Risk-tailored treatment of splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is a rare lymphoproliferative disease involving B-cells and affecting elderly patients. SMZL plague peripheral blood and bone marrow, spleen. Lymph nodes are generally spared. SMZL is due to a protracted antigen stimulation of B lymphocytes and of microenvironment leading B-cell to polyclonal and then oligoclonal/monoclonal growth, promoting lymphoproliferation. Integration of the NOTCH2 and NFk-B signaling has been recently identified as the primary mechanism of neoplastic proliferation in SMZL. In total 20% of cases carry mutations in NOTCH2. Although SMZL has an indolent course, progression to diffuse large B-cell lymphoma occurs in about 10-15% of patients. Establishing the prognosis is a key step in disease management, depending on both individual risk and patients' health status. This review discusses tailored treatment of SMZL patients. Progression risk factors include nodal and extra-nodal involvement, peripheral lymphocytosis, anemia and thrombocytopenia. Patients with two or more score points have a median survival of <5 years. Watch and wait strategy is appropriate in low-risk and asymptomatic patients, whereas treatment of symptomatic patients ranges from splenectomy to rituximab monotherapy or associated with chemotherapy.

Humoral Effect of a B-Cell Tumor on the Bone Marrow Multipotent Mesenchymal Stromal Cells.

The properties of bone marrow (BM)-derived multipotent mesenchymal stromal cells (MSCs) are altered in the patients with the diffuse large B cell lymphoma (DLBCL) without BM involvement. It was suggested that plasma from the patients contains soluble factors that affect MSCs. Plasma and BM-derived MSCs from the DLBCL patients at the onset of the disease and one month after the end of treatment were studied. Concentration of the plasma cytokines and gene expression in the MSCs were evaluated by the Bio-Plex Pro Human Cytokine Panel kit to measure 27 analytes and real-time PCR. Plasma and MSCs from the healthy donors were used as controls. Analysis of cytokines in the plasma from healthy donors and patients before and one month after the end of treatment revealed significant differences in the concentration of 14 out of 27 cytokines. Correlations between the levels of secreted cytokines were altered in the plasma from patients indicating that the immune response regulation was disturbed. Cultivation of the MSCs from the healthy donors in the medium supplemented with the plasma from patients led to the changes in the MSC properties, similar to those observed in the MSCs from patients. The BM-derived MSCs were shown to participate in the humoral changes occurring in the DLBCL patients. For the first time, it was shown that the precursors of the stromal microenvironment - multipotent mesenchymal stromal cells - are altered in the patients with DLBCL without bone marrow involvement due to the humoral effect of the tumor and the response of organism to it. Comprehensive analysis of the results shows that, when remission is achieved in the patients with DLBCL, composition of the plasma cytokines normalizes, but does not reach the level observed in the healthy donors. The discovery of a new aspect of the effect of the tumor B-cells on the organism could help to reveal general regularities of the humoral effect of various tumors on the bone marrow stromal cells.

The impact of selenium on regulatory T cell frequency and immune checkpoint receptor expression in patients with diffuse large B cell lymphoma (DLBCL).

For many decades, selenium (Se) has been known as a potential anti-cancer agent that can also improve the function of immune cells in a variety of solid tumors. However, there is no report on the role of Se on CD4+ T cell subsets like CD4+CD25+FOXP3+ regulatory T cells (Tregs) in lymphoma patients. In this randomized clinical trial, we investigated the effect of 3-month Se consumption on the frequency of CD4+CD25+FOXP3+ Tregs and the expression of immune checkpoint receptors in thirty-two non-Hodgkin lymphoma (NHL) patients (16 patients with Se (Se+) and 16 without Se (Se-) consumption) with diffuse large B-cell lymphoma (DLBCL) subtype at stable remission. The change in the frequency of Tregs and expression of immune checkpoint receptors including CTLA-4, LAG-3, TIM-3, and PD-L1 genes were evaluated after 3 months in both groups using flow cytometry and SYBR Green Real-time PCR method, respectively. The results showed that the frequency of CD4+CD25+FOXP3+ Tregs and expression of immune checkpoint receptors did not significantly change after 3-month Se consumption in DLBCL patients. However, alteration in the frequency of CD4+CD25-FOXP3+ Treg subsets was positively correlated with change in CTLA-4, LAG-3, and TIM-3 expression in the Se+ group. Three-month Se supplementation did not prevent relapse in Se+ group. Taken together, Se supplementation alone did not affect the frequency of CD4+CD25+FOXP3+ Tregs, expression of checkpoint receptors, and prevention of relapse in DLBCL patients at stable remission phase but might influence the functional properties of other Treg subsets like CD4+CD25-FOXP3+ Tregs.

Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1.

Richter's transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase-associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and diffuse large B-cell lymphoma. Multiomics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed an S100 protein-defined subcluster of highly aggressive lymphoma cells that developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation toward aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.

Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most widespread type of non-Hodgkin lymphoma (NHL). As the most aggressive form of the DLBCL, the activated B-cell-like (ABC) subtype is often resistant to standard chemotherapies. Bruton's tyrosine kinase (BTK) inhibitor ibrutinib provides a potential therapeutic approach for the DLBCL but fails to improve the outcome in the phase III trial. In the current study, we investigated the molecular mechanisms underlying ibrutinib resistance and explored new combination therapy with ibrutinib. We generated an ibrutinib-resistant ABC-DLBCL cell line (OCI-ly10-IR) through continuous exposure to ibrutinib. Transcriptome analysis of the parental and ibrutinib-resistant cell lines revealed that the ibrutinib-resistant cells had significantly lower expression of the unfolded protein response (UPR) marker genes. Overexpression of one UPR branch-XBP1s greatly potentiated ibrutinib-induced apoptosis in both sensitive and resistant cells. The UPR inhibitor tauroursodeoxycholic acid (TUDCA) partially reduced the apoptotic rate induced by the ibrutinib in sensitive cells. The UPR activator 2-deoxy-D-glucose (2-DG) in combination with the ibrutinib triggered even greater cell growth inhibition, apoptosis, and stronger calcium (Ca2+) flux inhibition than either of the agents alone. A combination treatment of ibrutinib (15 mg·kg-1·d-1, po.) and 2-DG (500 mg/kg, po, b.i.d.) synergistically retarded tumor growth in NOD/SCID mice bearing OCI-ly10-IR xenograft. In addition, ibrutinib induced the UPR in the sensitive cell lines but not in the resistant cell lines of the DLBCL. There was also a combined synergistic effect in the primary resistant DLBCL cell lines. Overall, our results suggest that targeting the UPR could be a potential combination strategy to overcome ibrutinib resistance in the DLBCL.

Pretreatment lymphocyte-to-monocyte ratios predict AIDS-related diffuse large B-cell lymphoma overall survival.

The lymphocyte-to-monocyte ratio (LMR) and platelet-to-lymphocyte ratio (PLR) have been reported to be useful for predicting the prognosis of various malignancies, including diffuse large B-cell lymphoma (DLBCL). However, little is known about the role of LMR and PLR in the prognosis of DLBCL patients with human immunodeficiency virus (HIV) infection. We retrospectively evaluated the prognostic value of the LMR and PLR in patients with newly diagnosed AIDS-related diffuse large B-cell lymphoma (AR-DLBCL) who were treated with CHOP-like chemotherapy at a single institution. In 33 AR-DLBCL patients, the median follow-up period was 32 months (range: 7-85 months), with an estimated 2-year overall survival (OS) rate of 79.9%. The univariate analysis confirmed the LMR ≤ 2.74 (p = .015), PLR ≥ 337.7 (p = .019), and moderate anemia (p = .045) were associated with inferior survival. The independent significant association between low LMR and poor OS in the multivariate analysis was identified (HR: 0.033, 95% CI: 0.001-0.853, p = .040). However, PLR (p = .459) and moderate anemia (p = .102) did not retain an independent significance in the multivariate analysis. Moreover, compared with the high-LMR group, patients with low-LMR more frequently had B symptoms (p = .010) and lower CD4+T cell count (p < .001). The pretreatment LMR may be an effective prognostic factor for predicting OS in patients with AR-DLBCL.

