A retrospective analysis of mature T-and NK-cell lymphomas

Mature T-and natural killer(NK)-cell lymphomas are heterogeneous groups of malignant lymphoid neoplasms arising from T and NK cells. The incidence of mature T-and NK-cell lymphomas is 2.1 per 100,000 people, according to a US report~1.

Hodgkin's lymphoma:2023 update on treatment

Hodgkin's lymphoma(HL)is a common,malignant hematological tumor of the lymph nodes and lymphatic system,accounting for 10%of all lymphomas.HL comprises 2 main subtypes:classical HL(cHL)and nodular lymphocyte predominant HL.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

The combination of chidamide with the CHOEP regimen in previously untreated patients with peripheral T-cell lymphoma: a prospective, multicenter, single arm, phase 1b/2 study

Objective:To assess the efficacy and safety of the novel histone deacetylase inhibitor,chidamide,in combination with cyclophosphamide,doxorubicin,vincristine,etoposide,and prednisone(Chi-CHOEP)for untreated peripheral T-cell lymphoma(PTCL).Methods:A prospective,multicenter,single arm,phase 1 b/2 study was conducted.A total of 128 patients with untreated PTCL(18–70 years of age)were enrolled between March 2016 and November 2019,and treated with up to 6 cycles with the Chi-CHOEP regimen.In the phase 1 b study,3 dose levels of chidamide were evaluated and the primary endpoint was determination of the maximumtolerated dose and recommended phase 2 dose(RP2 D).The primary endpoint of the phase 2 study was 2-year progression-free survival(PFS).Results:Fifteen patients were enrolled in the phase 1 b study and the RP2 D for chidamide was determined to be 20 mg,twice a week.A total of 113 patients were treated at the RP2 D in the phase 2 study,and the overall response rate was 60.2%,with a complete response rate of 40.7%.At a median follow-up of 36 months,the median PFS was 10.7 months,with 1-,2-,and 3-year PFS rates of 49.9%,38.0%,and 32.8%,respectively.The Chi-CHOEP regimen was well-tolerated,with grade 3/4 neutropenia occurring in approximately two-thirds of the patients.No unexpected adverse events(AEs)were reported and the observed AEs were manageable.Conclusions:This large cohort phase 1 b/2 study showed that Chi-CHOEP was well-tolerated with modest efficacy in previously untreated PTCL patients.

Chidamide combined with cyclophosphamide,doxorubicin,vincristine and prednisone in previously untreated patients with peripheral T-cell lymphoma

Objective:Chidamide is an oral histone deacetylase subtype-selective inhibitor approved for relapsed or refractory peripheral T-cell lymphoma(PTCL).This phase 1 b study evaluated the safety,pharmacokinetics,and preliminary efficacy of chidamide in combination with cyclophosphamide,doxorubicin,vincristine and prednisone(CHOP)for treatment-na?ve PTCL patients.Methods:This study was an open-label,multicenter trial composed of dose escalation and dose expansion.Patients received CHOP for six 21-d cycles and chidamide on d 1,4,8 and 11 in each cycle.Four dose levels of chidamide(20,25,30 and 35 mg)were evaluated.The primary objective was to evaluate the safety and tolerability of the combination regimen.Results:A total of 30 patients were evaluated in this study:15 in the dose-escalation part and 15 in the doseexpansion part.In the dose-escalation study,three patients were enrolled in the 35 mg chidamide cohort.One had dose-limiting toxicity with grade 3 vascular access complications,and one had grade 2 neutropenia with a sustained temperature>38°C.Dose escalation was stopped at this chidamide dose level.The most common(≥10%)grade 3 or 4 adverse events(AEs)were leukopenia(90.0%),neutropenia(83.3%),vomiting(13.3%),thrombocytopenia(10.0%)and febrile neutropenia(10.0%).No significant changes in chidamide pharmacokinetic properties were observed before and after combination treatment.The objective response rate for the 28 patients evaluable for preliminary efficacy was 89.3%(25/28),with 16(57.1%)achieving complete response or unconfirmed complete response.The estimated median progression-free survival was 14.0 months.In summary,we chose chidamide 30 mg as the recommended dose for phase 2.Conclusions:The addition of chidamide to standard CHOP chemotherapy was tolerable with promising preliminary efficacy in previously untreated PTCL patients,which supports further clinical studies with this combination regimen for the frontline treatment of PTCL.

