Challenges and optimal strategies of CAR T therapy for hematological malignancies / 中华医学杂志(英文版)

Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells' productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.

Different sites of extranodal involvement may affect the survival of patients with relapsed or refractory non-Hodgkin lymphoma after chimeric antigen receptor T cell therapy / 医学前沿

Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T (CAR-T) cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma (r/r NHL) have not been well characterized. In this study, we found that the different sites of extranodal involvement may affect response, overall survival (OS), and progression-free survival (PFS) in patients with r/r NHL treated with anti-CD19 CAR-T cells. In a cohort of 32 treated patients, 12 (37.5%) and 8 (25%) patients exhibited soft tissue lymphoma and bone marrow (BM) infiltrations, respectively, and 13 (41%) patients exhibited infiltration at other sites. The factors that may affect prognosis were identified through multivariable analysis. As an independent risk factor, soft tissue infiltration was the only factor significantly correlated with adverse prognosis (P < 0.05), whereas other factors did not reach statistical significance. Furthermore, the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy. PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone. Thus, anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.

Chimeric antigen receptor T-cell therapy: a promising treatment modality for relapsed/refractory mantle cell lymphoma / 医学前沿

Mantle cell lymphoma (MCL) is a distinct histological type of B-cell lymphoma with a poor prognosis. Several agents, such as proteasome inhibitors, immunomodulatory drugs, and inhibitors of B cell lymphoma-2 and Bruton's tyrosine kinase have shown efficacy for relapsed or refractory (r/r) MCL but often have short-term responses. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin's lymphoma. However, long-term safety and tolerability associated with CAR T-cell therapy are not defined well, especially in MCL. In this report, we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy. CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient. This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL, who are generally elderly and have comorbid conditions.

Urinary tract lymphoma: a clinical analysis of 16 cases and review of literature / 白血病·淋巴瘤

Objective To analyze the clinical features, treatment outcomes and prognosis of patients with urinary tract lymphoma. Methods The clinical data of 16 patients in Tongji Hospital of Tongji University from January 2009 to April 2016 were collected and retrospectively analyzed. Results The median age of these patients was 68 years. The onset symptoms of 14 cases were related to urinary system and imaging studies of 10 cases showed masses in the urinary system. The onset regions of lymphoma included:4 cases were renal lymphoma, 5 cases were adrenal lymphoma, 5 cases were testicular lymphoma, 1 case was prostate lymphoma and 1 case was from urethral mouth. The histological type of 12 cases was diffuse large B-cell lymphoma and 10 patients were non-germinal center B cell-like (non-GCB) molecular profiling. Twelve cases belonged to Ann Arbor stages ⅢE- ⅣE, 10 cases had international prognostic index scores ≥3, and 7 cases had B symptoms. 10 patients were confirmed by surgery. Fourteen cases accepted rituximab-containing regimen chemotherapy. Five cases achieved complete response and 3 were partial response. Conclusions The clinical manifestations and imagine examination of patients with urinary tract lymphoma are lack of specificity. The clinical features are highly aggressive and most of the patients are diagnosed at advanced stage. The main histological type is diffuse large B-cell lymphoma and non-GCB molecular profiling. Treatment regimens include surgery combined with chemotherapy and radiotherapy. Earlier diagnosis and treatment may improve the survival of patients.

A multicenter, retrospective study of pathogenic bacteria distribution and drug resistance in febrile neutropenic patients with hematological diseases in Shanghai / 中华血液学杂志

