Composite B-cell and T-cell lymphomas: clinical, pathological, and molecular features of three cases and literature review. / 三例复合性B细胞和Tç»†èƒžæ·‹å·´ç˜¤æ‚£è€ çš„ä¸´åºŠã€ç— ç†å’Œåˆ†å­å­¦ç‰¹å¾çš„åˆ†æžåŠæ–‡çŒ®å›žé¡¾.

Composite lymphoma (CL) involving B-cell lymphoma and T-cell lymphoma is extremely rare. Herein, we report three such cases using immunohistochemistry, flow cytometry, and the next-generation sequencing (NGS) to identify the pathological and molecular characteristics of CL. In the first case, the patient was admitted to hospital for generalized pruritic maculopapular rash over the whole body. An excisional biopsy of the skin lesions showed T-cell lymphoma. At the same time, the staging bone marrow (BM) biopsy revealed a diffuse large B-cell lymphoma (DLBCL). After R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapies, the patient produced a good response with substantial dissipation of the rashes and relief of skin. The other two patients were admitted to hospital due to lymphadenopathy and were diagnosed with DLBCL and follicular lymphoma (FL) after core needle biopsy of lymph nodes, BM biopsy, BM aspiration, and flow cytometry. Following R-CHOP and R-COP (rituximab, cyclophosphamide, vincristine, and prednisone) therapies, they achieved complete remission unconfirmed (CRu) and complete remission (CR). However, one or two years later, they suffered a relapse of lymphadenopathy. The shocking fact was that re-biopsy of lymphadenopathy revealed peripheral T-cell lymphoma (PTCL) and angioimmunoblastic T-cell lymphoma (AITL). NGS findings identified DNA methyltransferase 3a (DNMT3a), isocitrate dehydrogenase 2 (IDH2), Ras homolog gene family, member A (RHOA), splicing factor 3B subunit 1 (SF3B1), and tumor protein p53 (TP53) mutations. After immunochemotherapy, these patients achieved CRu and CR again. Nevertheless, they suffered a second relapse of T-cell lymphoma. Finally, they died due to progression of disease. We found that the occurrence of CL is associated with Epstein-Barr virus infection and DNMT3a, IDH2, and TP53 mutations, and the prognosis of the disease is closely related to the T-cell lymphoma components.

Analysis of the genomic landscape of primary central nervous system lymphoma using whole-genome sequencing in Chinese patients.

Primary central nervous system lymphoma (PCNSL) is an uncommon non-Hodgkin's lymphoma with poor prognosis. This study aimed to depict the genetic landscape of Chinese PCNSLs. Whole-genome sequencing was performed on 68 newly diagnosed Chinese PCNSL samples, whose genomic characteristics and clinicopathologic features were also analyzed. Structural variations were identified in all patients with a mean of 349, which did not significantly influence prognosis. Copy loss occurred in all samples, while gains were detected in 77.9% of the samples. The high level of copy number variations was significantly associated with poor progression-free survival (PFS) and overall survival (OS). A total of 263 genes mutated in coding regions were identified, including 6 newly discovered genes (ROBO2, KMT2C, CXCR4, MYOM2, BCLAF1, and NRXN3) detected in ⩾ 10% of the cases. CD79B mutation was significantly associated with lower PFS, TMSB4X mutation and high expression of TMSB4X protein was associated with lower OS. A prognostic risk scoring system was also established for PCNSL, which included Karnofsky performance status and six mutated genes (BRD4, EBF1, BTG1, CCND3, STAG2, and TMSB4X). Collectively, this study comprehensively reveals the genomic landscape of newly diagnosed Chinese PCNSLs, thereby enriching the present understanding of the genetic mechanisms of PCNSL.

