Lymphoproliferative Malignancies Research Articles

Clinical utility of EBV DNA testing of blood in immunocompetent and immunocompromised patients: A single-center experience.

Epstein-Barr virus (EBV) causes different clinical presentations in immunocompetent and immunocompromised persons, and thus indications for testing vary between these populations. We reviewed our institution's EBV DNA testing across these populations to understand its clinical utility and appropriateness. We conducted a retrospective chart review of adult patients with positive EBV nucleic acid amplification (NAAT) testing from November 2022 to 2023. We recorded demographics, indications for testing, EBV-related diagnosis, laboratory results, and whether testing influenced patient treatment. Of 3560 EBV NAAT tests, 187 (5.3%) were positive, representing 124 unique adult patients (51 immunocompetent and 73 immunocompromised). Reactivation of EBV was the most common diagnosis in both populations, followed by acute EBV infection in the immunocompetent and non-posttransplant lymphoproliferative disorder malignancies in the immunocompromised. In immunocompromised patients, positive tests led to treatment changes more frequently than in immunocompetent patients (27.4% vs 11.7%, P=.06). Testing affected clinical management in 0% to 2% of cases when sent for sepsis/shock and nonspecific viral syndromes compared to 37% to 49% of cases when sent for posttransplant and malignancy screening/monitoring. EBV NAAT testinginfrequently influenced clinical management in immunocompetent individuals but had a notable impact in immunocompromised patients, particularly those undergoing posttransplant or malignancy screening. This underscores the need for targeted testing to optimize resource utilization and cost-effectiveness.

Enhancing cell death in B-cell malignancies through targeted inhibition of Bcl-3

The t(14;19)(q32;q13) is a rare recurring translocation found in B-cell lymphoproliferative malignancies, involving the Bcl-3 gene. This chromosomal translocation is often found in patients under the age of 50 and causes a more progressive disease. The Bcl-3 gene encodes a protein belonging to the IκB family of proteins, which tightly regulates NFκB signaling by acting as an activator or repressor of transcription. Previously, we developed a second-generation Bcl-3 inhibitor that could directly interfere with Bcl-3 signaling pathway, resulting in reduced melanoma cell proliferation, invasion, and migration. The present study aimed to investigate the effect of a Bcl-3 inhibitor on B-cell lymphoma and leukemia cells. It was found that treatment of cells with this inhibitor caused a decrease in cell proliferation and cell survival. Furthermore, Bcl-3 inhibition in B-cell malignant cells resulted in the loss of mitochondrial membrane potential and functionality, as well as the increased expression of cleaved caspase 3, indicating that cell death occurs through the intrinsic apoptotic pathway. This observation is further supported by reduced expression of cIAP1 protein 1 (cIAP1) upon treatment of cancer cells. Given the current lack of clinical advancements targeting Bcl-3 in oncology, this opens a novel avenue for the development and investigation of highly specific therapeutic interventions against B-cell malignancies.

Dysregulated MicroRNAs in Chronic Lymphocytic Leukemia.

MiRNAs are a class of non-coding RNAs acting as gene expression regulators by modulating the lifespan of messenger RNA. Commonly referred to as the most frequent leukemia in the Western world, chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy characterized by clonal expansion of CD19, CD23, and CD5-positive mature B-cells. While this pathology is regarded as less aggressive and has a variety of treatment options, the cause of its clinical heterogeneity is not yet understood. Moreover, the prognostic markers and treatment recommendations based on predictive markers are limited. This review aims to investigate some miRNAs that are dysregulated and possibly involved in CLL pathogenesis as a starting point for the proposal of new prognostic and predictive markers and, as more agents targeting miRNA expression become available, their potential role as therapeutic targets.

Feasibility and Safety of Transesophageal Mediastinal Cryobiopsy in the Diagnosis of Mediastinal Pathologies

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.

Analysis of Cytotoxic Granules and Constitutively Produced Extracellular Vesicles from Large Granular Lymphocytic Leukemia Cell Lines.