Caracterización de pacientes adultos con linfoma no Hodgkin difuso de células grandes B / Characterization of adult patients with diffuse large B-cell non-Hodgkin lymphoma

Introducción: El linfoma difuso de células grandes B es el subtipo histológico más común de los linfomas no Hodgkin de curso agresivo. Objetivo: Caracterizar el comportamiento de pacientes adultos con linfoma difuso de células grandes B. Métodos: Se realizó un estudio observacional, descriptivo, longitudinal y retrospectivo que incluyó 56 pacientes adultos con linfoma difuso de células grandes B atendidos en el Instituto de Hematología e Inmunología desde enero 1998 hasta diciembre 2018. Resultados: El 55,4 por ciento de los pacientes fueron del sexo masculino; predominó el color de piel blanco (76,8 por ciento) y el grupo de 59 a 78 años (44,6 por ciento). Prevalecieron pacientes con comorbilidades fundamentalmente la hipertensión arterial (35,7 por ciento) y con validismo regular (55,4 por ciento). El 53,6 por ciento de los pacientes estaba en estadio IV al diagnóstico; predominaron los pacientes con síntomas B en 85,7 por ciento y fue más frecuente el grupo de riesgo bajo intermedio en 35,7 por ciento. El esquema más empleado fue R-CHOP, con el que se logró 85,7 por ciento de remisión completa. El 17,9 por ciento de los pacientes fallecieron y 41,1 por ciento recayeron. La sobrevida global a los 3, 5 y 10 años fue de 87,0 por ciento, 83,0 por ciento, y 80,0 por ciento, respectivamente. La sobrevida libre de enfermedad a los 3, 5 y 10 años fue de 74,0 por ciento, 67 por ciento y 56 por ciento, respectivamente. Conclusiones: La sobrevida global y la sobrevida libre de enfermedad de los pacientes fueron altas(AU)

Introduction: Diffuse large B-cell lymphoma is the most common subtype of aggressive non-Hodgkin lymphoma. Objective: Characterize the behavior of adult patients with diffuse large B-cell lymphoma. Methods: An observational retrospective longitudinal descriptive study was conducted of 56 adult patients with diffuse large B-cell lymphoma attending the Institute of Hematology and Immunology from January 1998 to December 2018. Results: Of the patients studied, 55.4 percent were male, and a predominance was found of white skin color (76.8 percent) and the 59-78 years age group (44.6 percent). Patients with comorbidities prevailed, mainly hypertension (35.7 percent) with an ability to perform activities of daily living (55.4 percent). 53.6 percent of the patients were in stage IV at diagnosis. Patients with type B symptoms prevailed with 85.7 (AU) , and the low to intermediate risk group was the most common with 35.7 percent. The regimen most frequently used was R-CHOP, obtaining 85.7 percent complete remission. 17.9 percent of the patients died and 41.1 percent relapsed. Overall survival at 3, 5 and 10 years was 87.0 percent, 83.0 percent and 80.0 percent, respectively. Disease-free survival at 3, 5 and 10 years was 74.0 percent, 67 percent and 56 percent, respectively. Conclusions: Overall and disease-free survival were high(AU)

Ulcerated cutaneous Richter syndrome.

Richter syndrome or Richter transformation comprises the conversion of chronic lymphocytic leukemia into an aggressive type of large cell lymphoma. Classically, patients have diffuse and abrupt lymphadenopathy and organomegaly, in addition to fever, weight loss, and fatigue. Cutaneous involvement is rare and often nonspecific. We report a patient with chronic lymphocytic leukemia who presented with a large and rapidly evolving ulcer, revealed to be a high-grade cutaneous lymphoma.

