Diffuse B-cell Research Articles

Usefulness of the 3-hydroxykynurenine/kynurenic acid ratio as a diagnostic biomarker for diffuse larger B-cell lymphoma.

Reports have shown that the kynurenine pathway, one of the pathways by which tryptophan is metabolized, is activated in patients with diffuse large B-cell lymphoma (DLBCL). Activation of the kynurenine pathway triggers the production of various metabolites, such as kynurenine (Kyn), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), kynurenic acid (KA) and anthranilic acid (AA), which contribute to immune tolerance. The current study aimed to investigate the changes in metabolites of kynurenine pathway in DLBCL patients and evaluate their performance predicting DLBCL. Changes in metabolites of kynurenine pathway were examined using high-performance liquid chromatography in 35 DLBCL patients (age 61.2 ± 13.5 years) and 44 healthy controls (age 58.5 ± 12.5 years). DLBCL patients had significantly higher levels of 3-HK, AA, and 3-HAA but lower levels of Tryptophan (Trp) and KA compared to healthy controls. Given that the ratio of each metabolite represents the change in the Kyn pathway, the 3-HK/KA ratio was examined. Notably, DLBCL patients had a significantly higher 3-HK/KA ratio compared to healthy controls. In DLBCL, the area under the receiver operative characteristic (ROC) curve for 3-HK/KA (0.999) was higher than that for lactate dehydrogenase (0.885) and comparable to that for soluble interleukin-2 receptor (sIL-2R) (0.997). Based on ROC curve analysis, the 3-HK/KA ratio was found to be useful biomarker for the diagnosis of DLBCL. Our results suggest that the 3-HK/KA ratio is a clinically useful biomarker of DLBCL. Moreover, its combination with existing markers, such as sIL-2R, can improve its effectiveness of diagnosing DLBCL.

S5074 Mycophenolate-Associated Diffuse B-Cell Lymphoproliferative Disorder Presenting as Abdominal Pain in a Heart Transplant Patient

S5074 Mycophenolate-Associated Diffuse B-Cell Lymphoproliferative Disorder Presenting as Abdominal Pain in a Heart Transplant Patient

Understanding splenic B-cell lymphoma/leukaemia with prominent nucleoli: Diagnosis, underpinnings for disease classification and future directions.

The 5th edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5) introduced a new category, splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN). The diagnostic entity B-cell prolymphocytic leukaemia (B-PLL) has been discontinued and the category of hairy cell leukaemia variant (HCLv) has been conceptually reframed. B-PLL and HCLv diagnoses were uncommon. Overlap existed between B-PLL and other indolent lymphomas like chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). HCLv lacked consistent cytomorphological, immunophenotypic and genetic features. To address these issues, the WHO-HAEM5 classification has introduced SBLPN to serve as a temporary holding ground for entities that do not neatly fit into the existing classification. Cases previously classified as CD5-negative B-PLL and HCLv fall under the SBLPN category. Some splenic marginal zone lymphoma and splenic diffuse red pulp small B-cell lymphoma cases with higher number of medium or large nucleolated B cells would also be classified as SBLPN under the WHO-HAEM5. This review explores the rationale for discontinuing B-PLL and HCLv diagnoses. It then examines the concept of SBLPN, offers practical guidance for diagnosis and discusses future directions in classifying splenic B-cell lymphomas.

Understanding P-Rex regulation: structural breakthroughs and emerging perspectives.

Rho GTPases are a family of highly conserved G proteins that regulate numerous cellular processes, including cytoskeleton organisation, migration, and proliferation. The 20 canonical Rho GTPases are regulated by ∼85 guanine nucleotide exchange factors (GEFs), with the largest family being the 71 Diffuse B-cell Lymphoma (Dbl) GEFs. Dbl GEFs promote GTPase activity through the highly conserved Dbl homology domain. The specificity of GEF activity, and consequently GTPase activity, lies in the regulation and structures of the GEFs themselves. Dbl GEFs contain various accessory domains that regulate GEF activity by controlling subcellular localisation, protein interactions, and often autoinhibition. This review focuses on the two phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3)-dependent Rac exchangers (P-Rex), particularly the structural basis of P-Rex1 autoinhibition and synergistic activation. First, we discuss structures that highlight the conservation of P-Rex catalytic and phosphoinositide binding activities. We then explore recent breakthroughs in uncovering the structural basis for P-Rex1 autoinhibition and detail the proposed minimal two-step model of how PI(3,4,5)P3 and Gβγ synergistically activate P-Rex1 at the membrane. Additionally, we discuss the further layers of P-Rex regulation provided by phosphorylation and P-Rex2-PTEN coinhibitory complex formation, although these mechanisms remain incompletely understood. Finally, we leverage the available data to infer how cancer-associated mutations in P-Rex2 destabilise autoinhibition and evade PTEN coinhibitory complex formation, leading to increased P-Rex2 GEF activity and driving cancer progression and metastasis.