Large granular lymphocyte leukemias (LGLLs) are rare lymphoproliferative malignancies caused by clonal expansion of granular lymphocytes. T-cell LGLL and natural killer (NK) cell LGLL are defined based on their cellular origin. Their clinical manifestation and pathophysiology vary depending on the subtype and include, e.g., neutropenia, anemia, recurrent infections, and autoimmunity. A limited number of available patient-derived cell lines are considered valuable tools to study the biology of these malignancies. They differ in the expression of lineage-specific surface markers, but generally contain cytotoxic effector molecules in characteristic granules. We investigated the presence and release of lysosome-associated effector proteins in patient-derived LGLL cell lines by flow and imaging cytometry, by Western blotting and by bottom-up proteomics profiling. The tested cell lines did not express FasL (CD178), but did express CD26/DPP4+. Intracellularly, we detected major differences in the abundance and subcellular distribution of granzymes, perforin, and granulysin. Similar differences were seen in enriched lysosome-related effector vesicles (LREVs). The proteomics profiling of enriched EVs from an NK-LGLL line (NKL) and a T-LGLL line (MOTN-1), confirmed individual profiles of effector molecules. Our analyses underscore the individual distribution of effector proteins but also open new routes to define the role of intra- and extracellular granules in the disease manifestation or pathology of LGLLs.

Extensive Multiorgan and Neurological Involvement on F-18 FDG PET-CT in a Case of Rosai-Dorfman Disease

AbstractRosai-Dorfman disease (RDD) is a rare benign proliferative disorder. Lymph nodes are the usual and common sites of involvement. Involvement of the extranodal site is also documented in the literature. 18F-fluorodeoxyglucose positron emission tomography computed tomography (F18-FDG PET CT) is a valuable whole-body imaging modality in staging and treatment response of various lymphoproliferative and solid organ malignancy. Similarly, PET CT survey can detect the involved sites of various body systems, infective or inflammatory diseases, and provide guidance for biopsy and to reach to diagnosis. Here, we present a case of RDD, who presented with neurological manifestations and on F18-FDG PET CT, diagnosed with multiorgan involvement.

Polyserositis as an Initial Manifestation of Chronic Lymphocytic Lymphoma

Abstract Chronic lymphocytic lymphoma (CLL) is a lymphoproliferative malignancy characterized by the generation and accumulation of CD5+ monoclonal B-cell lymphocytes, which are physically mature lymphocytes with aberrant immunological activity. The common presenting features are lymphadenopathy and leukocytosis. Because of its asymptomatic and indolent appearance, CLL requires a high index of suspicion to be diagnosed. Our patient presented with unusual symptoms of malignant polyserositis without substantial lymphadenopathy or hepatosplenomegaly. Ascitic fluid cytology and flow cytometry were done to confirm the diagnosis. The patient was staged modified Rai 0 and Binet A and categorized as low-risk status. Treatment is usually advised at Rai stage II and Binet stage B and higher. Although there is no mention of ascites or pleural effusion in the staging disease or deciding therapy, malignant polyserositis carries a poor prognosis and the decision to treat should be individualized. Our patient was offered chemotherapy but the patient denied it. He was on regular follow-ups receiving palliative therapy.

Metabolomics analyses reveal the crucial role of ERK in regulating metabolic pathways associated with the proliferation of human cutaneous T-cell lymphoma cells treated with Glabridin.

