The role of chidamide in the treatment of B-cell non-Hodgkin lymphoma: An updated systematic review.

B-cell non-Hodgkin lymphoma (B-NHL) is a lymphoid malignancy derived from B-cells that remains difficult to treat. Moreover, relapses and refractory cases are common. Abnormalities in epigenetic mechanisms, such as imbalanced histone acetylation affecting certain genes, contribute to relapses and refractory cases. Chidamide (tucidinostat) is a novel histone deacetylase inhibitor that can reverse this epigenetic imbalance and has been approved for the treatment of T-cell malignancies. However, the use of chidamide for B-NHL remains limited, and the lack of relevant literature exacerbates this limitation. We conducted this review to summarize the anticancer activity of chidamide against B-NHL and its clinical applications to overcome drug resistance. This systematic review was conducted according to the PRISMA 2020 guidelines, using some keyword combinations from MEDLINE and EBSCO. The inclusion and exclusion criteria were also defined. Of the 131 records retrieved from databases, 16 were included in the review. Nine articles revealed that chidamide limited tumor progression by modifying the tumor microenvironment, stopping the cell cycle, inducing apoptosis and autophagy, and enhancing complement-dependent and antibody-dependent cell-mediated cytotoxicities.According to seven other studies, administering chidamide in combination with another existing therapeutic regimen may benefit not only patients with relapsed/refractory B-NHL, but also those with newly diagnosed B-NHL. Chidamide plays many important roles in limiting B-NHL progression through epigenetic modifications. Thus, combining chidamide with other anticancer drugs may be more beneficial for patients with newly diagnosed and relapsed/refractory B-NHL.

HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) predicts a high risk of hepatitis B reactivation in patients with B-cell lymphoma receiving rituximab based immunochemotherapy.

Patterns of hepatitis B virus reactivation (HBV-R) in HBsAg (-)/HBcAb (+) patients with B-cell non-Hodgkin lymphoma (NHL) receiving rituximab based immunochemotherapy have not been well described. The retrospective study included 222 HBsAg (-)/HBcAb (+) NHL patients as training cohort and 127 cases as validation cohort. The incidence of HBV-R in HBsAg (-)/HBcAb (+) B-cell NHL patients was 6.3% (14/222), of which that in HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was 23.7% (9/38). Multivariate analysis showed that HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) correlated with a high risk of HBV-R in B-cell lymphoma patients (training phase hazard ratio [HR], 10.123; 95% confidence interval [CI], 3.389-30.239; p < 0.001; validation phase HR, 18.619; 95% CI, 1.684-205.906; p = 0.017; combined HR, 12.264; 95% CI, 4.529-33.207; p < 0.001). In the training cohort, the mortality rate of HBsAg (-)/HBcAb (+) B-cell NHL caused by HBV-R was 14.3% (2/14) while that for HBV reactivated HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was up to 44.4% (4/9). As a high incidence of HBV-R and high mortality after HBV-R was found in HBsAg (-)/HBsAb (-)/HBcAb (+)/HBeAg (-)/HBeAb (+) patients with B-cell NHL receiving rituximab based immunochemotherapy, prophylactic antiviral therapy is recommended for these patients.

BR (bendamustine plus rituximab) versus R-CHOP for patients with indolent B-cell lymphomas: a systematic review and Meta-analysis.

Bendamustine plus rituximab (BR) and rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) have been shown to be effective in the treatment of indolent B-cell lymphomas (iBCL). The survival outcomes and adverse events of BR and R-CHOP are still controversial, thus we did a systematic review and meta-analysis to assess them. We searched articles in Pubmed, Cochrane, Embase and Web of Science comparing BR to R-CHOP in patients with iBCL. A total of 3141 patients were included. The results of our meta-analysis revealed that BR has the potential of improving PFS (HR = 0.67, p = 0.03). No apparent benefit of BR was noted in patients with iBCL for OS (HR = 1.18, p = 0.04). Compared with R-CHOP, we found that BR regimen had the potential of prolonging PFS, minor toxicity, a better quality of life, and better cost-effectiveness. These results supported BR as a preferred first-line treatment option for patients (especially for elders) with iBCL.