A constellation of cutaneous reactions to CAR-T cell therapy.

This case report describes a cascading purpuric eruption progressing to bullae, ulceration and hypergranulation in a 76-year-old patient with diffuse B-cell lymphoma, following chimeric antigen receptor T-cell therapy. It is crucial to document and report these cutaneous reactions to raise awareness, improve management and monitor patient outcomes.

Laparoscopic Partial Splenectomy May Be Valuable for the Diagnosis of Malignant Lymphoma: A Case Report.

Diagnosing primary splenic malignant lymphoma (PSML) is challenging due to the non-specific nature of splenomegaly, necessitating splenic biopsy for confirmation. However, performing partial splenic resection for diagnostic purposes is an elective procedure due to the risk of major hemorrhage. Despite the longstanding practice of splenectomy over the past few decades, it remains invasive and may result in severe early or late complications. Hence, we present laparoscopic partial splenectomy (LPS) in a patient suspicious of PSML for diagnostic purposes in this study. An 81-year-old woman presented to our hospital with a one-month history of fever and dry cough. Atypical cells had been detected in her peripheral blood nine months ago. However, at that time, a bone marrow examination did not reveal any atypical cells. The laboratory tests revealed a soluble interleukin receptor-2 levels of 4,667 U/dl and atypical cells were also found in peripheral blood. Abdominal computed tomography showed splenomegaly without any other relevant findings. These findings are suspicious of PSML and LPS without vessel ligation was performed and a small fraction of the spleen from the inferior pole measuring 1.8×1.0 cm was resected. The operation lasted for 63 min with minimal estimated blood loss. Histopathological findings were compatible with the diagnosis of diffuse B-cell lymphoma. The postoperative clinical course was uneventful, and splenomegaly demonstrated improvement six months after the operation. LPS without vessel ligation for biopsy may be valuable for the diagnosis of malignant lymphoma, particularly when there are no swollen lymph nodes, as it offers a less invasive approach.

Abstract 5210: The Prognostic value of serum TK1 protein determinations using AroCell TK210 ELISA in DLBCL patients treated with R CHOP

Abstract Background: Diffuse large-cell B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin’s lymphomas (NHL) that accounts for approximately 25% of the patients. Earlier studies demonstrated the prognostic value of serum thymidine kinase 1 (STK1) activity determinations in different hematological malignancies. To date, the prognostic value of STK1 protein concentration in patients with DLBCL treated with R-CHOP has not been investigated. The purpose of this retrospective study was to determine the value of high TK levels on Overall survival among DLBCL patients treated with R-CHOP as first-line treatment. Materials and Methods: The study included 146 patients diagnosed with DLBCL between 2010 and 2016 from the Uppsala-Umeå Comprehensive Cancer Consortium (U-CAN). All patients included were treated using the standard chemotherapy regimen R-CHOP. Serum samples were collected at the time of diagnosis, during the treatment, 1 year after treatment, and after relapse. Non-infected and apparently healthy persons, matched to the DLBCL patients (57 males and 88 females), served as controls. The TK1 protein levels in all serum samples were determined by using AroCell TK 210 ELISA (AroCell AB, Sweden). The TK1 protein concentration was expressed as μg/L. Results: The TK1 concentrations in sera from DLBCL patients before treatment were significantly higher compared to the concentrations in healthy individuals, median 0.44 μg/L (IQ range 0.22 to 1.06 μg/L) vs. median 0.22 μg/L (IQ range 0.18 to 0.29 μg/L, P<0.00001). Serum TK1 was also significantly higher in patients with more advanced stages (P<0.00001), higher IPI (P<0.00001), and in patients with B-symptoms (P<0.0001). Patients with STK1 protein levels below the cut-off value (0.45 μg/L) had significantly better OS and DFS (P=0.04 and P=0.0006, respectively) compared to patients with STK1 concentration above the cut-off. In multivariate analyses, dichotomized S-TK1 measurements before treatment were found to be significant for the risk of relapse in combination with either aaIPI or IPI (p<0.01). Conclusions: These results confirmed that STK1 concentration correlates with risk factors such as tumor burden, Ann Arbor stage, and IPI. In conclusion, patients with high TK1 concentrations at the time of diagnosis have short overall survival and STK1 concentrations are apparently a prognostic indicator for survival in patients treated with modern chemo-immunotherapy. Citation Format: Kiran Jagarlamudi, Gustaf Hedström, Per Venge, Staffan Eriksson, Daniel Molin, Gunilla Enblad. The Prognostic value of serum TK1 protein determinations using AroCell TK210 ELISA in DLBCL patients treated with R CHOP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5210.