CD3-CD20-positive nodal lymphoma with cross-lineage rearrangement in a dog.

A 7-y-old mixed-breed male dog was presented with a history of generalized lymphadenopathy. Fine-needle aspirates of the enlarged peripheral lymph nodes were suggestive of lymphoma. Histologic examination of a retromandibular lymph node was suggestive of high-grade, medium large-cell lymphoma. Immunohistochemistry revealed concurrent expression of CD3 and CD20. The co-localization of the 2 antigens was confirmed by immunofluorescence. PCR for antigen receptor gene rearrangements (PARR) detected clonal rearrangements for both T-cell receptor gamma and B-cell receptor. The final diagnosis was CD3-CD20-positive anaplastic lymphoma with cross-lineage rearrangement.

Validation and comparison of prognostic values of GNRI, PNI, and CONUT in newly diagnosed diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma. Emerging evidence indicates that poor nutritional status determined with nutritional indices such as geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status score (CONUT) was associated with poor prognosis of DLBCL. We conducted this multicenter retrospective study to validate and compare prognostic values of the three indices in 615 newly diagnosed DLBCL patients. The overall survival (OS) in patients with poor nutritional status determined with each of these nutritional indices were significantly inferior compared with that in those without nutritional risks (5-year OS in patients with GNRI < 95.7 and GNRI ≥ 95.7 were 56.4% and 83.5%, P < 0.001; PNI < 42.4 and PNI ≥ 42.4 were 56.1% and 81.0%, P < 0.001; CONUT > 4 and CONUT ≤ 4 were 53.1% and 77.1%, P < 0.001). GNRI and CONUT were independent prognostic predictors for OS (GNRI < 95.7, hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.22-2.74, P = 0.0032; CONUT > 4, HR 1.53, 95% CI 1.05-2.23, P = 0.028) after multivariate analyses. Nutritional status determined with GNRI affected OS more strongly in the patients with nongerminal center B cell-like (nonGCB) DLBCL compared with that in those with GCB-type DLBCL. In conclusion, baseline poor nutritional status determined based on GNRI or CONUT was an independent risk factor of newly diagnosed DLBCL, and GNRI was also useful as an independent prognostic factor for patients with nonGCB-type DLBCL.

Síndrome de secreción inadecuada de hormona antidiurética en paciente con linfoma difuso de células grandes B / Syndrome of inappropriate antidiuretic hormone secretion in a patient with diffuse large B-cell lymphoma

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Extranodal site of diffuse large B-cell lymphoma and the risk of R-CHOP chemotherapy resistance and early relapse.

BACKGROUND: About 20%-30% of diffuse large B-cell lymphoma (DLBCL) patients experience early disease progression despite R-CHOP chemotherapy treatment. Revised international prognostic index (R-IPI) score could risk stratify DLBCL patients but does not identify exactly which patient will be resistant to R-CHOP therapy or experience early relapse. AIMS OF THE STUDY: To analyse pre-treatment clinical features of DLBCL patients that are predictive of R-CHOP therapy resistance and early disease relapse after R-CHOP therapy treatment. METHODS USED TO CONDUCT THE STUDY: A total of 698 lymphoma patients were screened and 134 R-CHOP-treated DLBCL patients were included. The Lugano 2014 criteria was applied for assessment of treatment response. DLBCL patients were divided into R-CHOP resistance/early relapse group and R-CHOP sensitive/late relapse group. RESULTS OF THE STUDY: 81 of 134 (60%) were R-CHOP sensitive/late relapse, while 53 (40%) were R-CHOP resistance/early relapse. The median follow-up period was 59 months ± standard error 3.6. Five-year overall survival rate of R-CHOP resistance/early relapse group was 2.1%, while it was 89% for RCHOP sensitive/late relapse group. Having more than one extranodal site of DLBCL disease is an independent risk factor for R-CHOP resistance/early relapse [odds ratio = 5.268 (1.888-14.702), P = .002]. The commonest extranodal sites were head and neck, gastrointestinal tract, respiratory system, vertebra and bones. Advanced age (>60 years), advanced disease stage (lll-lV), raised pre-treatment lactate dehydrogenase level, bone marrow involvement of DLBCL disease high Eastern Cooperative Oncology Group status (2-4) and high R-IPI score (3-5) showed no significant association with R-CHOP therapy resistance/early disease relapse (multivariate analysis: P > .05). CONCLUSION AND CLINICAL IMPLICATIONS: DLBCL patients with more than one extranodal site are 5.268 times more likely to be R-CHOP therapy resistance or experience early disease relapse after R-CHOP therapy. Therefore, correlative studies are warranted in DLBCL patients with more than one extranodal site of disease to explore possible underlying mechanisms of chemoresistance.