Research Progress of B-Cell Lymphoma/Leukemia-2 Inhibitor Combined with Azacytidine in the Targeted Therapy of Acute Myeloid Leukemia.

Objective: To investigate the efficacy and safety of azacytidine and B-cell lymphoma/leukemia-2 inhibitors in the treatment of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods: The clinical data of 31 patients with AML/MDS who were clearly diagnosed with AML/MDS were analyzed from 2018.10 to 2021.02, and the total amount of azacyclonol and B-cell lymphoma/leukemia-2 inhibitor was used for single or combined chemotherapy, with a total amount of 75 mg/m2 ∗7 d, divided into 7-10 days of continuous subcutaneous injection, every 28-30 days for a course of treatment. Overall response rate (ORR), median survival, poor response, and genetic mutations were observed. Results: A total of 104 courses of treatment were completed in 31 patients, the median course was 3 (1-12), and 6 patients who did not complete 2 courses of treatment were not counted in the statistics. After 2 courses, ORR was 72.0%, CRES was 2 (8.0%), mCR was 16 (64.0%), disease stable was 5 (20.0%), treatment failures were 2 (8.0%), mortality was 40.0%, and median survival time was >5 months. Single-agent and combined ORR was 64.3% and 81.8%, respectively, with median survival of 7.25 and 9 months; ORR for MDS and AML was 66.7% and 76.9%, respectively, median survival of 8 and 11 months was 66.7% and 80.0% of ORRs at 260 and V60 years, respectively, and median survival of 7 and 11.5 months; MDS-EB-1. The ORR of MDS-EB-2 was 75.0% and 62.5%, respectively, with median survival times of 11.5 and 6.5 months. During 2 courses and 4 courses, the rate of transfusion dependence was 64.0% and 55.5%, respectively. Fifteen cases were detected by second-generation sequencing, and the results were 14 cases of combined gene mutations. Conclusion: Azacytidine and B-cell lymphoma/leukemia-2 inhibitors have good efficacy and high safety in the treatment of AML and MDS, and the combined treatment is better than that of monotherapy, but the side effects of combination therapy are large.

The role of miRNAs in regulating the effect of prenatal cadmium exposure on ovarian granulosa cells in a transgenerational manner in female rats.

Cadmium (Cd) is known to affect ovarian granulosa cells (GCs), but no information on the transgenerational effects of Cd on GCs. In this study, pregnant Sprague-Dawley (SD) rats were orally dosed with Cd from gestation day 1 until birth. F1 or F2 female rats were mated with untreated males to produce the F2 or F3 generation. In the F1 generation, apoptotic cell bodies were observed in the Cd-treated group but not in the F2 generation. Moreover, significant changes in B-cell lymphoma 2 (Bcl2) expression were observed in both generations. Additionally, the expression of microRNAs (miRNAs) was significantly changed based on microarray analysis. Specifically, miR-16-5p and miR-181b-5p were upregulated in F1 and F2 rats, while miR-92a-2-5p demonstrated different expression patterns between the two generations. In F3 generation, miR-16-5p and miR-92a-2-5p were down-regulated. Further, another experiment was used to show that miR-16-5p and miR-92a-2-5p regulated the Bcl2-induced apoptotic effect of Cd on GCs by the Human ovarian GC tumor line (COV434 cell line) miRNA-knockdown model Overall, the results indicate that prenatal Cd exposure has epigenetic transgenerational effect on GCs, Moreover, the underlying mechanism may involve interference with miR-16-5p and miR-92a-2-5p-mediated regulation of Bcl2 genes in offspring.

Follicular B-Cell Lymphoma and Particulate Matter Associated with Environmental Exposure to Wood Dust.

