Plasmablastic lymphoma: current knowledge and future directions.

Plasmablastic lymphoma (PBL) is an aggressive non-Hodgkin lymphoma associated with HIV infection and immunodeficiency. However, PBL can also be seen immunocompetent individuals in recent studies. PBL was characterized by distinct clinical and pathological features, such as plasmablastic morphology and universal expression of plasma cell markers. The clinicopathologic features were different between HIV-negative and HIV-positive patients. Gene expression analysis identified the unique molecular feature in PBL, including frequent c-MYC rearrangement and downregulation of BCR signaling pathway. Despite the recent advances in the treatment of PBL, the prognosis of PBL patients remains dismal. The objectives of this review are to summarize the current knowledge on the epidemiology, molecular profiles, clinical and pathological features, differential diagnosis, treatment strategies, prognostic factors, and potential novel therapeutic approaches in PBL patients.

A national, multicenter, retrospective study of Castleman disease in China implementing CDCN criteria.

Background: Castleman disease (CD) is a group of rare and heterogenous lymphoproliferative disorders including unicentric CD (UCD), human herpesvirus-8(HHV-8)-associated multicentric CD (HHV8-MCD), and HHV-8-negative/idiopathic multicentric CD (iMCD). Knowledge of CD mainly comes from case series or retrospective studies, but the inclusion criteria of these studies vary because the Castleman Disease Collaborative Network (CDCN) diagnostic criteria for iMCD and UCD were not available until 2017 and 2020, respectively. Further, these criteria and guidelines have not been systematically evaluated. Methods: In this national, multicenter, retrospective study implementing CDCN criteria, we enrolled 1634 CD patients (UCD, n = 903; MCD, n = 731) from 2000 to 2021 at 40 Chinese institutions to depict clinical features, treatment options, and prognostic factors of CD. Findings: Among UCD, there were 162 (17.9%) patients with an MCD-like inflammatory state. Among MCD, there were 12 HHV8-MCD patients and 719 HHV-8-negative MCD patients, which included 139 asymptomatic MCD (aMCD) and 580 iMCD meeting clinical criteria. Of 580 iMCD patients, 41 (7.1%) met iMCD-TAFRO criteria, the others were iMCD-NOS. iMCD-NOS were further divided into iMCD-IPL (n = 97) and iMCD-NOS without IPL (n = 442). Among iMCD patients with first-line treatment data, a trend from pulse combination chemotherapy toward continuous treatment was observed. Survival analysis revealed significant differences between subtypes and severe iMCD (HR = 3.747; 95% CI: 2.112-6.649, p < 0.001) had worse outcome. Interpretation: This study depicts a broad picture of CD, treatment options and survival information in China and validates the association between the CDCN's definition of severe iMCD and worse outcomes, requiring more intensive treatment. Fundings: Beijing Municipal Commission of Science and Technology, CAMS Innovation Fund and National High Level Hospital Clinical Research Funding.

[Progress in the Treatment of Adult Langerhans Cell Histiocytosis --Review].

Langerhans cell histiocytosis (LCH) is a rare proliferative disease dominated by the proliferation of Langerhans cells, which is inflammatory myeloid neoplasms. Its clinical manifestations are variable, occurring at any age and at any site, and it is rarer in adults than in children. The gold standard for diagnosis is histopathological biopsy. Due to the rarity of adult LCH and the heterogeneity of this disease, treatment of adult LCH should be developed according to the extent of the disease and risk stratification. With the discovery of MAPK, PI3K and c-KIT signaling pathway activation, especially BRAF V600E and MAP2K1 mutations, targeted therapy has become a hot spot for therapeutic research. Meanwhile, the discovery of high expression of M2-polarized macrophages and Foxp3+ regulatory T cells (Treg) in LCH has provided an important basis for the immunotherapy. In this article, we will focus on reviewing the latest research progress in the treatment of adult LCH in recent years, and provide a reference for clinical research on the treatment of adult LCH patients.