弥漫性大B细胞淋巴瘤基因分型研究进展

弥漫性大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)在临床特征、基因表达和治疗反应及预后方面均表现出明显异质性。目前,R-CHOP(利妥昔单抗、环磷酰胺、阿霉素、长春新碱、强的松)作为标准治疗方案已不能满足临床需要,而近年的几项基于细胞起源分型进行的R-CHOP+X临床试验均未得到预期效果。因此,亟需对DLBCL的分子遗传学异常进行更为深入的研究,以探讨基于基因异常改变的基因亚型分型,从而为新的治疗方法及靶向药物的研发和选择应用提供更多的参考依据。基因检测技术在肿瘤分子病理诊断上越来越广泛的应用也为DLBCL基因分型的深入研究提供了良好的技术支持。本文就最新的DLBCL基因分子分型进展进行综述。

Targeting EZH1/2 induces cell cycle arrest and inhibits cell proliferation through reactivation of p57CDKN1C and TP53INP1 in mantle cell lymphoma

Objective: To explore the effect of dysregulation of epigenetic regulator EZH1 and EZH2 on the proliferation in MCL and the underlying mechanisms.Methods: In this study, we elucidated the role of EZH1 and EZH2 overexpression by immunohistochemistry and correlated them to clinical outcome in 41 MCL patients.Quantitative real-time PCR and Western blot were applied to confirm the level of EZH1 and EZH2 in well-characterized MCL cell lines which were compared to those of na?ve B cells.Then we manipulated the expression of EZH1 and EZH2 in MCL cells using CRISPR/Cas9 system to directly investigate their functional roles in MCL.We also evaluated the effect of two small molecule selective inhibitors, EPZ005687 and UNC1999, on MCL cell proliferation, cell cycle distribution and apoptosis in vitro.Finally, we performed RNA-sequencing(RNA-Seq) and Chromatin immunoprecipitation(ChIP) assay to further gain insight into the underlying molecular mechanisms.Results: We found that EZH2 protein is overexpressed in approximately half of this cohort of MCL cases.More importantly, the overexpression of EZH2 is associated with poor OS in the patients.Nevertheless, simple EZH2 depletion in vitro has little impact on the viability of MCL cells, predominantly because of the consequent up-regulation of EZH1.Consistently, UNC1999, a dual EZH1/2 inhibitor, unlike the EZH2 selective inhibitor EPZ005687, exerts a potent inhibitory effect on MCL cells.Furthermore, we discover CDKN1C and TP53 INP1 as the two important cell cycle regulators, the expression of which are repressed by EZH1/2 mediated epigenetic regulation and are restored by EZH1/2 dual inhibition.Conclusions: Our study suggests that EZH2 participates in the pathogenesis of MCL which may serve as a potential biomarker for prognosis prediction.The dual inhibition of EZH1/2 is a promising therapeutic strategy for MCL.

Anti-PT-symmetric Kerr gyroscope

Non-Hermitian systems can exhibit unconventional spectral singularities called exceptional points(EPs).Various EP sensors have been fabricated in recent years,showing strong spectral responses to external signals.Here we propose how to achieve a nonlinear anti-parity-time(PT)gyroscope by spinning an optical resonator.We show that,in the absence of any nonlinearity,the sensitivity or optical mode splitting of the linear device can be magnified up to 3 orders compared to that of the conventional device without EPs.Remarkably,the PT symmetry can be broken when including the Kerr nonlinearity of the materials and,as a result,the detection threshold can be significantly lowered,i.e.,much weaker rotations which are well beyond the ability of a linear gyroscope can now be detected with the nonlinear device.Our work shows the powerful ability of PT gyroscopes in practice to achieve ultrasensitive rotation measurement.