Doença de Castleman: Um relato de caso

Case presentation: A 59-year-old asymptomatic male patient was admitted for treatment of diffuse B-cell non-Hodgkin's lymphoma. Contrast-enhanced CT scans revealed a nodular lesion with intense enhancement, measuring 4.5 cm in the left paravertebral region, with fine calcification in between, located in the D9 and D10 planes, where he was referred to the thoracic surgery team.

Diffuse B-Cell Lymphoma of the Mandible Disguised as Acute Osteomyelitis.

Primary bone lymphoma (PBL) is a rare form of extra nodal non-Hodgkin's lymphoma (NHL). We describe a 39-year-old-male with no medical history who presented with unilateral facial swelling following a tooth extraction. Initial diagnoses after various presentations over the course of three weeks, based on inflammatory and infectious aetiologies. However, the patient was ultimately diagnosed with diffuse large B-cell lymphoma. Symptoms of PBL are very similar to inflammatory and infectious diseases of the bone, such as osteomyelitis or osteonecrosis. Clinical features of PBL involving the head and neck include persistent jaw pain, tooth mobility secondary to extensive destruction of bone, and in advanced cases, lip numbness and swelling. On examination it may present as an exposed necrotic bone with surrounding soft tissue oedema. Misdiagnosis of these lesions as an infectious or inflammatory aetiology may lead to an unnecessary delay in lymphoma treatment, and subsequently worsen the prognosis if caught at a later stage. Therefore, any concerning lesion, especially in the oral cavity, must be subjected to early histopathological evaluation to differentiate PBL from osteomyelitis and/or osteonecrosis. This case report highlights the importance of an early histopathological evaluation to prevent delay in the diagnosis of primary bone lymphomas. Resemblance in symptoms: Primary bone lymphoma (PBL) symptoms overlap with bone infections, necessitating careful consideration and differential diagnosis to prevent misjudgment.Head and neck manifestations: recognising PBL's signs in the head and neck region, such as jaw pain and bone destruction, aids in timely identification and treatment.Timely biopsy significance: swift histopathological assessment for suspicious lesions is critical to avoid delays in diagnosing primary bone lymphomas.

The impact of peripheral blood cell ratios in dogs with diffuse B-cellsmall lymphocytic lymphoma treated with CHOP protocol

In this study, pre-chemotherapy hematological values of 14 dogs diagnosed with diffuse B-cell small lymphocytic lymphoma were compared with the hematological data of 26 healthy dogs. Neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), platelet/lymphocyte ratio (PLR), and platelet/neutrophil ratio (PNR) were evaluated between two groups. Anemia and an increased total leukocyte count were observed in dogs with lymphoma compared to healthy ones. The PNR value was found to be significantly lower in dogs with lymphoma. It was concluded that more comprehensive studies are needed to clearly understand the diagnostic and prognostic importance of hematological parameters in B-cell small lymphocytic lymphoma of dogs.

Activity and Event-Free Survival in Intermediate Grade Non-Hodgkin's Lymphoma Treated with Chemoimmunotherapy Utilizing Single Dose Intravenous Methylprednisolone in Lieu of Oral Prednisone