miR-433 Inhibits Glioblastoma Progression by Suppressing the PI3K/Akt Signaling Pathway Through Direct Targeting of ERBB4.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor where new biomarkers and drug targets are much needed in the oncology clinic. miR-433 was identified as a tumor-suppressing miRNA in several different types of human cancer. However, the integrative biology of miR-433 in GBM is still largely unknown. By analyzing the expression profiles of miR-433 in 198 patients with glioma at The Cancer Genome Atlas, we found that the miR-433 expression was decreased in glioma whereas the low expression of miR-433 was significantly associated with shorter overall survival. We then conducted in vitro studies and demonstrated that increased expression of miR-433 suppressed the proliferation, migration, and invasion of LN229 and T98G cells, two representative glioma cell lines. Further, using in vivo mouse model, we found that upregulation of miR-433 inhibited the tumor growth of glioma cells. To situate the integrative biology understanding of the action of miR-433 in glioma, we identified ERBB4 as a gene targeted directly by miR-433 in LN229 and T98G cells. Overexpressed ERBB4 rescued the phenotype caused by overexpression of miR-433. Finally, we showed that miR-433 suppressed the PI3K/Akt pathway in glioma cells. In conclusion, our study demonstrated that miR-433 could potentially act as a tumor suppressor for GBM and may serve as a potential therapeutic target for GBM. Further integrative biology and clinical translational research are warranted to evaluate miR-433 in GBM.

Rituximab with high-dose methotrexate is effective and cost-effective in newly diagnosed primary central nervous system lymphoma.

Induction chemotherapy based on high-dose methotrexate is considered as the standard approach for newly diagnosed primary central nervous system lymphomas (PCNSLs). However, the best combination chemotherapeutic regimen remains unclear. This study aimed to determine the efficacy and toxicities of rituximab with methotrexate (R-M regimen). Consecutive 37 Chinese patients receiving R-M regimen as induction chemotherapy were retrospectively identified from January 2015 to June 2020 from our center in eastern China. Fourteen patients receiving rituximab plus methotrexate with cytarabine (R-MA regimen) at the same period were identified as the positive control group. The response rates, survival, toxicities, length of hospital stay (LOS), and cost were compared. Compared with the R-MA regimen, the R-M regimen showed comparable response rate and survival outcomes, but had fewer grade 3-4 hematological toxicities, shorter LOS, lower mean total hospitalization cost and lower mean total antibiotic cost. Complete remission at the end of induction chemotherapy and ECOG > 3 were independent prognostic factors for overall survival. In conclusion, R-M regimen is an effective and cost-effective combination treatment for PCNSLs, which warrants further evaluation in randomized trials.

Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma.

Introduction: Relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) has poor clinical outcomes when treated with conventional salvage chemotherapy. Monotherapy using zanubrutinib, a selective Bruton's tyrosine kinase (BTK) inhibitor, has achieved modest antitumor effect in R/R DLBCL. Here we aimed to evaluate the efficacy and safety of zanubrutinib plus salvage chemotherapy in R/R DLBCL patients. Methods: We retrospectively reviewed R/R DLBCL patients who were administered with zanubrutinib plus salvage chemotherapy in our center between January, 2019 and December, 2021. Targeted panel sequencing of 11 lymphoma-related genes was performed on 8 patients with poor responses to zanubrutinib-based chemotherapy. Results: 27 R/R DLBCL patients were enrolled. Median age at this study was 59 years (range, 15-72). The best overall response rate (ORR) was 74.1% and complete remission rate was 33.3%. With a median follow-up of 11 months (range, 1-17), the median progression-free survival (PFS) was 8.1 months, and the overall survival (OS) was not achieved. The most common grade-3/4 adverse events were neutropenia (70.4%), thrombocytopenia (66.7%), and febrile neutropenia (33.3%). In multivariate analysis, early treatment and overall response after chemotherapy were independent favorable prognostic factors for PFS. Overall response after chemotherapy was an independent favorable factor for OS. Among the 8 patients with poor response to zanubrutinib-based treatment, the majority of patients had NOTCH2 mutations (n=8, 100%) and TP53 mutations (n=7, 87.5%). However, these patients achieved an ORR of 75% at 3 months after CD19-CAR-T cell therapy (including 4 cases of complete remission and 2 cases of partial remission). With a median follow-up of 9 months from CAR-T cell infusion (range, 1-16 months), the median PFS was 14.5 months, and the median OS was not reached. Conclusion: With high efficacy and manageable tolerability, zanubrutinib plus salvage chemotherapy may be a potential treatment option for R/R DLBCL. CAR-T cell therapy may be a priority strategy for these poor responders to BTKi-based treatment.