The roles of exosomal immune checkpoint proteins in tumors.

Targeting immune checkpoints has achieved great therapeutic effects in the treatment of early-stage tumors. However, most patients develop adaptive resistance to this therapy. The latest evidence demonstrates that tumor-derived exosomes may play a key role in systemic immune suppression and tumor progression. In this article, we highlight the role of exosomal immune checkpoint proteins in tumor immunity, with an emphasis on programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as emerging evidence on roles of T cell immunoglobulin-3 (TIM-3), arginase 1 (ARG1), and estrogen receptor binding fragment-associated antigen 9 (EBAG9) expressed by exosomes.

LncRNA-NEAT1 promotes proliferation of T-ALL cells via miR-146b-5p/NOTCH1 signaling pathway.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant tumor of the hematopoietic system, which can develop at any age, with the symptoms of weakness, fatigue, enlarged lymph nodes, or weight loss. Nuclear paraspeckle assembly transcript 1 (NEAT1) is involved in the process of T-ALL, but the regulatory mechanism is still not known clearly. METHODS: The expression levels of NEAT1 and miR-146b-5p in T-ALL cells were performed by qRT-PCR and NOTCH1 protein level- wwWwas determined by western blot assay. Dual-luciferase reporter assay was used to detect the interaction between NEAT1 and miR-146b-5p, as well as miR-146b-5p and NOTCH1. The cell proliferation was measured by using MTT assay and colony formation assay. RESULTS: The expression levels of NEAT1 were markedly increased, but miR-146b-5p levels were reduced in T-ALL cells. Knockdown of NEAT1 or overexpression of miR-146b-5p decreased NOTCH1 expression, inhibited the proliferation of T-ALL cells. MiR-146b-5p bound both NEAT1 and NOTCH1 3'-UTR directly. Finally, inhibition of miR-146b-5p could abrogate the effects of NEAT1 knockdown on the proliferation of T-ALL cells. CONCLUSION: NEAT1 promotes the proliferation of T-ALL cells by sponging miR-146b-5p to upregulate the expression of NOTCH1. The results of this study provide new insight into the action mechanism of NEAT1 modulating T-ALL progression.

[Clinical Features of Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm].

OBJECTIVE: To analyze the clinical characteristics, pathological features, treatment response and prognosis of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), so as to provide reference for reducing clinical misdiagnosis and treatment regimens. METHODS: The clinical, pathological features, treatment regimens and treatment response of 9 patients with BPDCN diagnosed and treated from January 1, 2013 to June 30,2019 in Xiangya Second Hospital of Central South University were analyzed respectively. RESULTS: The most common site of involvement in 9 patients with BPDCN was skin; the pathological features were involvement of dermis, and the highest positive immunohistochemical indexes rate were CD4, CD43, LCA, CD123, and VIM (all 100%), followed by CD56 and CD68, TDT, CD5, PAX-5, CD3, CD8, CD20; MPO and EBER of 9 patients were negative. However, Ki-67 of the 9 patients showed a medican of 77. 5% (40%-90%), which suggests that CD4, CD43, LCA, CD123, and VIM were the most sensitive antigens for diagnosing BPDCN. Of the 9 patients, 2 cases were lost to follow-up, 2 cases were untreated, and 5 cases were treated, in which 2 cases received treatment of regiment for acute lymphoblastic leukemia and 3 cases received treatment of regimen for lymphoma. The PR of clinical symptoms in the first cycle in 5 patients were 100%, and 1 patient has survived for 6 years since the disease was diagnosed. CONCLUSION: BPDCN is a rare and highly invasive lymphoid hematopoietic malignancy. The most common initial symptom of the patients is skin lesions. The most sensitive pathological indicators are CD4, CD43, LCA, VIM, and the BPDCN patients received treatment of regimens for lymphoid tumor show a better response rate.

[Analysis of Clinical Characteristics in 31 Acute Myeloid Leukemia Patients with Chromosome 21 Aberrations].

