[The Efficacy and Safety of Daratumumab-Based Regimen in Treatment of Multiple Myeloma Patients with Renal Impairment].

OBJECTIVE: To investigate the efficacy and safety of daratumumab in treatment of multiple myeloma (MM) patients with renal impairment (RI). METHODS: The clinical data of 15 MM patients with RI who received daratumumab-based regimen from January 2021 to March 2022 in three centers were retrospectively analyzed. Patients were treated with daratumumab or daratumumab combined with dexamethasone or daratumumab combined with bortezomib and dexamethasone and the curative effect and survival were analyzed. RESULTS: The median age of 15 patients was 64 (ranged 54-82) years old. Six patients were IgG-MM, 2 were IgA-MM,1 was IgD-MM and 6 were light chain MM. Median estinated glomerular filtration rate (eGFR) was 22.48 ml/(min·1.73 M2). Overall response rate of 11 patients with MM was 91% (≥MR), including 1 case of stringent complete response (sCR), 2 cases of very good partial response (VGPR), 3 cases of partial response (PR) and 4 cases of minor response (MR). The rate of renal response was 60%(9/15), including 4 cases of complete response (CR), 1 case of PR and 4 cases of MR. A median time of optimal renal response was 21 (ranged 7-56) days. With a median follow-up of 3 months, the median progression-free survival and overall survival of all patients were not reached. After treatment with daratumumab-based regimen, grade 1-2 neutropenia was the most common hematological adverse reaction. Non-hematological adverse reactions were mainly infusion-related adverse reactions and infections. CONCLUSION: Daratumumab-based regimens have good short-term efficacy and safety in the treatment of multiple myeloma patients with renal impairment.

Primary hepatic mucosa-associated lymphoid tissue lymphoma with HP and previous HBV infection: A case report and literature review.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare disease with low malignancy, and its aetiology is unclear. A 65-year-old man presented with abdominal pain. Hepatitis virus examination revealed a previous hepatitis B virus (HBV) infection, and a carbon-13 urea breath test result was positive for the patient. Abdominal contrast-enhanced computed tomography revealed a patch of abnormal density in the right posterior lobe of the liver. The patient underwent VI segment hepatectomy and was pathologically diagnosed with hepatic MALT lymphoma. After the operation, he received quadruple anti-Helicobacter pylori (HP) therapy and refused other treatments. He has been followed up by telephone for 20 months after discharge and is now in a stable condition. In this study, we counted 105 cases of hepatic MALT lymphomas reported in English or Chinese since 1995 and summarised the clinical characteristics and concomitant diseases in this condition. Based on the literature review, we speculated that chronic infectious diseases, especially viral infections (including hepatitis C virus (HCV) and HBV) and HP infection, are associated with the pathogenesis of primary hepatic MALT lymphoma. In addition, autoimmune diseases might also play a role in this condition.

Chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance: A case report and literature review.

BACKGROUND: Study of the molecular biological characteristics of chronic neutrophilic leukemia complicated with plasma cell disorder (CNL-PCD) and lymphocytic proliferative disease (CNL-LPD). METHODS: The clinical data of a patient with chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance (CNL-MGUS) in our hospital were reviewed, and the Chinese and/or English literature about CNL-PCD and CNL-LPD in PubMed and the Chinese database CNKI in the past 10 years was searched to analyze the molecular biological characteristics of this disease. RESULTS: A 73-year-old male had persistent leukocytosis for 18 months. The white blood cell count was 46.77 × 109/L and primarily composed of mature neutrophils; hemoglobin: 77 g/L; platelet count: 189 × 109/L. Serum immunofixation electrophoresis showed IgG-λ monoclonal M protein. A CT scan showed splenomegaly. Next-generation sequencing (NGS) showed that CSF3R T618I, ASXL1 and RUNX1 mutations were positive. It was diagnosed as CNL-MGUS. We summarized 10 cases of CNL-PCD and 1 case of CNL-LPD who underwent genetic mutation detection reported in the literature. The CSF3R mutational frequency (7/11, 63.6%) was lower than that of isolated CNL. The ASXL1 mutations were all positive (3/3), which may represent a poor prognostic factor. The SETBP1 mutation may promote the progression of CNL-PCD. We also found JAK2, RUNX1, NRAS, etc. in CNL-PCD. CONCLUSIONS: Chronic neutrophilic leukemia may be more inclined to coexist with plasma cell disorder. The CSF3R mutation in CNL-PCD is still the most common mutated gene compared with isolated CNL. Mutations in SETBP1 and ASXL1 may be poor prognostic factors for CNL-PCD.

Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin (PRF1) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review. CASE SUMMARY: We report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of PRF1: c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation. CONCLUSION: The delayed onset of FHL2 may be related to the PRF1 mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some PRF1 mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.

Let-7f-5p ameliorates inflammation by targeting NLRP3 in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus.

Bone marrow-derived mesenchymal stem cells (MSCs) from systemic lupus erythematosus patients (SLE-BMSCs) exhibited abnormalities in cytokine production and immune modulation. Deregulation of Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in SLE. Herein, we explored whether miRNAs are involved in the regulation of NLRP3 in SLE-BMSCs. ELISA assay was used to detect the levels of inflammatory cytokines. The expression levels of let-7f-5p and gene mRNAs were determined by qRT-PCR assay. The protein levels of NLRP3, Cleaved caspase-1 and ASC were measured by western blot. The interaction between let-7f-5p and NLRP3 was verified using dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. In vivo assay was performed to explore whether let-7f-5p upregulation could ameliorate inflammation in MRL/lpr mice. Our data indicated that SLE patients had significantly serum higher levels of IFN-γ, IL-6, IL-18, IL-12, IL-13 and IL-1ß. We demonstrated that NLRP3 expression was upregulated in SLE-BMSCs. Let-7f-5p directly targeted NLRP3 and repressed NLRP3 expression. NLRP3 depletion or let-7f-5p upregulation repressed IL-1ß production and the expression of NLRP3 inflammasome components. Moreover, upregulated let-7f-5p-mediated anti-inflammation effect was significantly abrogated by NLRP3 expression restoration. Besides, let-7f-5p upregulation ameliorated inflammation through modulating NLRP3 in vivo. In conclusion, our study suggested that high level of let-7f-5p alleviated inflammation in SLE-BMSCs at least partly through targeting NLRP3, highlighting let-7f-5p as a novel promising therapeutic strategy for SLE treatment.

[Distribution of lymphomas subtypes in Jiangsu Province: a multicenter analysis of 5 147 cases].

OBJECTIVE: To investigate the epidemiological characteristics of lymphoma in Jiangsu province. METHODS: A total of 5 147 consecutive lymphoma samples collected from 18 hospitals in Jiangsu province from January 2007 to December 2013 and diagnosed according to the WHO classification were enrolled in this study. Basic epidemiological information including age, gender and lymphoma subtypes was analyzed. RESULTS: The median age of all lymphoma cases was 59(2-96) years, and gender ratio (M/F) was 1.6:1. The subtypes distribution analysis revealed that Hodgkin lymphoma (HL) accounted for 5.19% (n=241), whereas non-Hodgkin's lymphoma (NHL) accounted for 94.81% (n=4 400). Further analysis displayed B-NHL formed 75.44% (n=3 501) of all cases and T/NK-NHL 16.51% (n=766), diffuse large B-cell lymphoma and NK/T-cell lymphoma were the major subtypes of B-NHL and T/NK-NHL (53.50%, 1 873/3 501 and 31.85%, 244/766), respectively. CONCLUSION: Unique epidemiological characteristics of lymphoma in Jiangsu province was different from other regions in China and western country, which can provide strong theoretical basis for public health, clinical and basic research.

[Anti-CD20 monoclonal antibody RTX enhances radiosensitivity of lymphoma cells].

This study was aimed to investigate the effects of rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, on lymphoma cell injury induced by X ray irradiation. The human Burkitt EBV-infected and moderate radioresistance lymphoma cells (Namalwa) were used in the this study. Cytotoxicity of rituximab combined with X ray irradiation on Namalwa cells was measured by sulforhodamine B (SRB)-staining; the apoptosis of Namalwa cells was detected by flow cytometry with FITC-Annexin V/PI double staining; the morphologic changes of cells were observed under transmission electron microscope (TEM) and the change of intracellular free calcium level ([Ca(2+)]i) in response to irradiation and rituximab was determined by means of the fluorescent dye fluo-3 and confocal microscopy. The results showed that the growth inhibition in Namalwa cells exposed to irradiation was enhanced by treatment with rituximab. Compared with irradiation alone, rituximab combined with irradiation significantly induced the cell apoptosis and a sustained rise of intracellular free calcium ([Ca(2+)]i) level in Namalwa cells; the serial apoptotic appearances of cells could be observed under TEM. It is concluded that rituximab can enhance the sensitivity of lymphoma cells on X ray irradiation as to induce cell more apoptosis, in this process the intracellular free calcium ([Ca(2+)]i), as an intracellular signaling molecule probably plays an important role.

Alleviation of pre-exposure of mouse brain with low-dose 12C6+ ion or 60Co gamma-ray on male reproductive endocrine damages induced by subsequent high-dose irradiation.