Cutaneous T-cell lymphomas (CTC) are a heterogeneous group of T-cell lymphoproliferative malignancies of the skin with limited treatment options, increased resistance and remission. Metabolic reprogramming is vital in orchestrating the uncontrolled growth and proliferation of cancer cells. Importantly, deregulated signalling plays a significant role in metabolic reprogramming. Considering the crucial role of metabolic reprogramming in cancer-cell growth and proliferation, target identification and the development of novel and multi-targeting agents are imperative. The present study explores the underlying mechanisms and metabolic signalling pathways associated with Glabridin mediated anti-cancer actions in CTCL. Our results show that Glabridin significantly inhibits the growth of CTCL cells through induction of programmed cell death (PCD) such as apoptosis, autophagy and necrosis. Interestingly, results further show that Glabridin induces PCD in CTCL cells by targeting MAPK signalling pathways, particularly the activation of ERK. Further, Glabridin also sensitized CTCL cells to the anti-cancer drug, bortezomib. Importantly, LC-MS-based metabolomics analyses further showed that Glabridin targeted multiple metabolites and metabolic pathways intricately involved in cancer cell growth and proliferation in an ERK-dependent fashion. Overall, our findings revealed that Glabridin induces PCD and attenuates the expression of regulatory proteins and metabolites involved in orchestrating the uncontrolled proliferation of CTCL cells through ERK activation. Therefore, Glabridin possesses important features of an ideal anti-cancer agent.

#1494 Immunotactoid glomerulopathy: a comprehensive analysis of three cases

Abstract Background Immunotactoid glomerulopathy (ITG) is an uncommon cause of glomerular disease encountered in approximately 0.06% of native kidney biopsies. This fibrillary disease is strongly associated with haematologic disorders, including lymphoma (mainly chronic lymphocytic leukaemia/small lymphocytic lymphoma), monoclonal gammopathy, and multiple myeloma. It is usually managed with oral steroids and/or treatment of an underlying lymphoproliferative disorder. Here, we report three cases of ITG, all female patients with varying severity of the disease, timing of malignancy and required treatment. Case Scenarios: Case 1: A 76-year-old lady with no significant medical background presented in May 2020 with confusion and progressive peripheral oedema. She had AKI (serum creatinine 210 µmol/L from baseline 68 µmol/L) and a sodium of 104 mmol/l. Urine PCR was 1182 mg/mmol. She was admitted to the ITU, where hyponatraemia was managed with a good clinical response. Blood screening showed negative immune, myeloma and virology screens. Complement was low. A renal biopsy showed a diagnosis of ITG. She had an extensive malignancy screen, but no malignancy was detected. She was started on prednisolone 60 mg once daily and eventually weaned off the drug by March 2021, as she maintained remission of her disease. Two years after her initial presentation, she was seen by the ophthalmologist for a right lacrimal gland mass. This was excised, and a biopsy revealed a MALT Lymphoma. Case 2: A 50-year-old lady with splenomegaly being investigated under the haematology service was referred to our renal clinic for proteinuria in June 2019. Her serum creatinine was within normal limits, and her UPCR was 302 mg/mmol. She had no paraprotein in her blood, low serum immunoglobulins, low C3 and a negative viral screen. Perindopril, initiated by her GP, was up-titrated. Renal biopsy revealed features in keeping with Immunotactoid Glomerulopathy, and completed haematological investigations revealed Chronic Lymphocytic Leukaemia. Her UPCR peaked at 842 mg/mmol before reducing to 190 mg/mmol within a year after treatment with Veneclotax and Rituximab after not tolerating FCR (Fludarabine, Cyclophosphamide, Rituximab) Chemotherapy. Case 3: A 69-year-old lady presented to the renal clinic with proteinuria in September 2018. She had a background of breast cancer diagnosed in 2007 (She had surgical resection followed by radiotherapy). Her 24-hour urine protein was 2g, and UPCR was 155 mg/mmol. Serum creatinine was 81 µmol/l and eGFR 66 ml/min. P- ANCA was positive, while PR3 and ANA were negative. She had bilateral leg oedema due to long-standing lymphedema. The biopsy report showed immunotactoid glomerulopathy. Regular surveillance of previous breast cancer with mammography and CT-CAP has shown no evidence of malignancy recurrence, hepatitis virology and paraprotein were negative, and C3/C4 were within normal limits. She had improved UPCR and maintained normal kidney function on full-dose Losartan. Conclusion Immunotactoid Glomerulopathy is a rare form of glomerular disease with a strong association with lymphoproliferative malignancies, which may precede, occur concomitantly or present years after the initial diagnosis. This common association highlights the need for diligence in screening for malignancy in each case, and it is a reason for careful follow-up of these patients. Treatment of underlying disorders is associated with positive renal outcomes, and in some cases, there is a good response to steroids.