Schein et al first noted that patients with intermediate grade lymphoma treated with combination chemotherapy leading to complete response lasting 24 months were likely to remain relapse-free (Schein, Chabner, Canellos, Young, Berard, DeVita,1975). Subsequent changes in that original C-MOPP regimen have included the use of anthracyclines and rituximab. The University of Iowa/Mayo Clinic Molecular Epidemiology Resource and the Groupe d'Etude des Lymphomes de l'Adulte (GELA) program found that patients with diffuse large B-cell lymphoma achieving event-free status at 24 months with chemoimmunotherapy have subsequent overall survival equivalent to that of the general population (Maurer, 2014). While Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin], Oncovin [vincristine] and Prednisone (RCHOP) has served as the reference therapy for intermediate grade non-Hodgkin's lymphoma for two decades (Coiffier, 2002; Pfreundschuh, 2006), oral prednisone given daily for 5 days is problematic for individuals with underlying medical conditions such as diabetes, sleep or psychiatric disorders, or gastrointestinal symptoms. In this retrospective study between January, 2007 and March, 2023, 33 patients with intermediate grade Non-Hodgkin's Lymphoma, (26 with Diffuse Large B-cell subtype, 6 with follicular grade III, 1 with T-cell Immunoblastic) received Methylprednisolone 125 mg intravenously on day 1 instead of oral prednisone for 5 days as part of anthracycline-based treatment that consisted of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 2 mg (total dose) all given intravenously on day 1 with peg-filgastrim 6 mg subcutaneously on day 2 every 21 days. Three patients received mitoxantrone 12 mg/m2 intravenously on day 1 instead of doxorubicin. Patient characteristics: 23 males/10 females, median age-55 (range: 24-85), stages: IV (17 patients), III (4 patients), II (12 patients), B symptoms (16), subtypes: non-germinal center (13), germinal center (12), diffuse B-cell NOS (1), follicular grade III (6), T-cell Immunoblastic (1). Median cycles received (range): 6 (5-8). No patients required dose reduction or omission of methylprednisolone. Complete responses (determined by PET/CT) occurred in 26 (81%). 1 additional patient was PET negative but was lost to follow-up and is not counted as CR here. Three patients having PR after chemoimmunotherapy were converted to CR after involved site radiation. Two other patients achieved only short-lived PR. One patient is too early to evaluate. The median event-free survival has not been reached at 24.8+ months. Median overall survival exceeds 32.6+ months. Chemoimmunotherapy with the substitution of intravenous methylprednisolone on day 1 in place of 5 days of oral prednisone displays activity in intermediate-grade non-Hodgkin lymphoma and event-free survival beyond 24 months.

Splenic B Cell Lymphoma Innate Immune Cells: Detection of Red Versus White Pulp Lymphoma Differences in NK Cell Populations By High-Parameter Flow Cytometry

Introduction Splenic B-cell lymphomas, (SLs, total incidence ~1:100,000/year) comprise four distinct indolent B-cell non-Hodgkin lymphomas. Three predominantly involve the red pulp of the spleen (classical hairy cell leukemia (HCL), hairy cell leukemia variant (HCLv) and splenic diffuse red pulp small B-cell lymphoma (SDRPL)) and the fourth predominantly involves the white pulp (splenic marginal zone lymphoma (SMZL)). HCL is usually diagnosed by detection of an activation mutation in BRAF and responds well to treatment. We focused our study on the remaining three diseases, which have overlapping clinical presentations with only subtle differences in their morphology and phenotypes, but have considerable differences in prognosis, response to treatment and outcome. The white pulp lymphoma SMZL generally has good treatment responses and longer survival, whereas the red pulp SLs, HCLv and SDRPL are less responsive to treatments with shorter survival. Cells of the tumor microenvironment (TME) may have distinct characteristics between these three diseases. We hypothesized that TME innate immune cells from red pulp SLs (HCLv, and SDRPL) would be similar to each other and distinct from the white pulp SL, SMZL.In this study, we report that natural killer (NK) cells, which are important innate immune cells critical for immune surveillance, vary in proportions among red and white pulp SLs. Methods We studied splenectomy specimens from patients with SMZL (n=8), HCLv (n=8), SDRPL (n=7), and controls (healthy, post-trauma, n=8). Cryo-preserved bulk splenic suspension cell isolates from fresh (<4 hour) surgical specimens and intact formalin-fixed paraffin embedded (FFPE) tissue sections were used. Human specimen collection and usage was conducted with written informed consent after approval of the Institutional Research Subjects Review Board. FFPE tissue sections were studied by immunohistochemical (IHC) staining and splenic suspension cells were analyzed by high-parameter fluorescence flow cytometry using a Cytek Aurora spectral flow cytometer with a 25-color myeloid and a 28-color NK/B-cell panel. Results IHC characterization showed an extensive network of innate immune cells as reflected by CD163 + macrophages. Using high-parameter flow cytometry, we focused on innate immune cells in the non-B- non-T-cell (CD3 -CD19 -) population. The average proportions of this population were: NK cells 25-36%, monocyte/macrophages 20-34%, dendritic cells 5-11%, and granulocytes 2%. Among the patient groups, the median percentage of NK cells was greater for controls (34%) and SMZL (35%) as compared to red pulp lymphomas (HCLv (28%), SDRPL (24%)). Next, we examined NK subtypes: 1) cytotoxic NK cells (CD56 +CD16 +), 2) cytokine-secreting weakly cytotoxic NK cells (CD56 +CD16 -), and 3) undefined NK cells (CD56 -CD16 +) as a median percentage of total NK cells. The major subtype for control and SMZL was CD56 +CD16 - with values of 58 and 44%, respectively. This subtype comprises only 38%-40% of red pulp SLs. Proportionally the CD56 +CD16 + subtype was the largest for red pulp SLs at 52-57% as compared to 30% for control and 38% for SMZL. The remaining CD56 -CD16 + NK cell subtype was generally higher among red pulp SLs (HCLv (9%), SDRPL (12%)) as compared to control (6%) and SMZL (4%) patients. The increase in cytotoxic CD56 +CD16 + subtype among red pulp SLs was confirmed by measuring the percentage of granzymeB +perforin + cells among mature cytotoxic NK cells (CD56 +CD16 +/ CD57 +NKG2a -). SLs had higher proportions of this NK phenotype (78-86% compared to control 69%) and red pulp SLs had the most granzymeB +perforin + proportions with 82 and 86% for HCLv and SDRPL, respectively. Discussion In summary, spleens from patients with SMZL had similar percentages of total NK cells to controls, with lower percentages in red pulp SLs. All SLs had a higher percentage of cytotoxic NK cells than control, with the red pulp SLs having the most. These data suggest that monoclonal antibody treatments targeting SL antigen, such as anti-CD20, may be effective by activating cytotoxic NK cell to target lymphoma cells by antibody-dependent cellular cytotoxicity. Thus, uncovering the characteristics of the TME may aid the development of non-invasive diagnostic procedures and/or precision therapies.