OBJECTIVE: To investigate the clinical characteristics of 31 acute myeloid leukemia (AML) patients with chromosome 21 aberrations. METHODS: Karyotypes of 168 newly diagnosed AML patients in Second Xiangya Hospital from Jan 2014 to July 2016 were reviewed for the presence of chromosome 21 aberrations (accounting for 18.45%). Clinical manifestation, as well as prognostic gene mutations distribution and immune classification were analyzed. RESULTS: Out of 168 AML newly diagnosed patients, 31 cases with chromosome 21 aberrations including t(8;21) accounting for 67.74% (21/31), and trisomy 21 (16.13%,5/31), 2 variants were found as t(1; 21) and t(1; 21; 8); 77 cases had normal karyotype, and 60 cases possessed other chromosomes aberrations. Statistically significant differences did not exist among age, sex and white blood cell count (P>0.05). However, the 21 cases in chromosome aberrations group were predisposed to lower hemoglobin and platelet count(P<0.05). 5 cases of Trisomy 21 were characterized by M5 2 cases, M1 one case, M2 one case M4 one case. And the rate of C-kit/D816V mutation was higher in t(8;21) aberrations group when 7 prognostic genes including FLT3/ITD, C-kit/D816V, NPM1, DNMT3A, TET2 were analyzed, and the immune classification of t(8; 21) aberration group inclined to CD19+, CD34+ but CD33-, CD64-. And trisomy 21 displayed a trend to CD34+ and CD7+. CONCLUSION: Chromosome 21 is easily involved in acute myeloid leukemia. The patients with involvement of this aberration have characteristic clinic changes.

Bone marrow-derived innate macrophages attenuate oxazolone-induced colitis.

Previous studies have shown that a subpopulation of granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent F4/80high CD11bhigh innate macrophages could be derived from bone marrow cells by continuous in vitro culturing. These cells could be induced to differentiate into M1 or M2 macrophages in vitro. In the current study, we sought to determine whether bone marrow cell-derived innate macrophages (BMIMs) could be used to fulfill an anti-inflammatory purpose by intravenous transplantation in vivo after being stimulated to differentiate into M2 macrophages. Because Th2 cytokines, such as interleukin IL-4 and IL-13, can induce macrophage polarization into M2 macrophages, we treated the BMIMs with IL-4 and IL-13 in vitro. Next, the M2 macrophages were intravenously transplanted into a typical Th2-mediated inflammatory disease model, oxazolone (OXZ)-induced colitis, to assess the anti-inflammatory activity of BMIM-derived M2 macrophages (BMIM-M2Ms) in vivo. After transplantation, the severity of intestinal inflammation was attenuated. In addition, colon lengths and mouse body weights were noticeably improved. F4/80+ CD206+ double-positive cells (displaying the markers of M2 macrophages) had accumulated in the colon tissue of BMIM-M2M-transplanted mice. This evidence demonstrated that bone marrow-derived BMIM-M2Ms could be used to alleviate OXZ-induced Th2-mediated inflammation in a mouse model in vivo.

A TET2 rs3733609 C/T genotype is associated with predisposition to the myeloproliferative neoplasms harboring JAK2(V617F) and confers a proliferative potential on erythroid lineages.