Abstract Db1-01: Anthracyclines …to give or not to give? “For” argument

Abstract Anthracyclines have been one of the mainstays of early breast cancer treatment for decades. In a recent patient-level meta-analysis including data from over 18,000 patients, anthracycline-containing regimens were associated with improvements in disease-free survival and overall survival, regardless of estrogen receptor or nodal status. Importantly, trials specifically designed and powered to assess the safety of anthracyclines omission failed to demonstrate the non-inferiority of taxane-based anthracycline-free regimens and confirmed the benefit of these agents, particularly in patients with node-positive and hormone receptor-negative breast cancer. Several therapies incorporated into the management of early breast cancer were studied in populations largely treated with anthracycline-based chemotherapy backbones in both HER2-negative (i.e., perioperative pembrolizumab, post neoadjuvant olaparib and capecitabine) and HER2-positive disease (i.e., dual HER2 blockade, adjuvant T-DM1). It is uncertain whether the benefits demonstrated by these strategies would be maintained if anthracyclines were omitted. While anthracyclines are associated with some long-term toxicities, particularly with an increased risk of lymphoproliferative malignancies and dose-dependent cardiotoxicity, these adverse events are not associated with an increased risk of death (including deaths from cardiovascular causes) when compared to anthracycline-free regimens. The identification of risk factors for cardiotoxicity, combined with improvements in monitoring strategies, allows improvements in patient selection, early detection of myocardial damage and, possibly, implementation of cardioprotective interventions, leading to improved cardiovascular outcomes. Until high-quality evidence demonstrates the safety of omitting anthracyclines in high-risk populations, these agents should continue to be used in carefully selected patients after individual risk versus benefit assessment to be shared with the patient. Citation Format: Martine Piccart, Guilherme Nader-Marta. Anthracyclines …to give or not to give? “For” argument [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr Db1-01.

Role of Positron Emission Tomography/Computed Tomography (PET/CT) in Assessment and Follow-up of Gastrointestinal Tract Malignancies

Positron Emission Tomography/Computed Tomography (PET/CT) is a highly advanced imaging method that has several uses in oncology, such as determining the stage of cancer, evaluating the effectiveness of treatment, reevaluating the stage of cancer, and monitoring for the return of cancer over time. PET advancement has brought out a new capacity in medical diagnosis: being able to non-invasively examine the physiological condition of interior tissues. The integration of PET with simultaneous CT combines two procedures that enable the diagnosis of metabolic or receptor-specific abnormalities together with precise anatomical localization. In comparison to PET alone, the PET/CT combination is more effective in accurately identifying the location of abnormalities and distinguishing between normal and abnormal uptake of FDG along with additional tracers. PET/CT has become an essential component of management guidelines in many diseases such as lung, breast, and lymphoproliferative malignancies. The ability to image metabolic processes like glucose metabolism adds to the information provided by structural imaging, especially in the context of treatment monitoring, where metabolic changes can often precede structural changes.

Nonbacterial thrombotic endocarditis of mitral valve associated with a lymphoproliferative malignancy: case report and literature review