BACKGROUND In humans, wood dust is a carcinogen. Indeed, a strong association between wood dust and lung cancer risk has been reported in woodworkers, as well as in the general population. CASE REPORT The patient was a 58-year-old man with follicular B-cell lymphoma. In the 10 years preceding the cancer diagnosis, he lived within 1/4 mile of a paper mill, where wood was processed. Computed tomography of the chest, abdomen, and pelvis revealed right hilar, mediastinal, abdominal, and retroperitoneal lymphadenopathy, bilateral pleural effusions, and a large soft-tissue mass infiltrating the small bowel mesentery. Analysis of the pleural fluid revealed the presence of a web of thin filopodia-like filaments, which trapped clusters of mesothelial cells and atypical lymphocytes. Single tubular filaments, morphologically similar to tunneling nanotubes, were seen originating from atypical lymphocytes and reaching neighboring cells. Furthermore, long, thick, cylindrical fibers of unknown nature, probably from the external environment, were also observed. CONCLUSIONS Because the patient lived in an unhealthy environment for many years, the possibility that his clinical condition was related to exposure to toxic emissions should be entertained. Considered in this context, the foreign fibers in his pleural fluid could be a direct consequence of inhalation of contaminants in the polluted air.

Association Between Pesticide Use and Incidence of Diffuse Large B-Cell Lymphoma.

BACKGROUND/AIM: Exposure to pesticides has been reportedly associated with several types of cancer. MATERIALS AND METHODS: In this study, we used data from The United States Geological Survey (USGS), United States Census, and the Surveillance, Epidemiology, and End Results (SEER) database to analyze the association between the area density of specific agricultural pesticides and the county level annual incidence of diffuse large B-cell lymphoma (DLBCL). RESULTS: Incidence of DLBCL was significantly associated with an area density of 14 of the pesticides reported by USGS. CONCLUSION: This highlights the need for further investigation into the safety of the use of these pesticides. The importance of this study comes not only from the significant association it shows between pesticides and the incidence of cancer, but also from the fact that it included all compounds reported to USGS as being used in agriculture. This helps in prioritizing pesticides for further evaluation.

Gamma heavy chain disease (γ-HCD) as iatrogenic immunodeficiency- associated lymphoproliferative disorder: Possible emergent subtype of rheumatoid arthritis-associated γ-HCD.

Gamma heavy chain disease (γ-HCD) is a rare B-cell neoplasm that produces a truncated immunoglobulin γ-heavy chain lacking the light chain. The clinical features of γ-HCD are heterogeneous, resembling different types of B-cell lymphomas. Although rheumatoid arthritis (RA) is one of the common underlying diseases of γ-HCD, the therapeutic modality for RA has changed greatly in recent years; therefore, γ-HCD as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) should be taken into consideration. Here, we report such a γ-HCD case. A 69-year-old female was admitted because of fever, multiple lymph node swelling in the abdominal cavity, and peritoneal effusion. She had been treated using methotrexate for RA for 14 years, and using infliximab and adalimumab for Crohn's disease for one year. The serum concentration of IgG was 3,525 mg/dL, which was revealed to be monoclonal IgG lacking the light chain by rocket immunoselection assay. CD19+/CD20-/smκ-/smλ- large abnormal lymphocytes were observed in the peritoneal fluid, which were demonstrated to be clonal B-cells by PCR examination. Discontinuation of methotrexate did not improve her condition and she died of pneumonia. Many abnormal lymphocytes positive for IgG and EBER but negative for the light chain were found on immunohistological examination of necropsy specimens from the spleen and bone marrow.

Immunologic effects of chronic administration of tofacitinib, a Janus kinase inhibitor, in cynomolgus monkeys and rats - Comparison of juvenile and adult responses.

Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (T-dependent antibody response (TDAR), mitogen-induced T cell proliferation) assessed. Tofacitinib administration decreased circulating T cells and NK cells in juvenile and adult animals of both species. B cell decreases were observed only in rats. These changes and decreased lymphoid tissue cellularity are consistent with the expected pharmacology of tofacitinib. No differences were observed between juvenile and adult animals, either in terms of doses at which effects were observed or differential effects on immune endpoints. Lymphomas were observed in three adult monkeys. Tofacitinib impaired the primary TDAR in juvenile monkeys, although a recall response was generated. Complete or partial reversal of the effects on the immune system was observed.