Irradiation has been widely reported to damage organisms by attacking on proteins, nucleic acid and lipids in cells. However, radiation hormesis after low-dose irradiation has become the focus of research in radiobiology in recent years. To investigate the effects of pre-exposure of mouse brain with low-dose (12)C6+ ion or 60Co gamma (gamma)-ray on male reproductive endocrine capacity induced by subsequent high-dose irradiation, the brains of the B6C3F1 hybrid strain male mice were irradiated with 0.05 Gy of (12)C6+ ion or 60Co gamma-ray as the pre-exposure dose, and were then irradiated with 2 Gy as challenging irradiation dose at 4 h after pre-exposure. Serum pituitary gonadotropin hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), testosterone, testis weight, sperm count and shape were measured on the 35th day after irradiation. The results showed that there was a significant reduction in the levels of serum FSH, LH, testosterone, testis weight and sperm count, and a significant increase in sperm abnormalities by irradiation of the mouse brain with 2 Gy of (12)C6+ ion or 60Co gamma-ray. Moreover, the effects were more obvious in the group irradiated by (12)C6+ ion than in that irradiated by 60Co gamma-ray. Pre-exposure with low-dose (12)C6+ ion or 60Co gamma-ray significantly alleviated the harmful effects induced by a subsequent high-dose irradiation.

Germ cell loss induced by 12C6+ ion irradiation in young female mice.

The ovaries of Kun-Ming strain mice (3 weeks) were irradiated with different doses of 12C6+ ion in the Bragg peak or the plateau region. At 10th day after irradiation, ovarian and uterine weights were measured; normal and atretic (identified with the oocyte to be degenerating or absent) primordial, primary and preantral follicles were identified in the largest cross-section of each ovary. Percentage (%) of normal follicles of each developmental stage of oogenesis was calculated. The data showed that compared to controls, there was a dose-related decrease in percentage of normal follicles in each developmental stage. And the weights of ovary and uterus were also reduced with doses of irradiation. Moreover, these effects were much more significant in the Bragg peak region and the region close to the Bragg peak than in the beam's entrance (the plateau region). Radiosensitivity varied in different follicle maturation stages. Primordial follicles, which are thought to be extremely sensitive to ionizing irradiation, were reduced by 86.6%, while primary and preantral follicles reduced only by 72.5% and 61.8% respectively, by exposure with 6 Gy of 12C6+ ion in the Bragg peak region and the region close to the Bragg peak. The data suggested that due to their optimal depth-dose distribution in the Bragg peak region, heavy ions are ones of the best particles for radiotherapy of tumors located next of vital organs or/and surrounded by normal tissues, especially radiosensitive tissues such as gonads.

Ginsenoside R(e) increases fertile and asthenozoospermic infertile human sperm motility by induction of nitric oxide synthase.

We investigated the effects of Ginsenoside R(e) on human sperm motility in fertile and asthenozoospermic infertile individuals in vitro and the mechanism by which the Ginsenosides play their roles. The semen samples were obtained from 10 fertile volunteers and 10 asthenozoospermic infertile patients. Spermatozoa were separated by Percoll and incubated with 0, 1, 10 or 100 microM of Ginsenoside R(e). Total sperm motility and progressive motility were measured by computer-aided sperm analyzer (CASA). Nitric oxide synthase (NOS) activity was determined by the 3H-arginine to 3H-citrulline conversion assay, and the NOS protein was examined by the Western blot analysis. The production of sperm nitric oxide (NO) was detected using the Griess reaction. The results showed that Ginsenoside R(e) significantly enhanced both fertile and infertile sperm motility, NOS activity and NO production in a concentration-dependent manner. Sodium nitroprusside (SNP, 100 nM), a NO donor, mimicked the effects of Ginsenoside R(e). And pretreatment with a NOS inhibitor N(omega)-Nitro-L-arginine methyl ester (L-NAME, 100 microM) or a NO scavenger N-Acetyl-L-cysteine (LNAC, 1 mM) completely blocked the effects of Ginsenoside R(e). Data suggested that Ginsenoside R(e) is beneficial to sperm motility, and that induction of NOS to increase NO production may be involved in this benefit.

Chromosomal aberrations induced by (12)C6+ ions and 60Co gamma-rays in mouse immature oocytes.