BackgroundNon-bacterial thrombotic endocarditis (NBTE) is a rare condition marked by sterile vegetations on cardiac valves, often linked to rheumatologic diseases, autoimmune disorders, and advanced solid malignancies. An early diagnosis and treatment of the associated clinical condition are mandatory, although they do not usually eliminate valvular vegetations, making anticoagulation essential to prevent embolic events. Despite variability, the prognosis of NBTE is usually unfavorable due to recurrent embolic events and the severity of the primary condition, typically advanced cancer.Case presentationWe present a case of a 57 years-old male who presented to the emergency department with a 5-day history of painful bilateral digital edema and color change episodes (from pallor to cyanosis). Physical examination revealed erythrocyanosis in the distal extremities, prompting consideration of secondary Raynaud syndrome.Despite medical therapy, progressive digital ischemia led to multiple finger amputations. During etiological investigation, anticoagulation tests and autoimmune analysis yielded negative results. A transesophageal echocardiogram was performed, revealing an irregular hyperechogenic mass on the anterior leaflet of the mitral valve without valve dysfunction, and a thoracic computed tomography scan with contrast showed an enlarged right paratracheal lymph node. Histopathological analysis from a transthoracic needle biopsy of the paratracheal lymph node revealed diffuse large B-cell lymphoma. The patient underwent aggressive R-CHOP chemotherapy, achieving a favorable complete response.ConclusionThis is a particular case involving the occurrence of NBTE and Raynaud phenomenon as the initial paraneoplastic manifestations in a previously healthy young man. Reports of NBTE associated with lymphoproliferative conditions are quite rare, with fewer than ten cases described in the literature. To our knowledge, this is the first case of NBTE specifically associated with diffuse large B-cell lymphoma.

Clinical Characteristics and Treatment Outcome of Waldenstrom Macroglobulinemia: Experience from a Tertiary Cancer Centre

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 % respectivel. 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.

High monocytic MDSC signature predicts multi-drug resistance and cancer relapse in non-Hodgkin lymphoma patients treated with R-CHOP.

Non-Hodgkin Lymphoma (NHL) is a heterogeneous lymphoproliferative malignancy with B cell origin. Combinatorial treatment of rituximab, cyclophsphamide, hydroxydaunorubicin, oncovin, prednisone (R-CHOP) is the standard treatment regimen for NHL, yielding a complete remission (CR) rate of 40-50%. Unfortunately, considerable patients undergo relapse after CR or initial treatment, resulting in poor clinical implications. Patient's response to chemotherapy varies widely from static disease to cancer recurrence and later is primarily associated with the development of multi-drug resistance (MDR). The immunosuppressive cells within the tumor microenvironment (TME) have become a crucial target for improving the therapy efficacy. However, a better understanding of their involvement is needed for distinctive response of NHL patients after receiving chemotherapy to design more effective front-line treatment algorithms based on reliable predictive biomarkers. Peripheral blood from 61 CD20+ NHL patients before and after chemotherapy was utilized for immunophenotyping by flow-cytometry at different phases of treatment. In-vivo and in-vitro doxorubicin (Dox) resistance models were developed with murine Dalton's lymphoma and Jurkat/Raji cell-lines respectively and impact of responsible immune cells on generation of drug resistance was studied by RT-PCR, flow-cytometry and colorimetric assays. Gene silencing, ChIP and western blot were performed to explore the involved signaling pathways. We observed a strong positive correlation between elevated level of CD33+CD11b+CD14+CD15- monocytic MDSCs (M-MDSC) and MDR in NHL relapse cohorts. We executed the role of M-MDSCs in fostering drug resistance phenomenon in doxorubicin-resistant cancer cells in both in-vitro, in-vivo models. Moreover, in-vitro supplementation of MDSCs in murine and human lymphoma culture augments early expression of MDR phenotypes than culture without MDSCs, correlated well with in-vitro drug efflux and tumor progression. We found that MDSC secreted cytokines IL-6, IL-10, IL-1β are the dominant factors elevating MDR expression in cancer cells, neutralization of MDSC secreted IL-6, IL-10, IL-1β reversed the MDR trait. Moreover, we identified MDSC secreted IL-6/IL-10/IL-1β induced STAT1/STAT3/NF-κβ signaling axis as a targeted cascade to promote early drug resistance in cancer cells. Our data suggests that screening patients for high titre of M-MDSCs might be considered as a new potential biomarker and treatment modality in overcoming chemo-resistance in NHL patients.

Mogamulizumab Combined with Extracorporeal Photopheresis as a Novel Therapy in Erythrodermic Cutaneous T-cell Lymphoma.

