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.

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.

[Effect of gap junction on the cardioprotection of ischemic postconditioning in rat heart].

AIM: To determine whether the cardioprotection of ischemic postconditioning and heptanol in ischemic heart against ischemia/reperfusion (I/R) is mediated by gap junction. METHODS: The effect of ischemic postconditioning, heptanol at different doses (0.03, 0.06, 0.30, and 0.60 mg/kg) and AAP10 (10 mg/kg) on the intact rat heart during 30 min ischemia and 2 h of reperfusion was observed. Ischemic postconditioning was achieved by 3 cycles of 10 s reperfusion/10 s regional ischemia starting at the beginning of the reperfusion. The infarct size and the arrhythmia scores were measured. The effect of ischemic postconditioning, heptanol at different doses (0.05, 0.10, 0.50 and 1.00 mmol/L) and AAP10 (1 x 10(-7)mol/L) on the isolated heart during 30 min ischemia and 2 h of reperfusion was observed. Ischemic postconditioning was achieved by 6 cycles of 10 s reperfusion/10 s global ischemia starting at the beginning of the reperfusion. The arrhythmia scores and conduction velocity of ventricle muscle were measured. RESULTS: In the intact rat heart model, ischemic postconditioning and heptanol reduced infarct size and arrhythmia scores. In the Langendorff perfused rat heart model, ischemic postconditioning and heptanol reduced arrhythmia scores and conduction velocity of ventricle muscle. Administration of AAP10, an opener of gap junction attenuated the cardioprotection of ischemic postconditioning and heptanol. CONCLUSION: The cardioprotection of ischemic postconditioning and heptanol may be related to the attenuation of gap junction communication on myocardiac ischemia/reperfusion injury.