Alteration and significance of serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma: a retrospective study based on LEGEND-2 / 中华血液学杂志

Objective: To explore the dynamic changes in serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma (R/R MM) based on LEGEND-2. Methods: The data of patients with R/R MM who underwent BCMA-CAR-T therapy at our hospital between March 30, 2016, and February 6, 2018, were retrospectively collected. Serum lipid levels, controlled nutritional status (CONUT) score, and other clinical indicators at different time points before and after CAR-T-cell infusion were compared and analyzed. The best cut-off value was determined by using the receiver operator characteristic (ROC) curve. The patients were divided into high-CONUT score (>6.5 points, malnutrition group) and low-CONUT score groups (≤6.5 points, good nutrition group), comparing the progression-free survival (PFS) and total survival (OS) of the two groups using Kaplan-Meier survival analysis. Results: Before the infusion of CAR-T-cells, excluding triglycerides (TG), patients' serum lipid levels were lower than normal on average. At 8-14 d after CAR-T-cell infusion, serum albumin (ALB), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and apolipoprotein A1 (Apo A1) levels dropped to the minimum, whereas CONUT scores reached the maximum. In addition to TG, apolipoprotein B (Apo B) levels increased compared with baseline. After CAR-T-cell therapy, the patients' serum lipid levels significantly increased with well-improved nutritional status. Spearman's related analysis showed that TC, HDL, and ApoA1 levels after CAR-T-cell injection were significantly negatively correlated with the grade of cytokine-release syndrome (CRS) (r=-0.548, P=0.003; r=-0.444, P=0.020; r=-0.589, P=0.001). Furthermore, survival analysis indicated that the CONUT score was unrelated to PFS, and the median OS of patients with R/R MM in the high-CONUT score group was shorter than that in the low-CONUT score group (P=0.046) . Conclusions: During CAR-T-cell therapy, hypolipidemia and poor nutritional status were aggravated, which is possibly related to CRS. The patients' serum lipid levels and nutritional status were significantly improved after CAR-T-cell treatment. The CONUT score affected the median OS in patients treated with CAR-T-cells. Therefore, specific screening and intervention for nutritional status in patients receiving CAR-T-cell therapy are required.

Cloning of New Antigen Gene MLAA-34 Promoter and Identification of Core Region in Acute Monocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To clone the promoter sequence of acute monocytic leukemia new antigen gene.MLAA-34 and identify its promoter core region.@*METHODS@#The full-length fragment of MLAA-34 gene promoter region was amplified by PCR, then was ligated into pGL3-Basic vector, and the recombinant plasmid was cloned. Constructed a series of MLAA-34 gene promoter 5' flanking region truncated plasmid. These recombinant plasmids were transfected into U937 and HEK293 cells, and the dual luciferase reporter gene was used to detect the promoter activity of each fragment to determine the minimum active region. Transcription factor binding sites were analyzed by bioinformatics methods.@*RESULTS@#The recombinant plasmid containing MLAA-34 promoter sequence and its truncated plasmid were successfully constructed, and the promoter activity was significantly increased as compared with the empty vector (P＜0.001). The minimal active region of MLAA-34 located between 402 bp and 200 bp. It contained multiple transcription factor binding sites such as E2F1, MZF-1, SP1, USF2 and STAT3.@*CONCLUSION@#The promoter of luciferase reporter gene has been successfully constructed with different deletion fragments of MLAA-34, and its core promoter region may contain multiple transcription factor sequence.

Management of cytokine release syndrome related to CAR-T cell therapy / 医学前沿

Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.

Screening of Serum Peptidome-Based Biomarker for Multiple Myeloma Renal Impairment / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To screen serum peptide associated with renal impairment in patients with multiple myeloma(MM) and search early biomarker of MM renal impairment.</p><p><b>METHODS</b>The weak cation exchange magnetic bead combined with matrix assisted laser desorption/ionization time of flight mass spectrometry was used to compare and analyze serum peptidome of MM with or without renal impairment.</p><p><b>RESULTS</b>There were 18 peptide peaks with statistical significance in the molecular weight range from 700 to 10 000 Da(P<0.05), among them 7 peptides were upregulated and 11 were downregulated. The Quick Classifier diagnostic model composed of 3 peptides, which can strongly distinguish MM patients with or without renal impairment by means of Embedded Software. Its sensitivity and specificity were 97.14% and 94.12%, respectively. Peptides with molecular weight of 3908.85 Da and 3216.06 Da were significantly upregulated in MM patients with renal impairment, while the peptide with molecular weight of 2990.08 Da was significantly downregulated in MM patients with renal impairment.</p><p><b>CONCLUSION</b>Peptides associated with MM renal impairment obtained by serum peptidome technology can provide a new clue for early assessment and diagnosis of clinical MM renal impairment.</p>