Intravascular Large B-Cell Lymphoma: Clinical and Histopathologic Findings.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subset of extranodal non-Hodgkin lymphoma characterized by neoplastic lymphocytes within the lumina of small to medium-sized blood vessels. IVLBCLs are B-cell tumors that can present in essentially any organ system, including the skin. Cutaneous manifestations vary greatly and can mimic other skin disease which may delay diagnosis; in the absence of skin lesions, blind skin biopsies can be utilized for diagnosis. Early studies suggested that IVLBCL is a very aggressive lymphoma with high overall mortality rate and short survival times. However, earlier diagnosis and use of new treatment modalities have shown promise in recent studies. This case series illustrates the heterogeneity of clinical and pathologic presentations of this uncommon lymphoma.

Classifying DLBCL according cell of origin using Hans algorithm and its association with clinicopathological parameters: A single centre experience.

INTRODUCTION: In recent years, "double hit" and "double protein" involving gene rearrangement and protein expression of c-MYC and BCL2 and/or BCL6 are the most used terms to describe poor prognostic factors in diffuse large B-cell lymphoma (DLBCL). This study was to determine the frequency of double or triple protein expression by using immunohistochemistry (IHC) and comparing the result with clinicopathological features and cell of origin (COO) classification. METHODS: We conducted a cross-sectional study by using 29 archived formalin-fixed paraffin embedded tissue blocks of DLBCL. All the samples were evaluated for the subgrouping of COO DLBCL was determined by expression of CD10, BCL6 and MUM1 based on Hans classification. In addition, expressions of c-MYC, BCL2 and BCL6 were detected by IHC. RESULTS: Among the 29 cases, MYC, BCL2 and BCL6 proteins were detected in 72.4%, 62.1% and 62.1% of patients, respectively. Concurrent expression (c-MYC positive/BCL2 positive and/or BCL6 positive) was present in 58.6% of patients. 34.5% were categorised as germinal centre like (GCB) subgroup and 65.5% were categorised as nongerminal centre like (non-GCB) subgroup. Among the clinicopathological features, the double/triple protein expression lymphoma was significantly associated with elevated LDH level (p=0.018), IPI score (p=0.003), Ann Arbor stage (p=0.011) and complete response rate (p=0.011). CONCLUSION: Double/triple protein lymphoma was strongly associated more adverse clinical risk factors. Thus, analyses of MYC, BCL2 and BCL6 expression by IHC represents a rapid and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.

Adult primary testicular lymphoma: clinical features and survival in a series of patients treated at a high-volume institution in China.