Chidamide and sintilimab combination in diffuse large B-cell lymphoma progressing after chimeric antigen receptor T therapy.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is curable with first-line chemoimmunotherapy but patients with relapsed/refractory (R/R) DLBCL still face a poor prognosis. For patients with R/R DLBCL, the complete response rate to traditional next-line therapy is only 7% and the median overall survival is 6.3 mo. Recently, CD19-targeting chimeric antigen receptor T cells (CAR-T) have shown promise in clinical trials. However, approximately 50% of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective. CASE SUMMARY: Here, we report on 7 patients with R/R DLBCL whose disease progressed after CAR-T infusion. They received a PD-1 inhibitor (sintilimab) and a histone deacetylase inhibitor (chidamide). Five of the 7 patients tolerated the treatment without any serious adverse events. Two patients discontinued the treatment due to lung infection and rash. At the 20-mo follow-up, the median overall survival of these 7 patients was 6 mo. Of note, there were 2 complete response rates (CRs) and 2 partial response rates (PRs) during this novel therapy, with an overall response rate (ORR) of 57.1%, and one patient had a durable CR that lasted at least 20 mo. CONCLUSION: In conclusion, chidamide combined with sintilimab may be a choice for DLBCL patients progressing after CD19-targeting CAR-T therapy.

Case Report: Dual Inhibition of HDAC and BTK for Diffuse Large B-Cell Lymphoma After Failure to CD19-Targeted CAR-T Therapy.

Background: Failure to CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), is an emerging clinical problem. There is no consensus on the treatment for these patients and treatment remains empirical. Case Report: We reported a case of an elderly R/R DLBCL patient who had TP53 mutation and relapsed 12 months after initial response to CAR T-cell therapy. The patient did not respond to salvage chemotherapy with the GDP regimen and could not tolerate any aggressive chemotherapy. Thereafter, the patient was given chidamide and zanubrutinib. After two months of treatment, the patient achieved sustained complete remission. At the last follow-up, the patient remains in radiographic CR 22 months after CAR-T infusion and 10 months after the initiation of the combination treatment. Conclusion: We report the first successful case of dual inhibition of HDAC and BTK for the treatment of R/R DLBCL after failure to CAR-T cell therapy, which opens a new therapeutic possibility for the future.

CD19 CAR-T Cell Therapy Induced Immunotherapy Associated Interstitial Pneumonitis: A Case Report.

Background: Chimeric antigen receptor-modified T cells (CAR-T) targeting CD19 has produced a high durable response in refractory or relapsed diffuse large B-cell lymphoma. Besides well-known cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome during CAR-T cell therapy, there were several rarely encountered fatal complications. Case Report: A 63-year-old male patient with refractory EBV-positive diffuse large B-cell lymphoma, developed interstitial pneumonitis with prolonged hypoxemia at 16 weeks after CD19 CAR-T cell therapy. There was no evidence of CRS and any infections. The patient recovered after intravenous immunoglobulin without tocilizumab or glucocorticoid administration. Now he is still in remission without interstitial pneumonitis 3 years after CAR-T cell therapy. Conclusion: This is the first report of immunotherapy-associated interstitial pneumonitis after CAR-T cell therapy. Our finding suggested the importance of careful follow-up and proper treatments for immunotherapy-associated pneumonitis in the CAR-T cell therapy schedule.

Successful treatment with matched unrelated donor peripheral blood stem cell transplantation for very severe aplastic anemia in presence of active infections: A case report.

