcutis. The infiltrate also harbored scattered large cells that were positive for CD30 and demonstrated the immunohistochemical profile of monocytes. A diagnosis of histiocytoid Sweet syndrome with CD30+ cells was made. The case is unique, demonstrating a combination of Sweet syndrome variants with subcutis involvement, histiocytoid morphology, and large CD30+ cells. A prior history of B‐ALL and immunohistochemical profile of monocytes with immature morphology broadened the differential diagnosis and added to the diagnostic challenge. [ABSTRACT FROM AUTHOR]

Atypical cutaneous lymphoid hyperplasia is a rare tumour of the head and neck which represents a lymphoproliferative continuum and mimics cutaneous lymphoma. Hereby reporting the case of a 40-year-old gentleman who presented with a swelling over dorsum of nose. On evaluation, Fine needle aspiration cytology was inconclusive with only inflammatory cells. Contrast Enhanced CT Nose and PNS suggested a possibility of a haemangioma. Patient underwent laser assisted excision of mass and frozen section showed sheets of basaloid cells suggestive of basal cell carcinoma. Wide local excision and primary paramedian forehead flap closure was done. Histopathology was suggestive of CD30 + atypical cutaneous lymphoid hyperplasia which has potential for malignant transformation into overt lymphoma. Patient underwent pedicle division of flap and is on regular follow up. In this case, aspiration cytology and frozen section reports were discordant with the histopathology, and thereby enlightens us of a rare differential diagnosis for head and neck tumours. [ABSTRACT FROM AUTHOR]