A Case of cutaneous large B-cell lymphoma during treatment of multiple sclerosis with fingolimod.

The authors report a case of a 69-year-old woman with multiple sclerosis treated with fingolimod for duration of over one year who subsequently developed cutaneous large B cell lymphoma. There are few reported cases of lymphoma associated with fingolimod treatment for multiple sclerosis, but rates are higher than expected in the general population. The authors hope to promote awareness of the potential risk of this medication so that more diligent disease surveillance can be performed by both prescribing practitioners of fingolimod and their patients who receive it.

Methotrexate-associated Intravascular Large B-cell Lymphoma in a Patient with Rheumatoid Arthritis.

Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically aggressive lymphoma with an unfavorable prognosis. We report the case of a 50-year-old woman who was diagnosed with IVLBCL during treatment with methotrexate (MTX) and biologic agents for rheumatoid arthritis. The symptoms showed partial improvement only after the cessation of both treatments. She subsequently received chemotherapy and achieved a complete remission and has remained free of recurrence for 2 years without any further treatment. We herein describe a rare case of IVLBCL which presented with the features of an MTX-associated lymphoproliferative disorder.

Methotrexate-related primary hepatic lymphoma in a patient with rheumatoid arthritis.

A 56-year-old woman with rheumatoid arthritis treated with methotrexate (MTX) was admitted to our hospital due to multiple liver tumors. Contrast-enhanced computed tomography (CT) revealed multiple hypovascular masses, and 18F-fluorodeoxyglucose positron emission tomography CT showed diffuse abnormal accumulation in the liver only. We therefore made a diagnosis of MTX-related primary hepatic lymphoma (MTX-PHL) exhibiting features of diffuse large B-cell lymphoma. Although MTX has been reported to increase the risk of lymphoproliferative disorders, MTX-PHL has not been reported previously. The present case is the first case in which MTX appears to have been involved in the development of PHL.

Cutaneous lymphoproliferative disorders in organ transplant recipients: update 2014.

Post-transplant lymphoproliferative disorders (PTLD) are lymphoid or plasmacytic proliferations that develop after solid organ, bone marrow or stem cell transplantation. PTLD are the leading cause of cancer-related mortality and graft loss in both pediatric and adult solid organ transplant recipients (ORT). These disorders comprise a spectrum ranging from usually EBV-driven, mostly B-cell polyclonal proliferations to B- and T-cell lymphomas indistinguishable from their counterparts occurring in immunocompetent individuals. PTLD usually present in extranodal sites; isolated skin involvement of PTLD is rare. A recent multicenter European case series showed that primary cutaneous T-cell PTLD are more common than primary cutaneous B-cell PTLD, and along with its folliculotropic variant, mycosis fungoides (MF) is the most frequent form of posttransplant primary cutaneous T-cell lymphoma (CTCL). This case series also disclosed that primary cutaneous CD30+ lymphoproliferative disorders is the second most common posttransplant CTCL subtype, indicating that the spectrum of primary CTCL in OTR is similar to that in the general population. However, in contrast with the immunocompetent individuals, the prognosis of primary cutaneous CD30+ anaplastic large T-cell lymphoma is worse than posttransplant MF and than its counterpart in the general population which has an excellent prognosis. The recent case series indicated that the spectrum of primary cutaneous B-cell PTLD differs significantly from cutaneous B-cell lymphoma in the general population, with a predominance of EBV-associated forms. Currently, the best therapeutic intervention(s) for primary cutaneous PTLD remains unknown.

Methotrexate-associated B-cell lymphoproliferative disorders presenting in the skin: A clinicopathologic and immunophenotypical study of 10 cases.