RATIONALE: Very severe aplastic anemia (vSAA) with active infections is always fatal. Adequate infection control before hematopoietic stem cell transplantation is recommended. PATIENT CONCERNS: A 38-year-old woman with vSAA suffered from acute perforated appendicitis and invasive pulmonary fungal infection, and she failed to respond to intense antimicrobial therapies. DIAGNOSIS: She was diagnosed with refractory vSAA with stubborn acute perforated appendicitis and invasive pulmonary fungal infection. INTERVENTIONS: We successfully completed an emergent reduced intensity conditioning-matched unrelated donor (MUD)-peripheral blood stem cell transplantation (PBSCT) as a salvage therapy in the presence of active infections. The conditioning regimens consisted of reduced cyclophosphamide 30 mg/kg/day from day-5 to day-3, fludarabine 30 mg/m/day from day-5 to day-3 and porcine-antilymphocyte immunoglobulin 15 mg/kg/day from day-4 to day-2 without total body irradiation. Cyclosporin A, mycophenolate mofetil and short-term methotrexate were administered as graft-versus-host disease (GVHD) prophylaxis. Neutrophils and platelets were engrafted on day+15 and day+21. Appendiceal abscess and severe pneumonia developed after neutrophil engraftment, which were successfully managed with intense antimicrobial therapy and surgical intervention. OUTCOMES: Only limited cutaneous chronic GVHD was observed 5 months after transplantation. The patient still lives in a good quality of life 2 years after transplantation. LESSONS: Active infections may be no longer a contraindication to hematopoietic stem cell transplantation for some patients with vSAA.

Primary central nervous system lymphoma in China: a single-center retrospective analysis of 167 cases.

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin's lymphoma and a limited number of cases have been reported from China. This study aimed to investigate the clinicopathological features of newly diagnosed PCNSLs from a single center in eastern China and to identify the potential prognostic factors for overall survival (OS) and progression-free survival (PFS). All consecutive patients with histopathologically diagnosed PCNSLs at our center between January 2003 and October 2017 were recruited. Demographic and clinicopathological data were collected and reviewed retrospectively. The potential risk factors for OS and PFS were identified using the log-rank test and Cox regression analysis. A total of 167 immunocompetent cases were enrolled. The median age was 58 years (range 17-96 years), and the male:female ratio was 3:2. Headache (n = 65; 39%) and cerebral hemisphere (n = 96; 57%) were the most common presenting complaint and location, respectively. Out of 167 cases, 150 cases were diffuse large B cell lymphomas. With a median follow-up of 25 months (range 1-152 ), the median OS and PFS were 37 months (95% CI, 25-49) and 17 months (95% CI, 13-20), respectively. Residual tumor after operation, chemotherapy without HD-MTX and palliative treatment was revealed as independent prognostic markers. Moreover, ECOG > 3, multifocal lesions, and palliative treatment were revealed as unfavorable independent prognostic markers for PFS. In conclusion, Chinese patients with PCNSL have distinct characteristics. Further studies are warranted to confirm the prognostic value of these factors and to optimize treatments for these patients.

Chidamide, a histone deacetylase inhibitor, induces growth arrest and apoptosis in multiple myeloma cells in a caspase-dependent manner.

Chidamide, a novel histone deacetylase (HDAC) inhibitor, induces antitumor effects in various types of cancer. The present study aimed to evaluate the cytotoxic effect of chidamide on multiple myeloma and the underlying mechanisms involved. Viability of multiple myeloma cells upon chidamide treatment was determined by the Cell Counting Kit-8 assay. Apoptosis induction and cell cycle alteration were detected by flow cytometry. Specific apoptosis-associated proteins and cell cycle proteins were evaluated by western blot analysis. Chidamide suppressed cell viability in a time- and dose-dependent manner. Chidamide treatment markedly suppressed the expression of type I HDACs and further induced the acetylation of histones H3 and H4. In addition, it promoted G0/G1 arrest by decreasing cyclin D1 and c-myc expression, and increasing phosphorylated-cellular tumor antigen p53 and cyclin-dependent kinase inhibitor 1 (p21) expression in a dose-dependent manner. Treatment with chidamide induced cell apoptosis by upregulating the apoptosis regulator Bax/B-cell lymphoma 2 ratio in a caspase-dependent manner. In addition, the combination of chidamide with bortezomib, a proteasome inhibitor widely used as a therapeutic agent for multiple myeloma, resulted in enhanced inhibition of cell viability. In conclusion, chidamide induces a marked antimyeloma effect by inducing G0/G1 arrest and apoptosis via a caspase-dependent pathway. The present study provides evidence for the clinical application of chidamide in multiple myeloma.