CTNI-83. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY CNS DIFFUSE B-CELL LYMPHOMA

Abstract We report our experience treating 25 patients with newly diagnosed primary CNS diffuse B-cell lymphoma with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 66 y (range 30-85); 12 patients were men and 13 were women. Twenty-three had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 18 patients completed initial chemotherapy. Sixteen of these 18 went on to transplantation; one patient had had early disease progression, and in one no stem cells could be collected. Five patients (median 73 y; range 64-85 y) died early after 1-2 cycles. The causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One of the 16 patients who completed the entire regimen including transplantation died of fungal pneumonia and the other 15 experienced no serious acute toxicity. One patient had late disease progression and 2 developed symptomatic leukoencephalopathy. Seventeen of the 25 patients remain alive. Median TTP for the cohort is 605 days, and OS 738 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 65 y shows that the regimen is too toxic for older individuals.

Hairy Cell Leukemia with Severe Leukocytosis

Introduction Hairy cell leukemia (HCL) is a rare indolent mature B-cells neoplasm that typically manifests with pancytopenia and splenomegaly. Nevertheless, significant splenomegaly, high hairy cells count in the blood, elevated β 2 microglobulin, and increased LDH can predict resistance to purine analogs. The absence of BRAF V600E mutation in HCL is rare and is associated with poorer outcomes. Case Presentation A 68-year-old female patient presented with symptomatic massive splenomegaly, leukocytosis (89,000 /microliter), monocytopenia, and thrombocytopenia. β 2microgobulin level was 4.4 mcg/L. Lactate dehydrogenase was 521 U/L. Peripheral blood and bone marrow examinations revealed typical hairy cells morphology, and the cells were positive for CD19, CD20, CD103, CD25, CD11c, CD200 (dim), and surface-Kappa. CD38 was negative. BRAF V600E result was wild-type. IGHV was mutated (IGHV3-49). She received first-line therapy with a 5-day course of Cladribine (0.15 mg/kg/day) with initial resolution of leukocytosis, normalization of platelets, and a 50% reduction in spleen size. This was followed by consolidation with an 8-weekly course of Rituximab (375 mg/m 2). Soon after the 2 nd dose of Rituximab, leukocytosis recurred, and she was initiated on second-line therapy with Bendamustine (90 mg/m 2 on days 1 and 2) along with Rituximab (BR). She has not achieved any durable response following two cycles of BR. Unfortunately, she suffered a septic shock requiring admission to our intensive care unit. Upon routine mental status evaluation, brain MRI revealed innumerable supratentorial and infratentorial bilateral acute/subacute and old microhemorrhages (Figure 1). This prompted further evaluation of unexplained recurrent episodes of pulmonary hemorrhages while on mechanical ventilation that were found to be secondary to pulmonary end-arterial cavitating lesions suggestive of hairy cells infiltration (Figure 2 arrowheads). As she was clinically unstable, we attempted to control leukocytosis with corticosteroids, leukapheresis aggressively and started the patient on Ibrutinib, but she succumbed to her disease. Discussion Recently, the 5 th edition of the World Health Organization classification of hematolymphoid tumors highlighted the splenic B-cell lymphoma and leukemia family that encompasses hairy cell leukemia (HCL), splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN), formerly known as hairy-cell leukemia variant, splenic diffuse red pulp small B-cell lymphoma (SDRPL) and splenic marginal zone lymphoma (SMZL). HCL is typically an indolent mature B-cell neoplasm with characteristic pathologic features that preferentially insinuate the bone marrow and the spleen causing impaired hematopoiesis and splenomegaly. Unlike other disorders within this group, HCL commonly harbors BRAF V600E somatic mutation in almost all cases. Rarely, patients with HCL can have extramedullary involvement by the malignant cells. Leukocytosis in HCL appears to increase the risk of developing extramedullary lesions that can present unique clinical challenges necessitating early and effective therapy. According to the literature, brain lesions in HCL were described in three other cases, and leukocytosis was a common denominator. Our patient with significant leukocytosis had brainand pulmonary lesions, and the latter was the cause of her demise due tounusually aggressive and refractory disease. Therefore, we hypothesize that leukocytosis in HCL can be “the tip of the iceberg”. The higher the leukocytosis, the higher the burden of extramedullary disease, as in our case, who had simultaneous lesions in the brain and lungs. Patients with HCL and leukocytosis may warrant initial diagnostic evaluation to ensure the absence of potentially sinister lesions, which can inform subsequent monitoring and management plans. Additionally, more novel therapies could be considered sooner in the treatment course to control the disease and these lesions. Finally, our patient did not harbor BRAF V600E mutation, which likely resulted in further worse outcomes and limited the usage of targeted therapies like BRAF inhibitors.