Methotrexate (MTX)-associated B-cell lymphoproliferative disorders (B-LPD) may first present in the skin, but their clinicopathologic features are still ill defined. Differentiation from primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) is important, as MTX-associated B-LPD may show spontaneous regression after withdrawal of MTX therapy. In the present study, the clinicopathologic and phenotypical features of 10 patients with MTX-associated B-LPD first presenting in the skin, including 5 EBV(+) and 5 EBV(-) cases, were investigated. Six patients had skin-limited disease. Clinically, abrogation of MTX therapy resulted in a complete response in 4 cases and a partial response in another 2. The 5-year disease-specific survival was 90%. MTX-associated B-LPD differed from primary cutaneous follicle center lymphoma by the presence of ulcerating and/or generalized skin lesions, an infiltrate composed of centroblasts/immunoblasts rather than large centrocytes, reduced staining for CD79a, and expression of BCL2, IRF4, and FOXP1 in most cases. EBV(+) MTX-associated B-LPD differed from PCLBCL-LT by the presence ulcerative skin lesions, marked tumor cell polymorphism, reduced staining for CD79a, and expression of CD30 and EBV. EBV(-) cases showed morphologic and immunophenotypical similarities to PCLBCL-LT but differed by presentation with generalized skin lesions in 4 of 5 cases. The results of this study, showing a relatively good clinical outcome and spontaneous disease regression after only withdrawal of MTX in a considerable proportion of patients, underscores the importance of a careful wait-and-see policy before considering more aggressive therapies in patients with MTX-associated B-LPD of the skin.

Effects of a biologic agent in a patient with rheumatoid arthritis after treatment for methotrexate-associated B-cell lymphoma: a case report.

BACKGROUND: Several studies have suggested an increased risk of malignant tumor in patients with rheumatoid arthritis. It has been also reported that rheumatoid arthritis patients have a high incidence of lymphoma compared with the general population, and that patients receiving methotrexate, which is the anchor drug for rheumatoid arthritis treatment, can develop lymphoproliferative disease. Nevertheless, management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated. We here report a patient with rheumatoid arthritis who developed malignant lymphoma associated with methotrexate therapy. Moreover, we describe the use of a biologic agent for a rheumatoid arthritis patient after treatment for lymphoma associated with methotrexate. CASE PRESENTATION: A 60-year-old Japanese man with a 20-year history of rheumatoid arthritis was admitted to our hospital with a left inguinal tumor. Open biopsy was performed and a biopsy specimen revealed diffuse large B-cell lymphoma. As our patient had received methotrexate for 4 years, we diagnosed the lymphoproliferative disease as being methotrexate-related. This lymphoma was not associated with Epstein- Barr virus by Epstein-Barr virus-encoded ribonucleic acid in-situ hybridization, but this patient was an Epstein-Barr virus carrier, regarding serological testing. The lymphoma went into complete remission after 6 courses of rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone therapy. Two years later, however, rheumatoid arthritis activity gradually increased and was not controlled with salazosulfapyridine. Etanercept was administered in view of its possible effect on B-cells, and this reduced the level of disease activity without recurrence of lymphoma. CONCLUSION: The management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated yet. Etanercept appeared to be safe because of its B-cell effect, but further observation is necessary to make a firm conclusion. Further accumulation of cases is needed to clarify which biologics are safe and effective for treatment of methotrexate-associated B-cell lymphoma.

New brain lesions in a patient with sarcoidosis: is it neurosarcoidosis?

A 45-year-old woman with pulmonary sarcoidosis diagnosed 5 years previously, who was on treatment with prednisone and methotrexate for 1year, developed partial seizure with secondary generalization. MRI showed three non-cavitary enhancing lesions in the cerebello-occipital region. These lesions were presumed to be neurosarcoidosis. Methotrexate was discontinued, prednisone dose was increased and azathiopurine and levetiracetam were added. While on treatment, follow up imaging showed enlarging brain lesions. Biopsy of the lesions showed Epstein Barr virus (EBV) positive diffuse B cell lymphoma. Immunosuppressants were tapered off and she was begun on Rituximab. Because of lack of improvement after 4 cycles of Rituximab, she was then treated with high dose Methotrexate and Temozolamide. We present this case as a diagnostic challenge. New enhancing brain lesions occurring in a patient with long standing sarcoidosis, while likely to be neurosarcoidosis, may be due to a complication of immunosuppressant therapy. The need for early biopsy, if the lesions do not improve, should be considered.