Gorham-Stout syndrome in mainland China: a case series of 67 patients and review of the literature.

OBJECTIVE: Gorham-Stout syndrome (GSS) is a rare disorder of uncertain etiology and unpredictable prognosis. This study aims to present a comprehensive understanding of this rare entity. METHODS: A literature search in PubMed and three Chinese databases was performed to screen histologically proven GSS cases among Chinese residents in the mainland. We analyzed the patients' clinical characteristics, the value of different treatment modalities and their influence on the clinical outcome. RESULTS: Sixty-seven cases were finally enrolled. There were 43 men (64.2%) and 24 women (35.8%). The mean age at diagnosis was 28 years (1.5-71 years). The most common clinical symptoms included pain (n=40, 59.7%), functional impairment (n=13, 19.4%), and swelling (n=12, 17.9%). The radiographic presentation of 37 cases (55.2%) was disappearance of a portion of the bone. The others presented as radiolucent foci in the intramedullary or subcortical regions. A total of 42 cases provided data on therapy, these included surgery (n=27, 40.3%), radiation therapy (n=6, 9.0%), surgery combined with radiation therapy (n=2, 3.0%), and medicine therapy (n=7, 10.4%). For 30 of these 42 cases, follow-up data were available: 21 cases had the disorder locally controlled and 9 had a symptom progression. Fortunately, the disease is not fatal in the majority of cases. CONCLUSIONS: GSS has no specific symptoms and it should be taken into consideration when an unclear massive osteolysis occurs. The efficacies of different treatment modalities are still unpredictable and further research is required to assess the values of different treatments.

Oestrogen-deficiency inducing haematopoiesis dysfunction via reduction in haematopoietic stem cells and haematopoietic growth factors in rats.

Haematopoiesis is a self-renewing and multi-directional differentiation process of haematopoietic stem cells (HSCs), which is modulated very precisely by the haematopoietic microenvironment in bone marrow. Our previous study has demonstrated that oestrogen-deficiency leads to haematopoiesis dysfunction which manifests as a decrease in haematopoietic tissues and an increase in adipose tissues in bone marrow. However, the mechanism involved in the oestrogen-deficiency effects on haematopoiesis dysfunction is not completely understood. In this study, we established an oestrogen-deficiency rat model by ovariectomy (OVX group). Haematopoiesis was evaluated at the 12th, 16th, 20th, 24th and 28th weeks after operation in the OVX group and its control (Sham group) by pathological examination; the number and function of HSCs were evaluated by flow cytometry analysis and colony-forming assay respectively. Haematopoietic growth factors levels including granulocyte/macrophage-colony-stimulating factor (GM-CSF), stem cell factor (SCF) and interleukin-3 (IL-3) were examined by ELISA kits at different time points. We found that in the OVX group, haematopoiesis dysfunction in bone marrow was observed (P < 0.05) from the 12th week when compared with the Sham group, and extramedullary haematopoiesis began to appear in the liver and spleen from the 16th week. The number of HSCs and colony-forming units-granulocyte/macrophage (CFUs-GM) in bone marrow was reduced significantly (P < 0.05) from the 20th and 16th week respectively. Furthermore, GM-CSF, SCF and IL-3 in the OVX group decreased significantly (P < 0.05) since the 12th, 16th and 24th week respectively. Taken together, these results suggested that oestrogen is required for normal haematopoiesis. Oestrogen-deficiency inducing haematopoiesis dysfunction may be via reduction in HSCs and haematopoietic growth factors at a late stage.

High prevalence of hepatitis B virus infection in HIV-negative Castleman's disease.