Adverse cutaneous reaction to hydroxychloroquine in a patient with anti-SAE-1-positive dermatomyositis and a history of diffuse large B-cell lymphoma

This case report details the cutaneous findings of a patient with a history of diffuse B-cell lymphoma and SAE-1–positive dermatomyositis who developed an adverse cutaneous reaction after initiation of treatment with hydroxychloroquine. This adds to the sparse literature available detailing the correlation between anti–SAE-1 autoantibodies in dermatomyositis and the unique adverse cutaneous reactions in patients taking hydroxychloroquine. Additionally, our patient developed dermatomyositis years after a diagnosis of lymphoma. This report highlights the utility of the myositis-specific antibody panel to guide diagnosis and management, as well as the potential for developing dermatomyositis years after a lymphoma diagnosis.

CDC6, a key replication licensing factor, is overexpressed and confers poor prognosis in diffuse large B-cell lymphoma

BackgroundCell division cycle 6 (CDC6) is a key licensing factor in the assembly of pre-replicative complexes at origins of replication. The role of CDC6 in the pathogenesis of in diffuse larger B-cell lymphoma (DLBCL) remains unknown. We aim to investigate the effects of CDC6 on the proliferation, apoptosis and cell cycle regulation in DLBCL cells, delineate its underlying mechanism, and to correlate CDC6 expression with clinical characteristics and prognosis of patients with DLBCL.MethodsInitial bioinformatic analysis was performed to screen the potential role of CDC6 in DLBCL. Lentiviral constructs harboring CDC6 or shCDC6 was transfected to overexpress or knockdown CDC6 in SUDHL4 and OCI-LY7 cells. The cell proliferation was evaluated by CCK-8 assay, cell apoptosis was detected by Annexin-V APC/7-AAD double staining, and cell cycle was measured by flow cytometry. Real time quantitative PCR and western blot was used to characterize CDC6 expression and its downstream signaling pathways. The clinical data of DLBCL patients were retrospectively reviewed, the CDC6 expression in DLBCL or lymph node reactive hyperplasia tissues was evaluated by immunohistochemistry.ResultsIn silico data suggest that CDC6 overexpression is associated with inferior prognosis of DLBCL. We found that CDC6 overexpression increased SUDHL4 or OCI-LY7 cell proliferation, while knockdown of CDC6 inhibited cell proliferation in a time-dependent manner. Upon overexpression, CDC6 reduced cells in G1 phase and did not affect cell apoptosis; CDC6 knockdown led to significant cell cycle arrest in G1 phase and increase in cell apoptosis. Western blot showed that CDC6 inhibited the expression of INK4, E-Cadherin and ATR, accompanied by increased Bcl-2 and deceased Bax expression. The CDC6 protein was overexpressed DLBCL compared with lymph node reactive hyperplasia, and CDC6 overexpression was associated with non-GCB subtype, and conferred poor PFS and OS in patients with DLBCL.ConclusionCDC6 promotes cell proliferation and survival of DLBCL cells through regulation of G1/S cell cycle checkpoint and apoptosis. CDC6 is overexpressed and serves as a novel prognostic marker in DLBCL.