Primary cutaneous T-cell lymphomas (CTCLs) are rare lymphoproliferative malignancies characterized by significant morbidity and mortality in advanced disease stages. As curative approaches apart from allogeneic stem cell transplantation are lacking, establishing new treatment options, especially combination therapies, is crucial. This retrospective study included 11 patients with SS or MF receiving therapy with mogamulizumab in combination with ECP from four European expert centers. The response rates in the skin and blood as well as treatment use and adverse events (AE) were described. 8/11 patients (73%) showed an overall response (OR) in the skin. The mean mSWAT decreased from 98.2 ± 40.8 to 34.6 ± 23.8. The overall response rate (ORR) in the blood was 64% with two complete responses. During combination therapy, the mean number of Sézary cells decreased from 3365.3 × 106/L before treatment to 1268.6 × 106/L. The mean minimum known period without progress was 7.2 months in the skin and 7.6 months in the blood. The most common AEs were mogamulizumab-associated rash (MAR) (45.5%), anemia (27.3%), lymphocytopenia (27.8%), and infusion related reaction (16.7%). No AE led to treatment discontinuation. Our study presents the combination of mogamulizumab and ECP as an effective therapy in the blood and skin in CTCL with good tolerability, similar to mogamulizumab monotherapy.

An investigation on the nutritional status and support of in-patients with common variable immunodeficiency

The study aimed to reveal for the first time the clinical characteristics, nutritional and metabolic status and support of hospitalized patients with common variant immunodeficiency disease (CVID), and provide reference to improve the long-term nutritional management for such patients. This is a retrospective cross-sectional study. Through searching the electronic medical record system of Peking Union Medical College Hospital, the study included 33 consecutive in-patients with CVID diagnosed in Jan 2016 to Jun 2021, with the male to female ratio of 16∶17. All their medical data, nutritional assessment and intervention retrospectively summarized and analyzed. Data with normal distribution were described using (x¯±s), and analyzed with independent sample t-test. Data with non-normal distribution were compared with non-parametric test. The results showed that the median onset-age of the included patients was 22 (10.0,36.5) years old, and the median duration was 9.0 (2.0,16.0) years. All patients had recurrent infections involving various systems (33/33), with development of autoimmune diseases (8/33) and lymphoproliferative disease or malignancy (9/33) in some cases among them. The nutritional risk screening 2002 (NRS 2002) scores revealed that 85.19% of adults had an NRS 2002≥3 points, and 33.33% of children had a BMI-for-age z score<-2. Weight loss occurred in 66.67% of patients (22/33), while 87.88% (29/33), 69.70% (23/33) and 81.82% (27/33) of patients respectively had anemia, hypoalbuminemia and decreased prealbumin. Among 22 patients with micronutrients status evaluated, 77.27% (17/22), 22.73% (5/22) and 31.82% (7/22) of patients respectively had lowered serum iron, folate deficiency and vitamin B12 insufficiency. Six patients underwent 25-OH-VD3 measurement, and were all testified to have vitamin D deficiency. Among all patients with nutritional risk, 56.00% of them underwent nutritional support: oral nutritional supplements (14 cases), enteral feeding (4 cases) and parenteral nutrition (5 cases). In conclusion, the condition of malnutrition was prevalent in patients with CVID, but was under-recognized and undertreated to some degree.

Breast Cancer and Autoimmune Hemolytic Anemia: A Rare Paraneoplastic Syndrome

Autoimmune hemolytic anemia (AIHA) is a pathological process involving the destruction of red blood cells by the humoral immune system. Although there is a well-established relationship between the presence of AIHA and lymphoproliferative malignancies, AIHA rarely presents in association with solid malignancies. Few cases of solid cancer associated with AIHA have been reported. AIHA rarely presents as a paraneoplastic syndrome indicative of solid cancer. We report a case of breast cancer revealed by AIHA.