Common germline single-nucleotide polymorphisms (SNPs) at JAK2 locus have been associated with Myeloproliferative neoplasms (MPN). And, the germline sequence variant rs2736100 C in TERT is related to risk of MPN, suggesting a complex association between SNPs and the pathogenesis of MPN. Our previous study (unpublished data) showed that there was a high frequency distribution in rs3733609 C/T genotype at Ten-Eleven Translocation 2 (TET2) locus in one Chinese familial primary myelofibrosis. In the present study, we evaluate the role and clinical significance of rs3733609 C/T genotype in JAK2V617F-positive sporadic MPN (n = 181). TET2 rs3733609 C/T genotype had a higher incidence (13.81%; 25/181) in JAK2V617F-positive sporadic MPN patients than that in normal controls (n = 236) (6.35%; 15/236), which was predisposing to MPN (odds ratio(OR) = 2.361; P = 0.01). MPN patients with rs3733609 C/T genotype had increased leukocyte and platelets counts, elevated hemoglobin concentration in comparison with T/T genotype. Thrombotic events were more common in MPN patients with rs3733609 C/T than those with T/T genotype (P < 0.01). We confirmed that rs3733609 C/T genotype downregulated TET2 mRNA transcription, and the mechanism may be involved in a disruption of the interaction between CCAAT/enhancer binding protein alpha (C/EBPA) and TET2 rs3733609 C/T locus.TET2 rs3733609 C/T genotype stimulated the erythroid hematopoiesis in MPN patients. Altogether, we found a novel hereditary susceptible factor-TET2 rs3733609 C/T variant for the development of MPN, suggesting the variant may be partially responsible for the pathogenesis and accumulation of MPN.

Thalidomide Effects in Patients with Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic Zebrafish Model.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasia, and arteriovenous malformations. The efficacy of traditional treatments for HHT is very limited. The aim of this study was to investigate the therapeutic role of thalidomide in HHT patients and the effect in FLI-EGFP transgenic zebrafish model. METHODS: HHT was diagnosed according to Shovlin criteria. Five HHT patients were treated with thalidomide (100 mg/d). The Epistaxis Severity Score (ESS), telangiectasia spots, and hepatic computed tomography angiography (CTA) were used to assess the clinical efficacy of thalidomide. The Fli-EGFP zebrafish model was investigated for the effect of thalidomide on angiogenesis. Dynamic real-time polymerase chain reaction assay, ELISA and Western blotting from patient's peripheral blood mononuclear cells and plasma were used to detect the expression of transforming growth factor beta 3 (TGF-ß3) messenger RNA (mRNA) and vascular endothelial growth factor (VEGF) protein before and after 6 months of thalidomide treatment. RESULTS: The average ESS before and after thalidomide were 6.966 ± 3.093 and 1.799 ± 0.627, respectively (P = 0.009). The "telangiectatic spot" on the tongue almost vanished; CTA examination of case 2 indicated a smaller proximal hepatic artery and decreased or ceased hepatic artery collateral circulation. The Fli-EGFP zebrafish model manifested discontinuous vessel development and vascular occlusion (7 of 10 fishes), and the TGF-ß3 mRNA expression of five patients was lower after thalidomide therapy. The plasma VEGF protein expression was down-regulated in HHT patients. CONCLUSIONS: Thalidomide reverses telangiectasia and controls nosebleeds by down-regulating the expression of TGF-ß3 and VEGF in HHT patients. It also leads to vascular remodeling in the zebrafish model.

Dramatic response to itraconazole in central nervous system aspergillosis complicating acute promyelocytic leukemia.

Abstract Fungal infection is a rare complication of acute leukemia, in which a combination of voriconazole and amphotericin B is a first-line regimen of treatment. Here administration of itraconazole plus caspofungin resulted in a dramatic response in a patient with acute promyelocytic leukemia (APL).

Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis.

PURPOSE: To estimate the effects of BRCA1 and BRCA2 mutations on ovarian cancer and breast cancer survival. EXPERIMENTAL DESIGN: We searched PubMed and EMBASE for studies that evaluated the associations between BRCA mutations and ovarian or breast cancer survival. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS). RESULTS: From 1,201 unique citations, we identified 27 articles that compared prognosis between BRCA mutation carriers and noncarriers in patients with ovarian or breast cancer. Fourteen studies examined ovarian cancer survival and 13 studies examined breast cancer survival. For ovarian cancer, meta-analysis demonstrated that both BRCA1 and BRCA2 mutation carriers had better OS (HR, 0.76; 95% CI, 0.70-0.83 for BRCA1 mutation carriers; HR, 0.58; 95% CI, 0.50-0.66 for BRCA2 mutation carriers) and PFS (HR, 0.65; 95% CI, 0.52-0.81 for BRCA1 mutation carriers; HR, 0.61; 95% CI, 0.47-0.80 for BRCA2 mutation carriers) than noncarriers, regardless of tumor stage, grade, or histologic subtype. Among patients with breast cancer, BRCA1 mutation carriers had worse OS (HR, 1.50; 95% CI, 1.11-2.04) than noncarriers but were not significantly different from noncarriers in PFS. BRCA2 mutation was not associated with breast cancer prognosis. CONCLUSIONS: Our analyses suggest that BRCA mutations are robust predictors of outcomes in both ovarian and breast cancers and these mutations should be taken into account when devising appropriate therapeutic strategies.