Research progress in vasculogenic mimicry in multiple tumors / 中南大学学报(医学版)

Vasculogenic mimicry (VM) is a brand-new tumor vascular pattern with the ability to form vessellike networks without participation of endothelial cells and independent on angiogenesis.It can provide adequate blood supply for tumor growth.The formation of VM involves multiple molecule mechanisms and signal pathways,including cancer stem cell and epithelial-mesenchymal transition.As a unique blood-supply pattern,VM is associated with cancer invasion,metastasis and poor prognosis.Because of its important role in cancer progression,VM will become a new target for therapy of cancers.

Screening of Serum Markers in Primary Immune Thrombocytopenia / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analyze the serum protein fingerprints of immune thrombocytopenia (ITP) patients and healthy controls by using weak cation exchange nanometer magnetic beads and MALDI-TOF-MAS technology, to identify the proteins with different expression, to establish the diagnostic model for ITP and to explore the pathogenesis of ITP.</p><p><b>METHODS</b>A total of 40 patients with ITP and 40 healthy controls were selected, the serum protein components were captured by using weak cation exchange nanaometer magnetic beads, the protein spectra of all specimens were detected by Autoflex II matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI- TOF-MS) and then the data were analyzed by CliprotoolsTM2.2 software, by which the distinct protein molecules were screened to set up ITP diagnostic model. To identify the established model, the sera of 20 ITP patients and 20 healthy controls were selected to make category and cross validations.</p><p><b>RESULTS</b>The detection of Clinprot system and the analysis of CliprotoolsTM2.2 software showed that about 55 protein peaks were detected with the range of 700 Da to 10 000 Da of molecular weight in the protein spectrum of serum speciments from 40 ITP patients and 40 healthy controls. Compared with healthy controls, 19 protein expression peaks with statistically significant difference were found in ITP patients (P < 0.05), among them 5 expressions were up-regulated and 14 expressions were down-regulated. The diagnostic model on basis of Supervised Neural Network Algorithm (SNN) was established through 10 MS peaks with strongest capability in ITP group and control group automatically distinguished by software, and it is expected that the sensitivity of model group reached to 100%, and the specificity to 100%. The category validation showed that this diagnostic model correctly identificed all 20 ITP patients and 20 healthy controls, and in cross validation, the model sensitivity was 100% and the specificity was 100%.</p><p><b>CONCLUSION</b>The ITP SNN model ertablished by using ChinProt System with high flax and good repetition is composed of 10 protein peaks with significant difference, this model can effectively distinguish ITP patients and healthy controls.</p>