Castleman's disease (CD) is a rare non-neoplastic lymphoproliferative disorder with ambiguous etiology. This study aimed to evaluate the potential association between hepatitis B virus (HBV) and CD and to characterize the HBV-positive CD patients in China, an endemic area for HBV infection. We compared the prevalence of HBV infection in 35 consecutive CD patients initially diagnosed in our hospitals over a 10-year period with an age- and sex-matched healthy control, a national population-based control, and a non-Hodgkin's lymphoma (NHL) control. We found that the prevalence of HBV infection in CD was 17.1% (6/35), which was as high as the NHL control (19.9%, P = 0.693), but significantly higher than the age- and sex-matched healthy control (6.9%, P = 0.033) and the national population-based control (7.2%, P = 0.037). Next, we compared the clinicopathological characteristics between HBV-positive and HBV-negative CD patients. We found that HBV-positive CD patients had a significantly higher NHL malignant transformation rate (33.3% vs. 0%, P = 0.025), higher splenomegaly rate (83.3% vs. 27.6%, P = 0.019), and much poorer prognosis (estimated mean overall survival time (50.83 vs. 64.34 months, P = 0.016). In conclusion, our findings suggest an association between HBV infection and development of CD. CD patients with HBV infection have their own distinguished features.

Renal complications of Castleman's disease: report of two cases and analysis of 75 cases.

Biopsy-proven renal complications of Castleman's disease (CD) are rare and current knowledge is largely based on sporadic case reports. We reported two more cases, both of which were multicentric CD with hyaline-vascular pathological pattern and presented with chronic renal failure. Case 1 was multicentric CD with renal mesangial proliferative glomerulonephritis complications, and case 2 was multicentric CD with membranoproliferative glomerulonephritis-like complications. Although both were eventually administered corticosteroids combined with cytotoxic drugs, both behaved in an aggressive and relapsing manner. We then made an analysis of 75 cases of biopsy-proven renal complications of CD (including our two cases) which were reported in 51 English literatures from January 1954 to March 2011. We found that the clinical and histological findings of renal complications of CD were heterogeneous. Death was observed in 17% patients after a median follow-up time of 22 months (0-204 months) since histological diagnosis of renal complications. The estimated 5-year cumulative survival rate was 75%. Better understanding and therapeutic interventions are required in further investigations.

MicroRNAs expression signatures are associated with lineage and survival in acute leukemias.

MicroRNAs (miRNAs) are small ( approximately 22 nucleotide) non-coding RNAs whose altered expression has been associated with various types of cancers, including leukemia. In the present study, we conducted a quantitative PCR (qPCR) analysis of expression of 23 human precursor miRNAs in bone marrow specimens of 85 Chinese primary leukemia patients, including 53 acute myeloid leukemia (AML) and 32 acute lymphoblastic leukemia (ALL) cases. We show that 16 miRNAs were differentially expressed between AMLs and ALLs. Of them, eight were previously reported (i.e., miR-23a, miR-27a/b, miR-128a, miR-128b, miR-221, miR-222, miR-223, and let-7b) and eight were newly identified (i.e., miR-17, miR-20a, miR-29a/c, miR-29b, miR-146a, miR-150, miR-155, and miR-196b). More importantly, through correlating miRNA expression signatures with outcome of patients, we further show that expression signatures of a group of miRNAs are associated with overall survival of patients. Of them, three (i.e., miR-146a, miR-181a/c, and miR-221), five (i.e., miR-25, miR-26a, miR-29b, miR-146a, and miR-196b), and three (i.e., miR-26a, miR-29b, and miR-146a) miRNAs are significantly associated with overall survival (P<0.05) of the 32 ALL, 53 AML, and 40 non-M3 AML patients, respectively. Particularly, the expression signature of miR-146a is significantly inversely correlated with overall survival of both ALL and AML patients. The prognostic significance of miR-146a in AML has been confirmed further in an independent study of 61 Chinese new AML patient samples. We also identified 622 putative target genes of miR-146a that are predicted by at least three out of the five major prediction programs (i.e., TragetScan, PicTar, miRanda, miRBase Targets, and PITA). Through gene ontology analysis, we found that these genes were particularly enriched (2- to 9-fold higher than expected by chance) in the GO categories of "negative regulation of biology processes," "negative regulation of cellular processes," "apoptosis," and "cell cycle," which may be related to the association of miR-146a with poor survival.