Clinical Outcome of Covid-19 in Haematologic Malignancy Patients with a Fourth Dose of Anti-Sars-Cov-2 Vaccine: A Final Epicovideha Report

Background: There is a general scepticism on anti-SARS-CoV-2 fourth dose efficacy due to lack of data. In pts with haematological malignancies (HM), this results that only few individuals received a fourth dose. We evaluted the clinical outcome of breakthrough SARS-CoV2 infections in HM who previously received a fourth dose of anti-SARS-CoV-2 vaccine, in particular HM from a multi-national European registry. Methods: Patients (pts) from the EPICOVIDEHA registry were eligible as long as they could fulfil these criteria: a) active HM within the last five years (ys) before COVID-19 diagnosis, b) pts ≥18 ys old, c) laboratory-based diagnosis of SARS-CoV-2 infection, and d) reception a fourth anti-SARS-CoV-2 dose before COVID-19 diagnosis. Results. As of August 2023, 6867 HM pts with SARS-CoV-2 infection have been registered in the EPICOVIDEHA registry. Out of these, 51 (0.7%) were diagnosed with COVID-19 after having received a fourth vaccine dose. Most of those (30/51, 58.8%) were male; median age was 71 ys of age (IQR 65-73), with only three pts below the age of 50 ys of age. Twelve pts (12/51, 23.5%) did not present any baseline underlying conditions besides the HM. Lymphoproliferative malignancies were prevalent (47/51, 92%). Most pts had a controlled HM at the time of COVID-19 diagnosis (30, 58.8%). Pts had their fourth vaccine dose at a median of 32 days (IQR 13-54) before COVID-19 diagnosis, almost exclusively mRNA based (50/51, 98%). COVID-19 remained asymptomatic or mild in almost all pts (49/51, 96%), with only one patient with critical infection (2%) requiring intensive care. Hospital admission rate was 47.1% with a median hospital stay of 9 days (IQR 5-14). Only 26 pts (51%) received a specific treatment for SARS-CoV-2, with almost all of them (18/26, 69.2%) receiving monoclonal antibodies. Pts were followed up for a median of 65 days (IQR 26-86) and only two died (3.9%) due to COVID-19. Conclusions. With the caution derived from the limited number of pts and the intrinsic nature of this study, our data show favourable clinical presentation and outcome of breakthrough SARS-CoV2 infections in HM who previously received a fourth dose of anti-SARS-CoV-2 vaccine. The data suggests that a second vaccine booster may be of particular importance to protect this vulnerable HM patient population from severe or potentially life-threatening COVID-19.

Single Cell RNA Sequencing Enables Identification of Mantle Cell Lymphoma Subclones with Drug-Resistant Profiles Already at Diagnosis and May be Used for Therapy Prognostication and Personalization

