Intravascular large B‐cell lymphoma is a rare disease of the large B cells characterized by selective growth in the lumina of small vessels in systemic organs. Since first reported in 1959, the ...difficulty of obtaining sufficient tumor cells from biopsy specimens has hampered the elucidation of its underlying biology. Recent progress using xenograft models and plasma cell‐free DNA has uncovered genetic features that are similar to those of activated B‐cell type diffuse large B‐cell lymphoma, including MYD88 and CD79B mutations and frequent alterations in immune check point‐related genes such as PD‐L1 and PD‐L2. Given the improvement in clinical outcomes and a higher risk of secondary central nervous system (CNS) involvement in the rituximab era, a phase 2 trial of R‐CHOP combined with high‐dose methotrexate and intrathecal chemotherapy as a CNS‐oriented therapy has been conducted. This trial, the PRIMEUR‐IVL study, has displayed good progression‐free survival and a low cumulative incidence of secondary CNS involvement. Long‐term follow‐up within this trial is still ongoing. Further understanding of the pathophysiology of the disease and improvements in clinical outcomes are still needed.
Intravascular large B‐cell lymphoma is a rare type of extranodal large B‐cell lymphoma. Recent progress on clinical and translational research on IVLBCL allows us to understand the biological features of the disease and to apply an active treatment. Further investigations are warranted to deepen our understanding of the disease and to establish optimal treatments.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Primary effusion lymphoma (PEL) is a rare B-cell malignancy that most often occurs in immunocompromised patients, such as HIV-infected individuals and patients receiving organ transplantation. The ...main characteristic of PEL is neoplastic effusions in body cavities without detectable tumor masses. The onset of the disease is associated with latent infection of human herpes virus 8/Kaposi sarcoma–associated herpes virus, and the normal counterpart of tumor cells is B cells with plasmablastic differentiation. A condition of immunodeficiency and a usual absence of CD20 expression lead to the expectation of the lack of efficacy of anti-CD20 monoclonal antibody; clinical outcomes of the disease remain extremely poor, with an overall survival at 1 year of ∼30%. Although recent progress in antiretroviral therapy has improved outcomes of HIV-infected patients, its benefit is still limited in patients with PEL. Furthermore, the usual high expression of programmed death ligand 1 in tumor cells, one of the most important immune-checkpoint molecules, results in the immune escape of tumor cells from the host immune defense, which could be the underlying mechanism of poor treatment efficacy. Molecular-targeted therapies for the activating pathways in PEL, including NF-κB, JAK/STAT, and phosphatidylinositol 3-kinase/AKT, have emerged to treat this intractable disease. A combination of immunological recovery from immune deficiency, overcoming the immune escape, and the development of more effective drugs will be vital for improving the outcomes of PEL patients in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The tumor microenvironment is deeply involved in the process of tumor growth and development. In this study, we focused on cancer-associated fibroblasts (CAFs) and their derived exosomes on the ...lymphoma microenvironment to uncover their clinical significance. CAFs were established from primary lymphoma samples, and exosomes secreted from CAFs were obtained by standard procedures. We then investigated the roles of CAFs and their derived exosomes in the survival and drug resistance of lymphoma cells. CAFs supported the survival of lymphoma cells through increased glycolysis, and the extent differed among CAFs. Exosomes were identified as a major component of the extracellular vesicles from CAFs, and they also supported the survival of lymphoma cells. The suppression of RAB27B, which is involved in the secretion of exosomes, using a specific siRNA resulted in reduced exosome secretion and decreased survival of lymphoma cells. Moreover, anti-pyrimidine drug resistance was induced in the presence of exosomes through the suppression of the pyrimidine transporter, equilibrative nucleoside transporter 2 (ENT2), and the suppression of ENT2 was significant in in vivo experiments and clinical samples. RNA sequencing analysis of miRNAs in exosomes identified miR-4717-5p as one of the most abundant miRNAs in the exosome, which suppressed the expression of ENT2 and induced anti-pyrimidine drug resistance in vitro. Our results suggest that exosomes including miR-4717-5p secreted from CAFs play a pivotal role in the lymphoma microenvironment, indicating that they are a promising therapeutic target.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancer‐associated fibroblasts (CAF) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that ...CAF isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Herein, we analyzed the mechanisms underlying this support of tumor‐cell survival by CAF. As direct contact between lymphoma cells and CAF was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAF. Moreover, survival of lymphoma cells was promoted by the presence of pyruvate, and this promotion was canceled by inhibition of monocarboxylate transporters. Metabolome analysis of lymphoma cells in coculture with CAF demonstrated that intermediates in the citric acid cycle were significantly increased, indicating that tumor cells produced energy by aerobic metabolism. These findings indicate that energy production in lymphoma cells is regulated in coordination not only with anaerobic glycolysis, but also with aerobic metabolism termed the reverse‐Warburg effect, involving the secretion of pyruvate from CAF resulting in increased use of the citric acid cycle in lymphoma cells.