Comparison of the Effectiveness and Safety of Combined Chemotherapy with PEG-Asp for Treatment of ALL and T-NHL Patients / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To explore the effectiveness and safety of combined chemotherapy with pegasparaginase (PEG-Asp) for treatment of patients with acute lymphoblastic leukemia (ALL) and T cell non-Hodgkin's lymphoma (T-NHL) patients.</p><p><b>METHODS</b>A total of 62 ALL or T-NHL patients were diagnosed and treated in our department and were enrolled in this study. Among them, 22 patients received the combined chemotherapy with PEG-Asp, while the other 40 patients received the standard chemotherapy with L-asparaginase (L-Asp) as the control. Therapeutic effectiveness, adverse effects, duration and expense of hospitalization, treatment-related mortality and survival were evaluated and compared in 2 different groups.</p><p><b>RESULTS</b>In group of combined chemotherapy with PEG-Asp, the overall response rate was 90.91% (20 cases), among them CR rate and PR rate are 77.27% (17 cases) and 13.64% (3 cases), respectively. In the group of standard chemotherapy with L-Asp, the overall response rate was 87.5% (35 cases), among them CR rate and PR rate were 72.5% (29 cases) and 15% (6 cases), respectively. The difference neither between PEG-Asp and L-Asp chemotherapy groups nor between ALL and T-NHL subgroups was significant (P > 0.05). The 6-month and 12-month overall survival rates were not significantly different between the PEG-Asp and L-Asp chemotherapy groups, respectively (P > 0.05). The adverse effects were identified as degree 1-2 according to the WHO criteria of drug toxicity. Neither the adverse effects identified as degree 3-4 nor the treatment-related death were observed. Expect for allergy and hyperglycaemia, the difference of side-effect incidence between the two groups were not significant (P > 0.05). The treatment for all the patients in PEG-Asp chemotherapy group was completed, while the treatment with L-Asp was completed only in 29 cases. Moreover, both average duration and expense of hospitalization after the combined chemotherapy were less than the control.</p><p><b>CONCLUSION</b>With higher response rate, lower drug toxicity and allergy incidence, the combined chemotherapy with PEG-Asp can replace the standard chemotherapy with L-Asp in the treatment of ALL and T-NHL. The optimization of the combined chemotheropeutic protocols for more cases and long-term survival rates need to further and deeply explorate.</p>

Effects of Thalidomide on Peripheral Blood Th17 Cells of Patients with Multiple Myeloma / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To explore the change of T help cell 17 (Th17) in the peripheral blood of patients with multiple myeloma (MM) before and after treatment with thalidomide.</p><p><b>METHODS</b>A total of 35 MM patients treated with thalidomide and 35 healthy controls were enrolled in this study. The percentage of Th17 cells were detected by flow cytometry. The mRNA levels of retinoid-related orphan receptor gamma-t (RORγt) were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and the plasm IL-17 levels were measured by enzyme linked immunosorbent assay (ELISA).</p><p><b>RESULTS</b>The percentage of Th17 cells, the mRNA expression of RORγt and the plasm IL-17 levels in patients with MM were statistically higher than those in normal controls (P < 0.05). The percentage of Th17 cells was not correlate with the sex, age, disease type, globulin, immune globulin, light chain, M-protein and the proportion of plasmocytes (P > 0.05), but correlated with ISS stage, the level of β2-microglobulin and the plasm IL-17 levels (P < 0.05). The percentage of Th17 cells, the mRNA expression of RORγt and the plasm IL-17 levels in patients with response to thalidomide were statistically lower than those in patients before treatment (P < 0.05).</p><p><b>CONCLUSION</b>The Th17 cells increase in the peripheral blood of patients with MM, the Th17 cells may participate in the occurrence of MM. Thalidomide may exert anti-MM through down-regulating Th17 cells.</p>

Coculture of human umbilical vein endothelial cells and bone marrow mesenchymal stem cells / 中国组织工程研究

BACKGROUND:Coculture of bone marrow mesenchymal stem cel s and human umbilical vein endothelial cel s can improve both osteogenic and angiogenic outcomes and provide a promising strategy for bone tissue engineering and osteanagenesis. OBJECTIVE:To summarize recent researches and related progresses in coculture of human umbilical vein endothelial cel s and bone marrow mesenchymal stem cel s. METHODS:A computer-based online search of CNKI database from January 2000 to March 2012, PubMed database and Web of Knowledge database from January 1980 to March 2012, was performed with the keywords of“human umbilical vein endothelial cel s, bone mesenchymal stem cel s, coculture, tissue engineering”both in Chinese and English. A total of 135 articles were screened out, 103 of them were excluded due to unrelated study objective and repeated contents, and final y 32 articles were involved in further analysis. RESULTS AND CONCLUSION:At present, studies on coculture of bone marrow mesenchymal stem cel s and human umbilical vein endothelial cel s mainly focus on mimicking in vivo environments, the interactions between cel s, and the influence of different cel ratios and culture media. Most of these researches play important roles in bone tissue engineering and bone regeneration therapy, but the mechanism of action and concrete regulation in vivo between bone marrow mesenchymal stem cel s and human umbilical vein endothelial cel s stil need further research and analysis.