Objective@#To investigate the pathogen spectrum distribution and drug resistance of febrile neutropenic patients with hematological diseases in Shanghai.@*Methods@#A retrospective study was conducted on the clinical isolates from the febrile neutropenic patients hospitalized in the departments of hematology in 12 general hospitals in Shanghai from January 2012 to December 2014. The drug susceptibility test was carried out by Kirby-Bauer method. WHONET 5.6 software was used to analyze pathogenic bacteria and drug susceptibility data.@*Results@#A total of 1 260 clinical isolates were collected from the febrile neutropenic patients. Gram-positive bacteria accounted for 33.3% and Gram-negative bacteria accounted for 66.7%. Klebsiella pneumoniae (12.5%) , Stenotrophomonas maltophilia (9.5%) , Escherichia coli (9.1%) , Pseudomonas aeruginosa (8.7%) , Acinetobacter baumannii (6.6%) , Staphylococcus aureus (5.6%) and Enterococcus faecium (5.0%) were ranked in the first 7 of all pathogens. In the respiratory tract secretions specimens, non-fermented strains accounted for 56.2%. Stenotrophomonas maltophilia accounted for 15.2%. Enterobacteriaceae and coagulase-negative Staphylococci accounted for 42.3% (104/246) and 32.6% (85/246) respectively in blood samples. Enterobacteriaceae and Enterococcus bacteria accounted for 39.4% (76/193) and 28.5% (55/193) respectively in pus specimens. The detection rates of methicillin resistant Staphylococcus aureus (MRSA) and methicillin resistant coagulase negative Staphylococci (MRCNS) were 54.3% and 82.5%, respectively. Staphylococcus bacterial strain was not found to be resistant to linezolid, vancomycin and teicoplanin. The detection rate of Enterococcus vancomycin-resistant strains was 8.9%. Enterococcus was not detected resistance to oxazolidinone strains. Enterobacteriaceae bacteria were highly sensitive to carbapenems. The resistance rate of Pseudomonas aeruginosa to imipenem and meropenem was 34.1% and 15.8%, respectively. Stenotrophomonas maltophilia was more sensitive to minocycline hydrochloride, levofloxacin and sulfamethoxazole. The resistance rate of Acinetobacter baumannii only to cefoperazone-sulbactam was less than 10.0%. The antibiotic resistance rate of Klebsiella pneumoniae, Stenotrophomonas maltophilia, Pseudomonas aeruginosa and Acinetobacter baumanii to most of common antibiotics was lower than that of the CHINET surveillance.@*Conclusions@#The pathogenic strain distribution in common infection sites of febrile neutropenic patients was characterized. Bacterial resistance surveillance was better than the CHINET nationwide large sample surveillance in China.

Analysis of protein tyrosine phosphatase 1B gene mutation in myeloproliferative neoplasms / 白血病·淋巴瘤

Objective To analyse protein tyrosine phosphatase 1B (PTP1B) gene mutation in myeloproliferative neoplasms (MPN).Methods DNA sequencing technology was used to detect DNA sequences of PTP1B in MPN patients (n =84) and normal controls (n =37).Results For Exon1-6,Exon9 and Exon10,84 cases of MPN patients and 37 cases of control group were not detected mutation.For EXON 8,18 of 84 MPN patients had Exon8 C/T heterozygous mutation and 10 of 37 normal controls were detected C/T heterozygous mutation.There was no significant difference between MPN patients and normal controls (x2 =0.453,P =0.501).Exon7 was detected in 38 MPN patients and 2 cases of patients were found C/T heterozygous mutation,while in the control group,1 case with G/C heterozygous mutation.All of the cases were not detected homozygous mutation.Conclusion Using DNA sequencing technology to detect gene mutations of PTP1B,there is no significant difference between MPN patients and normal controls.

Treatment of Ph-adult acute lymphoblastic leukemia patients with Tongji-96 regimen / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the efficacy and side effects of the consecutive chemotherapeutic protocol, Tongji-96, for adult patients with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph-aALL).</p><p><b>METHODS</b>A retrospective analysis was conducted on 95 cases of Ph-aALL patients treated between January 2004 and December 2012 with Tongji-96 regimen in Tongji hospital, Shanghai.</p><p><b>RESULTS</b>Among these 95 patients, the overall complete remission (CR) rate was 92.6%, 7-year overall survival (OS) and event-free survival (EFS) rates were (39.3±5.9)% and (31.5±5.3)%, respectively, with the median survival of 28 months. Based on multivariable COX proportional hazards regression model analysis, patients with the poor karyotype and failed to achieve CR after first course induction therapy had a higher risk of mortality compared to those who had good or normal cytogenetics and achieved CR after 1 course of induction treatment [the risk ratios (RR) were 3.380 (95% CI 1.530-7.463, P=0.003) and 3.005 (95% CI 1.522-5.933, P=0.002)，respectively]. By means of Kaplan-Meier analysis and Log-rank test，patients aged less than 60 years and successively achieved CR after first induction therapy had more favorable 7-year OS and EFS rates. Patients with normal karyotype and hyperdiploidy had significantly higher 2-year OS and EFS rates compared with those with complex karyotype, t(4;11) translocation and other karyotypes.</p><p><b>CONCLUSION</b>Age (60 years as the cut-off)，treatment courses for achieving CR and cytogenetics were predictive factors for the prognosis of Ph-aALL from this retrospective study. As a comprehensive and sequential therapy protocol, Tongji-96 regimen was proved to obtain long-term survival, reduce risks for relapse and improve outcomes for part Ph-aALL patients.</p>

Advances in the diagnosis and treatment of adult acute lymphoblastic leukemia / 中国癌症杂志

Acute lymphoblastic leukemia (ALL) is a common hematopoietic malignancy. The initial complete remission rates of adult ALL reach over 80%, but most of the patients eventually relapse and the long-term survival re-mains poor. This article reviewed advances in the biological features and treatment of adult ALL during the past decade with a view to further improving the survival quality rate of the patients.