Mantle cell lymphoma (MCL) is a chronically relapsing B cell lymphoproliferative malignancy characterized by translocation t(11;14)(q13;q32), cyclin D1 overexpression and significant chromosomal instability. One of the main hypotheses of MCL relapses is a clonal evolution driven by therapy selection of subpopulations carrying adverse genetic and epigenetic aberrations. Our previous whole exome sequencing analysis of 25 MCL tumors showed that the majority of the detected single-nucleotide variants and copy number variants (CNV) were already detectable at diagnosis. To further analyze the subclonal structure of MCL at diagnosis and clonal evolution at relapse, we implemented single cell RNA sequencing analysis of five patients with MCL at diagnosis and at the first clinical relapse after failure of standard immunochemotherapy. All analyzed patients achieved at least partial remission. Fresh-frozen tumor cells were sorted to obtain Hoechst − CD45 + population which was processed using single cell 3′ protocol (10X Genomics). The libraries were paired-end sequenced on Novaseq 6000 (Illumina). The reads were aligned to GRCh38 human genome. The MCL cells were distinguished from the normal B cells based on of CCND1 expression and unsupervised clustering. CNVs were predicted using inferCNV package. These CNVs shared a high degree of similarity with the CNVs predicted using available exome sequencing data. The t-SNE representation of the data clearly showed unique positions for the malignant lymphocytes obtained from each of the five analyzed patients ( Figure 1a). In contrast, non-malignant cells (T cells, B cells and monocytes) have grouped together irrespective of the patient or compartment of origin ( Figure 1b). These data suggest two conclusions. First, each patient's malignant cells have unique genetic background. Second, the impact of the microenvironment does not override the impact of the genetic makeup of the non-malignant cells. The data thus suggest comparability of the malignant cells obtained from different compartments. Hierarchical clustering of the per-cell CNV profiles revealed subclonal heterogeneity of the MCL population in all analyzed compartments both at diagnosis and at relapse. In all analyzed patients the clustering identified several large subclones with significant differences (DG L) and at least one minor subclone (DG S) with significant similarities compared to the major clone detectable at relapse (R L). These data suggest that the majority of the diagnostic MCL cells (i.e., DG L clones) were indeed eliminated by therapy, which on clinical level corresponded to achieving remission. On the other hand, the data also suggest that MCL cells with CNV profiles highly similar to the major relapse clone (i.e., R L) were detectable already at diagnosis (i.e., DG S, Figure 1c). To gain a better insight into the biology of the DG S clones with potential drug-resistant phenotype, we analyzed transcriptome differences between DG S and DG L clones. For each patient we identified different sets of significantly upregulated genes in DG S compared to DG L. These included genes coding for important cell surface molecules ( MARCKS, CD52, CD79A, LTB), regulators of cell motility and cytoskeleton dynamics ( STMN1, SWAP70, CFL1, TUBB, TUBA1B, TMSB4X), transcription factor PRDM2, energy metabolism proteins ( MT-ND4, MT-CO1, ATP5MG), protein degradation proteins ( UBA52, PSMC4, UFD1, UBE2L3) and others. Among these genes, significant upregulation of TMSB4X, SWAP70, HLA-A, TUBB4B, RPS26, UBA52, PSMB2, SNRPG, ARPC1B, ATP5MG was detected in three out of five patients. Many of these genes code for oncogenes involved in cell motility and aggressiveness. To further characterize subclonal clusters in MCL population we used marker gene detection and subsequent gene set enrichment analysis, which identified cell adhesion molecules as major category upregulated in four out of five patients in clusters associated with relapse. Our data shows the applicability of the single cell genomic approaches not only to analyze subclonal heterogeneity for the study of disease biology, but also to identify drug-resistant subclones at diagnosis, predict response to various types of therapies thereby enabling therapy personalization. Acknowledgement: Supported by Grant Agency of the Czech Republic GA23-05474S and National Institute for Cancer Research (EXCELES) LX22NPO5102.

Abstract 17431: A Rare Cause of Constrictive Pericarditis in a Case of Adult T-cell Lymphoma

Introduction: Adult T-cell lymphoma (ATCL) is a rare T cell lymphoproliferative malignancy that typically presents with lymphadenopathy, hepatosplenomegaly, lytic lesions, hypercalcemia or skin lesions. Cardiac involvement is rare. Case presentation: A 66-year-old male with a history of chronic kidney disease and hypertension presented with dyspnea. Transthoracic echocardiography revealed a moderate pericardial effusion and a left ventricular ejection fraction of 45%. Further workup with MRI and transesophageal echocardiography found extensive circumferential pericardial thickening with enhancement and extensive mediastinal and hilar lymphadenopathy along with a mass along the course of the superior vena cava with extension of disease into the right atrium along the right atrial wall (Figure 1). Endobronchial biopsy of the mediastinal lymph nodes was positive for T-cell lymphoma. Chemotherapy was initiated; however, the patient decided to focus on comfort measures only. Discussion: Cardiac involvement in ATCL is rare and usually detected in postmortem autopsies. Incidence is unknown, and experience is limited to case reports. The largest case series to date found 16 patients who had antemortem diagnosis of symptomatic cardiac involvement of ATCL. The characteristic features included infiltration of the myocardium, pericardial effusion, valvular lesions, and masses in the atrium, similar to what was seen in our patient. To our knowledge, there have been no reported cases of ATCL causing constriction. Prognosis is poor, with median survival of 5 months after development of symptoms (n = 15, range 0-120 months). Conclusion: The incidence of cardiac ATCL is unknown, but it is an extremely rare occurrence. It can present with a wide variety of cardiac involvement, including constriction. The prognosis of cardiac ATCL remains poor.