Preventive and therapeutic effects of xiaobanxia fuling decoction on cisplatin-induced pica rats / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To investigate the preventive and therapeutic effects of Xiaobanxia Fuling Decoction (XBFD) on cisplatin-induced pica rats and to study its mechanism.</p><p><b>METHODS</b>Forty-two male Sprague-Dawley rats were randomly divided into the following 7 groups, i.e., the blank control group, the model group, the high-, middle-, and low-dose XBFD groups (at the daily dose of 30, 15, and 7. 5 g/kg, respectively), the aprepitant (at the daily dose of 13 mg/kg), and pure Chinese medicine group (at the daily dose of XBFD 15 g/kg), 6 in each group. On the 3rd day of this study, 3 mg/kg cisplatin was intraperitoneally injected to rats except the blank control group and the model group to establish the pica rat model. The consumptions of kaolin, food, and the general situation of rats were observed. The protein and mRNA expressions of neurokinin 1 receptor (NK1R) in both the medulla oblongata and the gastric antrum were measured by immunohistochemical assay and Real-time fluorescent quantitative PCR respectively on the sixth day of this study.</p><p><b>RESULTS</b>On the third, fourth, and fifth day of this study, the consumption of kaolin of rats significantly increased when compared with the blank control group (P<0.01). Compared with the model group, the consumption of kaolin significantly decreased in the high-, middle-, and low-dose XBFD groups on the third, fourth, and fifth day of this study (P<0.05). The food intake of rats in the high-dose XBFD groups significantly increased when compared with the model group on the third day of this study (P<0.05). The protein and mRNA expressions of NK, R in the medulla oblongata and the gastric antrum significantly decreased in the high- and middle-dose XBFD groups when compared with the model group (P<0.05).</p><p><b>CONCLUSIONS</b>XBFD could prevent and treat cisplatin-induced pica in rats. Its effect might be correlated with decreasing expressions of NK, R in the medulla oblongata and the gastric antrum.</p>

Fluorodeoxyglucose positron emission tomography/computed tomography and magnetic resonance imaging of uterine leiomyosarcomas: 2 cases report / 中华医学杂志(英文版)

Uterine leiomyosarcoma is an uncommon malignant neoplasm of smooth muscle origination and is associated with a poor prognosis. We report two cases of uterine leiomyosarcoma that presented with pulmonary metastases. 2-deoxy-2-(¹⁸F)fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) was performed to identify the primary carcinoma and found the focus located in the uterus. The follow-up magnetic resonance imaging (MRI) confirmed the diagnosis was uterine leiomyosarcoma.

Preliminarily screening of serum characteristic markers in acute myeloid leukemia and clinical significance / 中国实验血液学杂志

This study was purposed to preliminarily screen characteristic tumor markers of acute myeloid leukemia (AML) and to investigate the serum proteomics characteristics of patients with AML and their significance in pathogenesis. 14 patients with AML and 28 healthy controls were enrolled in this study. The serum protein components were captured by weak cation exchange nanometer magnetic beads, the protein mass-spectra of all samples were detected by Autoflex II matrix-assisted laser desorption/ionization time of flight mass spectrometer, and the detection data were analyzed by means of CliprotoolsTM2.2 software, then the differential protein molecules were screened and the diagnostic model was established. Sera of 7 AML patients and 14 healthy controls were selected to verify the established model by using blind test. The results indicated that about 69 protein peaks could be detected within the range of 0.7-10 kD in protein spectra of serum samples from AML patients and controls. Compared with healthy controls, there were 44 statistically differential expression peaks in AML group (p<0.0001). Among them, 10 protein peaks were upregulated protein peaks and 34 protein peaks were downregulated. Diagnostic model was established on the basis of Quick Classifier Algorithm (QC), and the three mass peaks had the strongest power for software to automatically distinguish AML group from control group. Mass charge ratios (m/z) were 3216.57, 4089.7, and 7762.87 respectively. Sensitivity was expected as 86.4% while 82.8% in this established model group. Category validation showed that this diagnostic model correctly identified all 6 cases out of AML and 12 cases out of 14 healthy controls. In cross validation, the model sensitivity and specificity both were 85.7%. It is concluded that the AML QC model is composed of three protein peaks, which can effectively distinguish AML patients from healthy controls. Owing to higher sensitivity and specificity, they may act as serum tumor markers of AML. Among the three proteins, the one with m/z 7762.87 is the platelet-derived protein chemokine (PF4) protein. This finding will probably provide significant experimental evidence for understanding pathogenesis, molecular type, prognosis and treatment effect of AML.