Association of reduced immunohistochemical expression of E-cadherin with a poor ovarian cancer prognosis--results of a meta-analysis.

PURPOSE: E-cadherin is a transmemberane protein which is responsible for adhesion of endothelial cells. The aim of our study was to assess existing evidence of associations between reduced expression of E-cadherin and prognosis of ovarian cancer with a discussion of potential approaches to exploiting any prognostic value for improved clinical management. METHODS: We conducted a meta-analysis of 9 studies (n=915 patients) focusing on the correlation of reduced expression of E-cadherin with overall survival. Data were synthesized with random or fixed effect hazard ratios. RESULTS: The studies were categorized by author/year, number of patients, FIGO stage, histology, cutoff value for E-cadherin positivity, and methods of hazard rations (HR) estimation, HR and its 95% confidence interval (CI). Combined hazard ratios suggested that reduced expression of E-cadherin positivity was associated with poor overall survival (OS), HR=2.10, 95% CI:1.13-3.06. CONCLUSION: The overall survival of the E-cadherin negative group with ovarian cancer was significant poorer than the E-cadherin positive group. Upregulation of E-cadherin is an attractive therapeutic approach that could exert significant effects on clinical outcome of ovarian cancer.

[Screen of phosphopeptide specific for acute leukemia].

OBJECTIVE: To screen phosphopeptide specific for acute leukemia. METHODS: Mononuclear cells from bone marrow were collected from 16 newly diagnosed acute lymphoblastic leukemia (ALL) and 20 acute myeloid leukemia (AML) patients. Peptides were extracted and purified, analyzed by immunoprecipitation and liquid chromatography coupled with tandem mass spectrometry (LC-MS). RESULTS: (1) Non-receptor tyrosine kinase family members Fyn, Yes, Src widely expressed in acute leukemia; (2) Some phosphopeptides, including non-receptor tyrosine kinase family members Abl/iso1 and Abl, non-receptor Ser/Thr protein kinase family members Bcr, JNK2, JNK2 iso2, Adaptor/scaffold members Cas-L, Cbl, CrkL CENTD1 (Centaurin delta1) ZO2, transcriptor GFR-1 and phosphatase SHIP-2 were detected in Ph positive ALL, but not in other kinds of ALL. (3) Hck, Lyn and Fgr selectively expressed in AML (except AML-M(3)). CONCLUSION: Some phosphopeptides were specific for ALL and AML, and may be useful for diagnosis and therapy of acute leukemia.

Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat.

Orlistat is an orally administered anti-obesity drug that has shown significant antitumor activity in a variety of tumor cells. To identify the proteins involved in its antitumor activity, we employed a proteomic approach to reveal protein expression changes in the human ovarian cancer cell line SKOV3, following Orlistat treatment. Protein expression profiles were analyzed by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and protein identification was performed on a MALDI-Q-TOF MS/MS instrument. More than 110 differentially expressed proteins were visualized by 2-DE and Coomassie brilliant blue staining. Furthermore, 71 proteins differentially expressed proteins were positively identified via mass spectrometry (MS)/MS analysis. In particular, PKM1/2, a key enzyme involved in tumorigenesis, was found to be significantly downregulated in SKOV3 cells following treatment with Orlistat. Moreover, PKM1/2 was proved to be downregulated in SKOV3 cells by western blot analysis after treatment with Orlistat. Taken together, using proteomic tools, we identified several differentially expressed proteins that underwent Orlistat-induced apoptosis, particularly PKM2. These changes confirmed our hypothesis that Orlistat is a potential inhibitor of ovarian cancer and can be used as a novel adjuvant antitumor agent.