Advances in Polatuzumab Vedotin-PIIQ Therapy: A Review of Treatment Efficacy in Diffuse Large B Cell Lymphoma and High-Grade B Cell Lymphoma.

Polatuzumab vedotin (PV) is an antibody-drug conjugate that has shown promising results in the treatment of diffuse B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL). This abstract summarizes the current understanding of PV's use in these malignancies based on available clinical data. Multiple clinical trials have evaluated PV as a part of combination therapy regimens in relapsed/refractory DLBCL and HGBCL. The pivotal Phase II study, GO29365, demonstrated that PV in combination with bendamustine and rituximab (BR) significantly improved progression-free survival and overall survival compared to BR alone in patients with relapsed/refractory DLBCL who ineligible for stem cell transplantation were. Subsequently, the US Food and Drug Administration granted accelerated approval to PV in this setting. PV's mechanism of action involves targeting CD79b, a cell surface receptor expressed in B-cell malignancies, and delivering the cytotoxic agent monomethyl auristatin E to CD79b-expressing cells. This approach enhances the selective killing of cancer cells while sparing normal cells. The safety profile of PV is generally manageable, with adverse events including infusion-related reactions, cytopenia, peripheral neuropathy, and infections. Overall, PV has emerged as a valuable treatment option for patients with relapsed/refractory DLBCL and HGBCL, offering improved outcomes when combined with appropriate chemotherapy regimens. Ongoing research and clinical trials are further exploring PV's potential in various treatment settings, including frontline therapy and in combination with other novel agents.

Lymphoma Accompanyıng Pneumoconıosıs; Case Report

Non-Hodgkin Lymphoma (NHL) is the most common hematological malignancy, and Diffuse Large B-Cell Lymphoma (DLBCL) is the most common histological type. A 56-year-old male patient was admitted to our clinic with complaints of shortness of breath and fatigue for 1 month. It was learned in his professional history that he had been a dental technician for 30 years. He was diagnosed with pneumoconiosis in 2020 and his chest radiograph was q/t 3/3 according to the International Labor Organization (ILO) International Classification of pneumoconiosis radiographs. Laboratory examinations revealed an increase in erythrocyte sedimentation rate (ESR 50 mm/h) and serum lactate dehydrogenase (LDH 368 IU/L) levels. On thoracic computed tomography (CT), enlarged lymph nodes and lymphadenopathies (LAP) with local conglomeration and calcifications in the mediastinal, subcarinal and bilateral hilar areas were seen. Widely disseminated inhomogeneous mass-like consolidation areas, including internal calcifications, extending from the hilum to the parenchyma in both lungs, were observed more prominently in the right middle zone. Diffuse interstitial thickenings, infiltrations and centrilobular nodular density increases in both lungs, nodular consolidated areas with recessed contours and nodules and ground glass densities were observed, especially in the left upper zone. In the lateral part of the left 5th rib, a heterogeneous soft tissue mass of approximately 12x5 cm, causing cortical destruction, invading the surrounding soft tissues and muscle planes, and containing internal cystic-necrotic components was observed. On abdominal CT, enlarged lymph nodes and LAPs, some of which contain calcifications, were observed in the abdomen. The pathology result was reported as Diffuse B-Cell Lymphoma in the patient who underwent transthoracic biopsy due to radiographic appearances that are not typical for PMF. Here, we presented a case of pneumoconiosis with occupational carcinogen exposure and presenting with lymphoma.