Figure 2 shows that CAF and conditioned media support survival of primary lymphoma cells. We show CAF support survival of various disease types and lineages of primary lymphoma cells in Figure 2.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: SYMPLICITY HTN-Japan is a prospective, randomized, controlled trial comparing renal denervation (RDN) with standard pharmacologic therapy for treatment of uncontrolled hypertension (HTN). ...Methods and Results: Patients enrolled had uncontrolled HTN, defined as office systolic blood pressure (SBP) ≥160 mmHg and 24-h ambulatory SBP ≥135 mmHg, on ≥3 antihypertensive drugs of maximally tolerated dose for at least 6 weeks prior to enrollment. Randomization was 1:1 to RDN or maintenance of current medical therapy (control). Patients were followed every 6 months post-randomization for up to 36 months. There were 22 patients randomized to RDN and 19 to control, and 11 patients were crossed over and received RDN at 6 months post-randomization. For the RDN group (n=22), office SBP reduction was −32.8±20.1 mmHg and office DBP reduction was −15.8±12.6 mmHg at 36 months post-procedure, both P<0.001. For the combined RDN and crossover group (n=33), office SBP reduction was −26.7±18.9 mmHg and office DBP reduction was −12.7±11.8 mmHg at 30 months post-procedure, both P<0.001. There were no procedural-, device- or treatment-related safety events through 36 months. Conclusions: SYMPLICITY HTN-Japan is the first randomized controlled trial to evaluate RDN in an Asian population. Despite the small number of enrollments, results show patients who received RDN therapy maintained SBP reduction out to 36 months.
Intravascular large B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding ...of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n = 18), patient-derived xenograft tumors (n = 4), and tumor DNA from bone marrow (BM) mononuclear cells (n = 2). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large B-cell lymphoma (DLBCL) (P < .0001) and healthy donors (P = .0053), allowing us to perform WES; most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated B-cell–type DLBCL, with the former showing conspicuously higher frequencies (compared with nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 IVLBCL (38%) harbored rearrangements of programmed cell death 1 ligand 1 and 2 (PD-L1/PD-L2) involving the 3′ untranslated region; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL.
•Genetic alterations in immune checkpoint–related genes are frequent in IVLBCL.•Plasma cfDNA is an alternative tumor DNA source of IVLBCL to detect genetic alterations by comprehensive analyses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) typically arises from sites such as the stomach, where there is no organized lymphoid tissue. Close associations ...between
and gastric MALT lymphoma or
and immunoproliferative small intestinal disease (IPSID) have been established. A subset of tumors is associated with chromosomal rearrangement and/or genetic alterations. This disease often presents as localized disease, requiring diverse treatment approaches, from antibiotic therapy to radiotherapy and immunochemotherapy. Eradication therapy for
effectively cures gastric MALT lymphoma in most patients. However, treatment strategies for
-negative gastric MALT lymphoma are still challenging. In addition, the effectiveness of antibiotic therapy has been controversial in intestinal MALT lymphoma, except for IPSID. Endoscopic treatment has been noted to usually achieve complete remission in endoscopically resectable colorectal MALT lymphoma with localized disease. MALT lymphoma has been excluded from post-transplant lymphoproliferative disorders with the exception of Epstein-Barr virus (EBV)-positive marginal zone lymphoma (MZL). We also describe the expanding spectrum of EBV-negative MZL and a close association of the disease with the gastrointestinal tract.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and the most common gastrointestinal lymphoma. The prognostic/predictive indicators among patients with gastric and ...intestinal DLBCL (giDLBCL) are controversial beyond their anatomical sites. We compared giDLBCL cases and investigated the clinical utility of newly emerging indicators with an emphasis on programmed cell death ligand 1 (PD-L1) expression.
Methods
This retrospective study included 174 patients with primary gastric (
n
= 129) or intestinal (
n
= 45) DLBCL treated with rituximab-containing chemotherapy between 1995 and 2018.
Results
Compared with gastric DLBCL (gDLBCL) cases, patients with intestinal DLBCL (iDLBCL) had a significantly higher rate of advanced Lugano stage (71% vs 37%,
P
< 0.001), perforation (13% vs. 0.8%,
P
= 0.001), PD-L1 expression on microenvironment immune cells (miPD-L1, 70% vs 46%,
P
= 0.008), CD10 positivity (47% vs 28%,
P
= 0.027), and CD5 positivity (9% vs 1.6%,
P
= 0.040). The iDLBCL patients showed significantly worse progression-free survival (PFS) and overall survival (OS) than gDLBCL cases (
P
= 0.0338 and
P
= 0.0077, respectively). PD-L1 expression on tumor cells was detected in only 3 (2%) of 174 cases with early relapse and/or an aggressive clinical course; whereas, miPD-L1-positive cases had significantly better OS than the miPD-L1-negative gDLBCL and iDLBCL cases (
P
= 0.0281 and
P
= 0.0061, respectively). Multivariate analysis revealed that miPD-L1 negativity (
P
= 0.030) was an independent adverse prognostic factor for OS in giDLBCL.
Conclusions
The anatomical site of disease did not influence outcome in giDLBCL cases treated with rituximab-containing chemotherapy; while, miPD-L1 expression had a favorable impact on the outcome.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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