Primary discussion on the classification of the TCM patterns and measurable diagnosis of 760 cases of protracted abstinent syndrome by heroin-addiction / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To discuss the TCM pattern classification and measurable diagnosis criterion of the protracted symptoms of heroin-addiction abstinence (PSHAA).</p><p><b>METHODS</b>Through literature review and clinical study, the concept of TCM patterns and diagnostic standard were established, and a TCM pattern scale for quantitatively analysis of PSHAA was formulated. The scale were used on the clinical investigation on the abuser for 5 times on day 15, 30, 60, 90 and 120 after abstinence. Then the TCM patterns of PSHAA was classified using methods of DME and quantitative diagnosis, to create a corresponding scale of diagnostic indexes referring maximum likelihood method.</p><p><b>RESULTS</b>(1) The TCM patterns of PSHAA commonly seen were Toxin-stasis accumulation (TSA) with Qi-blood insufficiency, TSA with Qi-yin deficiency, TSA with Yin-deficiency and Fire-excess and TSA with Yin-Yang deficiency. (2) The retrospective and prospective verification of the scale of diagnostic indexes showed it has high sensitivity and speciality, with low rates of misdiagnosis and of missed diagnosis.</p><p><b>CONCLUSION</b>It is feasible to develop measurable diagnosis on the TCM patterns of PASAA using DME method and measurable diagnostic methods. The scale of diagnostic indexes formulated with the maximum likelihood method of quantified diagnosis has a certain clinical practicability.</p>

A Case of Visceral Botryomycosis Accompanied by Early Lung Cancer / 대한내과학회지

Botryomycosis is a rare, chronic and suppurative di- sease that is often mistaken clinically and histologically for a fungal infection, because the histologic feature shows a cluster of bacteria found within an eosinophilic matrix or capsule, giving the appearance of granules mimicking the sulfur granules of actinomycosis. Staphy- lococcus aureus is the most common organism cultured from lesions of botryomycosis, but other bacteria have also been isolated and implicated, including Psudomonas aeruginosa, E. coli, Proteus spp., Bacillus spp.. In some case, multiple pathogenic bacteria were found on cul ture. This disease has two patterns of organ involve ment. The more common type is cutaneous type, which involves the skin, subcutaneous soft tissue, muscle and bone. The other is visceral type which involves the lungs, liver, tongue, orbit, bowel, brain, kidney or pros tate. We report a case of brain and pulmonary botry omycosis in a 60 year-old man, who have early lung cancer. Botryomycosis was diagnosed by brain mass removal, PCNA and bronchoscopy, and lung cancer was detected incidentally by bronchoscope. The patient was treated with the Penicillin G after operation of brain mass, and right pneumonectomy was done.

A Case of Hantavirus Pulmonary Syndrome / 결핵

Hantavirus pulmonary syndrome(HPS) is a systemic disease that is caused by a newly discorved and characterized virus of the Hantavirus genus, which is most frequently referred to as the sin nombre virus. The clinical syndrome resembles other hantavirus syndromes worldwide, except that it is characterized by a brief prodromal illness followed by rapidly progressive, noncardiogenic edema, and that it is more deadly than any previously recognized hantavirus infection. The clinical manifestations of HPS are characterized by four clinical phases prodrome, pulmonary edema and shock, diuresis, and convalescence. Mortality is greatest in the first 24 hours of the pulmonary edema and shock phase of the illness. These phases are strikingly similar to the clinical phases of Hemorrhagic fever with renal syndrome(HFRS) induced by Hantaan virus, except that HPS has not been associated with renal failure and Disseminated intravascular coagulation(DIC). We here report a case of hantavirus pulmonary syndrome developed in a 58 year-old man. He had a flu-like illness followed by the rapid onset of respiratory failure due to noncardiogenic pulmonary edema. HPS was diagnosed by clinical manifestations, identification of high titer antibody to Hantaan virus antigen and histologic finding of transbronchial lung biopsy (TBLB) specimen. The patient was treated with mechanical ventilation and initial corticosteroid pulse therapy resulting in successful outcome.