The ovaries of Kun-Ming strain mice (3 weeks) were irradiated with different doses of (12)C6+ ion or (60)Co gamma-ray. Chromosomal aberrations were analyzed in metaphase II oocytes at 7 weeks after irradiation. The relative biological effectiveness (RBE) of (12)C6+ ion was calculated with respect to 60Co gamma-ray for the induction of chromosomal aberrations. The (12)C6+ ion and 60Co gamma-ray dose-response relationships for chromosomal aberrations were plotted by linear quadratic models. The data showed that there was a dose-related increase in frequency of chromosomal aberrations in all the treated groups compared to controls. The RBE values for (12)C6+ ions relative to 60Co gamma-rays were 2.49, 2.29, 1.57, 1.42 or 1.32 for the doses of 0.5, 1.0, 2.0, 4.0 or 6.0 Gy, respectively. Moreover, a different distribution of the various types of aberrations has been found for (12)C6+ ion and 60Co gamma-ray irradiations. The dose-response relationships for (12)C6+ ion and 60Co gamma-ray exhibited positive correlations. The results from the present study may be helpful for assessing genetic damage following exposure of immature oocytes to ionizing radiation.

Current status of tumor radiogenic therapy.

Although tumor gene therapy falls behind its clinical use, the combination of irradiation and gene therapy is full of promise in cancer therapy based on traditional radiotherapy, chemotherapy and surgery. We have termed it as radiogenic therapy. This review focuses on the following aspects of radiogenic therapy in recent years: improvement of gene transfer efficiency by irradiation, radiotherapy combined with cytokine gene delivery or enhancement of the immunity of tumor cells by transgene, direct stimulation by radiation to produce cytotoxic agents, increase of tumor cell radiosensitivity in gene therapy by controlling the radiosensitivity genes and adjusting the fraction dose and interval of radiation so as to achieve the optimum antitumor effect while reducing the normal tissue damage, radioprotective gene therapy enhancing radiation tumor killing effect while protecting the normal tissue and organs with transgene using transfer vectors.

Effect of exogenous wild-type p53 on melanoma cell death pathways induced by irradiation at different linear energy transfer.

We investigated the effect of exogenous wild-type p53 on the radiation-induced cells apoptosis and necrosis at different levels of linear energy transfer (LET) to evaluate its mechanisms. The human melanoma cell line A375, which bears wild-type p53 gene status, was used, as well as the transfectant A375 cells (A375/p53) with adenoviral vector containing the wild-type p53 gene. We exposed these cells to X-rays and to accelerated carbon-ion (C-) beams. Cellular sensitivities were determined by using clonogenic assay. Apoptotic and necrotic cell deaths were determined morphologically by dual staining (acridine orange and ethidium bromide) using fluorescence microscopy. We discovered that (1) there was no significant difference in survival fraction between A375 cells and A375/p53 cells irradiated by C-beams with greater than 32 KeV/microm LET, (2) although apoptosis in the two kinds of cells increased in an LET-dependent manner, exogenous wild-type P53 induced cell apoptosis efficiently in A375/p53 relative to A375 cells with X-rays or high-LET irradiation, and (3) by high-LET irradiation, the number of necrosis in A375 cells increased significantly (P < 0.05) in comparison with A375/p53 cells. These results indicate that in high-LET irradiation apoptosis induction is p53 dependent partly and exogenous wild-type P53 plays an important role in modulating cell death type, although there was no significant difference in cellular radiosensitivities. Our observation in the study offers the potential application of high-LET radiation combined with p53 in the management of human patients with melanoma.

Allogeneic peripheral blood hematopoietic stem cell transplantation in malignant hematopoietic diseases.

To evaluate the use of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for treatment of acute and chronic leukemia, from March 1997 to January 2003, 21 adult patients with malignant hematopoietic diseases underwent allo-PBSCT from HLA-identical siblings (19 patients) and haplo-identical mother (one) and one B point site mismatched sibling (one). All donors were mobilized with G-CSF for 4 days and peripheral blood stem cells were collected by CS-3000 separator. The conditioning regimen included the high dose combination chemotherapy and TBI. Cyclosporine-A (CsA) plus a short course of MTX was used for GVHD prophylaxis in all patients. The results showed that after trans plantation, median time for the recovery of granuocyte > or = 0.5 x 10(9)/L and platelets > or = 20 x 10(9)/L were 12 (10 - 20) and 15 (11 - 35) days, respectively. Acute GVHD was observed in 8/17 patients (47%), of which one transplanted from HLA-haploidentical mother. Chronic GVHD occurred in 12/17 patients (70%). All of four female survivals did not show acute and chronic GVHD. Day 100 transplantation-related mortality was 14% (3/21). Relapse occurred in two patients (9.5%) who underwent allo-PBSCT in stage of non-remission at one and six months. After follow-up of 40 (15 - 70) months, 11 patients (52.4%) are still disease-free survival. These results suggested that peripheral blood stem cells produce a faster hematopoietic recovery and a lower relapse of leukemia. The rate of aGVHD is not increased when using the peripheral blood as source of stem cells; however, cGVHD continues to be a significant problem. Donors tolerated the procurement procedure without complications.