BACKGROUND: To retrospectively investigate the clinical characteristics, initial treatment, relapse, therapy outcome, and prognosis of Chinese patients with primary testicular lymphoma (PTL) through analysis of the cases of our institute. METHODS: From December 2008 to July 2018, all patients with PTL were included in this study. Kaplan-Meier method was used to estimate PFS and OS. The Cox proportional hazards model was used to compare the survival times for groups of patients differing in terms of clinical and laboratory parameters. RESULTS: All 28 PTL patients (24 DLBCL, three NK/T lymphomas, and one Burkkit's lymphoma) with a median age of 65.5 years were included in this study. Six patients were observed recurrence among all the 22 individuals evaluated. Following orchiectomy and systemic chemotherapy, with or without intrathecal prophylaxis, complete response was achieved in 15 (68%) patients. For DLBCL patients, the median progression-free survival (PFS) was 44.63 months (95% CI 17.71-71.56 months), and the median overall survival (OS) was 77.02 months (95% CI, 57.35-96.69 months). For all the DLBCL patients, the 5-year PFS and 5-year OS were 35.4% (95%CI, 14.8-56.0%) and 53.4% (95%CI, 30.1-76.7%). Without further chemotherapy following orchiectomy (HR = 3.4, P = 0.03) were associated with inferior PFS of DLBCL patients. Advanced Ann Arbor stage (HR =5.9, P = 0.009) and high (international prognostic index, IPI) score: 3-5 (HR =3.9, P = 0.04) were correlated with shorter OS of DLBCL patients. CONCLUSION: This study confirms that PTL is an aggressive malignant with a poor prognosis. Limited Ann Arbor stage, further chemotherapy following orchiectomy, and low IPI score (less than 2) are correlated with superior survival for DLBCL patients.

Demyelinating Neuropathy Due to Intravascular Large B-cell Lymphoma.

We herein report the case of a 67-year-old man who presented with the acute onset of limb weakness. Brain magnetic resonance imaging revealed multiple abnormal-signal-intensity lesions. Steroids were administered, and the patient initially responded. Nerve conduction testing findings were consistent with demyelinating polyneuropathy. A sural nerve biopsy specimen revealed fascicles with extensive onion-bulb formation. Although skin and sural nerve biopsies showed no atypical cellular infiltration, the histopathological diagnosis of intravascular large B-cell lymphoma was obtained by a brain biopsy. The neuropathy in this patient may be attributed to a demyelinating process independent of ischemic damage by lymphoma.

Pulmonary Intravascular Large B-cell Lymphoma in a Patient Administered Methotrexate for Rheumatoid Arthritis.

A 70-year-old woman with rheumatoid arthritis undergoing methotrexate (MTX) treatment presented with dyspnea and a subfever. Computed tomography (CT) revealed a diffuse minimal ground-glass appearance in both lungs and splenomegaly. The gallium scintigram showed a diffuse, mild uptake in both lungs and the spleen. The lung biopsy specimen revealed the presence of CD20-positive atypical lymphocytes in the small pulmonary vessels. The patient was diagnosed with pulmonary intravascular diffuse large B-cell lymphoma (IVLBCL) and exhibited spontaneous regression after MTX was discontinued. This report describes a rare case of MTX-associated lymphoproliferative disorder expressing pulmonary IVLBCL.

The IL-6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B-cell lymphoma.

Interleukin-6 (IL-6) is a growth factor for normal B cells and plasma cell-derived malignancies. Here, we show that the IL-6 signaling pathway is also active in a subset of diffuse large B-cell lymphoma (DLBCL) patients with particularly poor prognosis. Primary DLBCL cells and DLBCL cell lines expressing IL-6R engraft and form orthotopic lymphomas in humanized mice that ectopically produce human IL-6, and in mice reconstituted with a human immune system. We show that a subset of DLBCL cases have evolved mechanisms that ensure constitutive activation of the IL-6 signaling pathway, i.e., the expression of both chains of the IL-6R, the expression of the cytokine itself, and the mutational inactivation of a negative regulator of IL-6 signaling, SOCS1. IL-6 signaling promotes MYC-driven lymphomagenesis in a genetically engineered model, and treatment with the IL-6R-specific antibody tocilizumab reduces growth of primary DLBCL cells and of DLBCL cell lines in various therapeutic settings. The combined results uncover the IL-6 signaling pathway as a driver and negative prognosticator in aggressive DLBCL that can be targeted with a safe and well-tolerated biologic.