Comparison of the influence of Eperythrozoon infection on human and mouse erythrocytes / 中华传染病杂志

Objective To evaluate the influence of Eperythrozoon infection on human and mouse erythrocytes and to explore the pathogenesis of Eperythrozoonosis. Methods The specific gene fragment of Eperythrozoon was detected by polymerase chain reaction (PCR) from the venous blood samples of five patients infected with Eperythrozoon. The complement receptor type I (CD35) expression on erythrocytes of these five patients was determined by flow cytometry. Thereafter, the Eperythrozoons were purified from human samples and injected into mice through the tail veins. Blood smear microscopy, PCR and transmission electron microscopy were used to assure the successful infection. The hematological indicators of human and mice, such as red blood cell (RBC) count,hemoglobin (Hb) content, hematocrit and superoxide dismutase (SOD) were evaluated. All results were analyzed by t test. Results More than 80% of treated mice were confirmed to be infected with Eperythrozoon successfully. A fragment of 801 bp specific gene of Eperythrozoon was detected by PCR in samples from both infected patients and infected mice, which were not detected in samples from healthy control people or control mice. CD35 was highly expressed on the erythrocytes of infected patients, but not expressed on the erythrocytes of infected mice. Both RBC counts and Hb content dramatically decreased in infected patients and infected mice. Hematocrit and the activity of SOD also slightly decreased in infected patients and infected mice. Conclusions Eperythrozoon can spread between human and mice and destroy erythrocyte structure. Eperythrozoon can upregulate CD35 expression in human, but there is no CD35 expression in mice.

The expression and significace of immunity associated genes mRNA in patients with pulmonary embolism / 中华内科杂志

ssociated genes,especially down-regulated expression of T cell mediated function genes,in patients with PE indicates that the etiology of PE might be related to viral infection.

Experimental study of apoptosis in leukemic cell lines induced by combined use of Bevacizumab and chemotherapeutic drug / 白血病·淋巴瘤

Objective To investigate the potential application of targeting at vascular endothelial growh factor (VEGF) induced apoptosis in leukemic cell lines by combined use of Bevacizumab and chemotherapeutic drug. Methods Leukemic cells were treated with several drugs at different concentrations in culture. The effect of VEGF, Bevacizumab and co-treated with Ara-C on leukemic cells proliferation were evaluated by CCK-8 and apoptosis and cell cycle were detected by flow cytometry (FCM). Results VEGF could enhance the proliferation of leukemic cells and caused a dose-dependent manner on U937 cell. It also increased the percentage of cells in S phase, tested by, and Bevacizumab group was decreased. Apoptotic rate of cells treated with Bevacizumab or co-treated with Bevacizumab and Ara-C for 48 h were significantly higher when compared with control or Ara-C group, respectively (P0.05). There was no significant difference in apoptotic rate between control and combined use of VEGF, Bevacizumab and Ara-C group(P>0.05). Conclusion VEGF could enhance the proliferation of some leukemic cells, and may contribute to leukemic cells survival and a resultant resistance to chemotherapy-triggered cell death. The study also showed that leukemic cells growth was significantly inhibited by Bevacizumab through directly against VEGF, and the sensitivity of leukemic cells for chemotherapeutic drug was increased.

The clinical outcome of childhood malignant lymphoma with bony erosion / 中国癌症杂志

Purpose:To study the clinical and imaging characteristics of childhood malignant lymphoma with bony erosion, and explore the treatment protocol and prognosis.Methods:Through pathologic tests, immunohistochemical studies and imaging analyses, 6 patients were diagnosed as malignant lymphoma with bony infiltration. The 6 cases were treated and followed up. Results:There were different kinds of bony involvement in CT and MIRI imaging in 6 patients. All cases were type B as to immunology classification. Following treatment by protocol MCP, 1 case was dead and the others are in constant compete remission (CCR). Conclusions:The childhood malignant lymphoma with bony involvement is rarely seen, it is relatively easy to diagnose by CT/MRI and pathologic tests. The prognosis is related to clinical classification. It can be treated by protocol MCP.