Prognostic value of vascular endothelial growth factor expression in patients with prostate cancer: a systematic review with meta-analysis.

BACKGROUND: The vascular endothelial growth factor (VEGF) mediates vasculogenesis and angiogenesis through promoting endothelial cell growth, migration and mitosis, and has involvement in cancer pathogenesis, progression and metastasis. However, the prognostic value of VEGF in patients with prostate cancer remains controversial. OBJECTIVES: The aim of our study was to evaluate the prognostic value of VEGF in prostate cancer, and summarise the results of related research on VEGF. METHODS: In accordance with an established search strategy, 11 studies with 1,529 patients were included in our meta-analysis. The correlation of VEGF-expression with overall survival and progression-free survival was evaluated by hazard ratio, either given or calculated. RESULTS: The studies were categorized by introduction of the author, demographic data in each study, prostate cancer-relatived information, VEGF cut-off value, VEGF subtype, methods of hazard ratio (HR) estimation and its 95% confidence interval (CI). High VEGF-expression in prostate cancer is a poor prognostic factor with statistical significance for OS (HR=2.32, 95%CI: 1.40-3.24). However, high VEGF-expression showed no effect on poor PFS (HR=1.30, 95%CI: 0.88-1.72). Using Begg's, Egger's test and funnel plots, we confirmed lack of publication bias in our analysis. CONCLUSION: VEGF might be regarded as a prognostic maker for prostate cancer, as supported by our meta-analysis. To achieve a more definitive conclusion enabling the clinical use of VEGF in prostate cancer, we need more high-quality interventional original studies following agreed research approaches or standards.

Icaritin shows potent anti-leukemia activity on chronic myeloid leukemia in vitro and in vivo by regulating MAPK/ERK/JNK and JAK2/STAT3 /AKT signalings.

PURPOSE: To explore the effects of Icaritin on chronic myeloid leukemia (CML) cells and underlying mechanisms. METHOD: CML cells were incubated with various concentration of Icaritin for 48 hours, the cell proliferation was analyzed by MTT and the apoptosis was assessed with Annexin V and Hoechst 33258 staining. Cell hemoglobinization was determined. Western blotting was used to evaluate the expressions of MAPK/ERK/JNK signal pathway and Jak-2/Phorpho-Stat3/Phorsph-Akt network-related protein. NOD-SCID nude mice were applied to demonstrate the anti-leukemia effect of Icaritin in vivo. RESULTS: Icaritin potently inhibited proliferation of K562 cells (IC50 was 8 µM) and primary CML cells (IC50 was 13.4 µM for CML-CP and 18 µM for CML-BC), induced CML cells apoptosis and promoted the erythroid differentiation of K562 cells with time-dependent manner. Furthermore, Icaritin was able to suppress the growth of primary CD34+ leukemia cells (CML) and Imatinib-resistant cells, and to induce apoptosis. In mouse leukemia model, Icaritin could prolong lifespan of NOD-SCID nude mice inoculated with K562 cells as effective as Imatinib without suppression of bone marrow. Icaritin could up-regulate phospho-JNK or phospho-C-Jun and down-regulate phospho-ERK, phospho-P-38, Jak-2, phospho-Stat3 and phospho-Akt expression with dose- or time-dependent manner. Icaritin had no influence both on c-Abl and phospho-c-Abl protein expression and mRNA levels of Bcr/Abl. CONCLUSION: Icaritin from Chinese herb medicine may be a potential anti-CML agent with low adverse effect. The mechanism of anti-leukemia for Icaritin is involved in the regulation of Bcr/Abl downstream signaling. Icaritin may be useful for an alternative therapeutic choice of Imatinib-resistant forms of CML.