Neurolymphomatosis in Non-Hodgkin's Lymphoma

non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of hematopoietic puffins, with diphun B-velicocyclotinous lymphoma accounting for 25% of all NHLs and having the greatest midline to axis growth (Leeuwenуе et al., 2014). Of all NHLs, the central and peripheral nervous systems are most often affected in diphytic B-lycocytic lymphoma (Padala, & Kallam, 2022. Liu, & Barta, 2019). In NHL, infiltration of cranial and peripheral nerves can be detected - neurolymphomatosis (NL) emerges. NL is a very rare condition and occurs in about 0.2% of patients with NHL (Baehring, Damek, Martin, Betensky & Hochberg, 2003). These infiltrations can manifest with detection of mononeuropathy, multiple neuropathy, symmetric neuropathy or plexopathy (Grisold W., Grisold A., Marosi, Meng, & Briani, 2015). The aim of the work was to study the features of the clinical course, diagnosis and treatment of neurolymphomatosis in the form of lesions of the trigeminal, facial cranial nerve and the left ulnar nerve in diffuse B-bollichelial non-Hodgkin lymphoma based on a clinical case. We present a review of a clinical case of peripheral nervous system involvement in a patient born in 1977 with diffuse B-cell non-Hodgkin's lymphoma. The diagnosis was established on the basis of clinical manifestations of lesions of the branches of the trigeminal and left facial nerves, the left ulnar nerve, magnetic resonance imaging of the head and brain, electroneuromyography, and immunohistochemical examination of the infiltrate biopsy from the affected buccal branch of the left facial nerve. In March 2022, the patient developed moderate peripheral paresis of the mimic muscles on the left side, burning pain with impaired tactile and pain sensitivity of the dorsum, wing of the nose, and left instep. A week later there was a decrease in the strength, tactile and pain sensitivity, and patience of the fourth and fifth fingers of the left hand. Within a month, the burning pain had spread to the left cheek, periorbital, and chin areas of the face. In 2021, the patient was diagnosed with B-bollichelial non-Hodgkin's lymphoma with involvement of the right axillary, supraclavicular lymph nodes, left breast, followed by chemotherapy and clinical remission. Magnetic resonance imaging of the head revealed a perineural lesion of the third branch of the right trigeminal nerve, the second branch of the left trigeminal nerve, and the cheek branch of the left facial nerve. Electroneuromyography revealed an axonal lesion of the left ulnar nerve. The results of examination of the infiltrate biopsy from the affected buccal branch of the facial nerve specimens confirmed non-Hodgkin's diffuse B-cell lymphoma, GCB-phenotype and nerve damage due to NHL. Treatment of multiple neuropathy with glucocorticosteroids, nonsteroidal anti-inflammatory drugs, acelicholinesterase inhibitors, and specific chemotherapy resulted in limited therapeutic effect. Prescribing pregabalin resulted in decreased reduction of neuropathic facial pain. Thus, neurolymphomatosis is a rather rare manifestation of non-Hodgkin's lymphomas, the use of magnetic resonance imaging of the head and brain as well as immunohistochemical examination of the affected nerve infiltrate biopsy is important to confirm the diagnosis.
 In the Ukrainian scientific medical literature, there are few descriptions of cases of neurolymphomatosis in NHL, although they occur in patients, and it is necessary to describe in more detail the peculiarities of the collicular course of the diagenesis and treatment in these cases.

Primary plasmablastic lymphoma of the gastrointestinal tract: A series of 13 HIV-negative cases and a review of literature

ContextPrimary gastrointestinal plasmablastic lymphoma (GI-PBL) is a rare variant of diffuse B-cell lymphoma with an aggressive clinical course. PBL was initially reported among HIV-positive patients; however, subsequent studies have shown that it also occurs among HIV-negative patients. Its clinical characteristics remain poorly understood. This study aims to retrospectively analyze the clinicopathological findings of primary GI-PBLs in HIV-negative patients. DesignPrimary HIV-negative GI-PBL cases from 2008 to 2022 were reviewed. Clinicopathologic features and outcomes were analyzed. ResultsThe cohort of 13 patients had a male-to-female ratio of 9:1 (3 patients' genders not available), with an average age of 61 (range, 30–92) years. The most involved location was the colon (n = 7 [53.8 %]), followed by the small bowel (n = 3 [23.1 %]), stomach (n = 2 [15.4 %]), rectum (n = 1 [7.7 %]), and anus (n = 1 [7.7 %]). Most patients (n = 10 [77 %]) showed isolated GI tract involvement. Eight patients had chronic inflammatory and/or immunocompromised status, including 4 with inflammatory bowel disease (all of whom underwent treatment), 3 with post–organ transplant status, and 1 with irritable bowel syndrome. All cases exhibited cytokeratin-/CD20-/PAX-5-/CD138+ and/or MUM1+ immunophenotype. Based on available data, 8 of 11 (72.7 %) patients had Epstein-Barr virus reactivation. Among 11 patients with follow-up data, the mean follow-up duration was 13.5 (range, 3–40) months; at the end of follow-up, 45.5 % of patients (5 of 11 patients) showed complete remission after chemotherapy. ConclusionPrimary HIV-negative GI-PBL occurs predominantly in the colon of relatively elderly males with immunosuppression. Its clinical course can be heterogenous, presenting a comorbidity with inflammatory bowel disease or post–organ transplantation status.