Multidisciplinary team for the diagnosis and treatment of 2cases of primary intestinal yolk sac tumor

Extragonadal primary yolk sac tumor of the intestinal tract origin is exceedingly rare. Through a multiple disciplinary team, the diagnosis and treatment of primary intestinal yolk sac tumor were further defined. We report 2 such cases with detailed histologic and immunohistochemical analysis. The two patients were a 7-year-old girl and a 29-year-old woman. Both of them preoperatively had an elevated serum alpha fetoprotein(AFP) level(≥ 1,210 ng/mL). The tumors are located in the intestine and imaging examination indicated the rectum as the primary site. Grossly the mass was grey-white and crisp texture. Microscopic examination featured reticular, microcystic, macrocystic, papillary, solid, and some glandular patterns. Immunohistochemically,tumor cells of both cases were positive for SALL4, AFP, pan-cytokeratin(AE1/AE3), and glypican-3. Simultaneously, a stain for EMA, OCT4, CD30, HCG, vimentin and CK20 were negative in all 2 neoplasms. The features of morphology,immunohistochemistry, laboratory examinations and imaging studies consist of the diagnosis of primary yolk sac tumor of the intestine.

Expression of Preprotachykinin-I (PPT-I), Neurokinin-1 (NK-1) and Neurokinin-2 (NK-2) in Breast Cancer Cells Improves Tumor Cell Survival in Bone Marrow in the Early Stage of Metastasis

OBJECTIVE To study the potential relationship between the expression of PPT-I, NK-1, NK2 and the development of breast cancer cells in bone marrow stroma and to provide evidence of potential molecular mechanisms of breast cancer patients. of bone metastasis in early stage METHODS The cocultures of breast cancer cell line T-47D and marrow-derived mesenchymal stem cells （MSC） were established with equal numbers. T-47D cells were separated from the coculture system at 48 h and 96 h after coculture by MACS magnetic cell sorting （MicroBeads）. The expression of PPT-I, NK-1, NK-2 in T-47D was then examined before and after coculture by real-time PCR and by Western blot. Alterations in cellular ultrastructure of T-47D cells were detected before and after coculture under electron microscope. Finally, changes in cell cycle distribution were examined by flow cytometry, and growth curves from before and after coculture were drawn and analyzed. RESULTS Following coculture of T-47D and MSC, the expression of PPT-I mRNA and protein was significantly upregulated, while the expression of NK-1 and NK-2 mRNA and protein was greatly downregulated. The analysis of cell cycle distribution by flow cytometry showed that the proportion of T-47D during S phase was increased, and the duration of the G2/M phase was sharply decreased. Under electron microscope, we observed that the synthesis of hereditary material was increased, but the hepatin granules were shown prominent stacking in T-47D cells. These results suggest that although the synthesis of DNA was increased, the proliferation of cells was inhibited after coculture. The cell growth curve confirmed the findings from the observation under the electron microscope and flow cytometry. CONCLUSION Tumor cells could survive through the upregulation in expression of preprotachykinin-I gene during early bone metastasis in breast cancer. The phenomenon of growth suppression in breast cancer cells after coculture in the current study could be induced by downregulation in expression of NK-1 and NK-2.

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy

Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation.A multi-center phase I/II trial of anti-CD19 CD28z CAR-T(FKC876,ChiCTR1800019661)was conducted.Among 22 evaluable DLBCL patients,seven achieved complete remission,10 experienced partial remissions,while four had stable disease by day 29.Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients,and compared at different stages of treatment.M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells,leading to CAR-T cell therapy failure and disease progression in DLBCL.Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy,during both cell expansion and disease progression,which could not be altered by infiltrating CAR-T cells.Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments.Thus,our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

China Anti‑Cancer Association(CACA)guidelines for holistic integrative management of lymphoma(version 2022)Lymphoma,Guideline,Diagnosis,Treatment,Holistic integrative medicine

Purpose Lymphoma has become a major threat to human health.Fortunately,the diagnosis and treatment of lymphoma have developed rapidly,and research progress has emerged in an endless stream,with new drugs emerging one after another.These results are constantly rewriting guidelines changing clinical practice,need to be popularized and applied more widely.Methods This guideline has integrated consensuses reached by the Lymphoma Committee of China Anti-Cancer Association(CACA),based on China’s practice,tracking previous results of the most advanced clinical researches,absorbing the latest clinical evidence,and referring to domestic and international lymphoma guidelines.Results This holistic integrative guideline of lymphoma introduces the latest progress in the diagnosis and treatment of different subtypes of lymphoma,guide the clinical application of new drugs,standardized and precise management for lymphoma patients.Conclusions CACA guidelines for holistic integrative management of lymphoma(version 2022)enhance standardization and precision of the management for lymphoma patients in China.

miR-10a inhibits cell proliferation and promotes cell apoptosis by targeting BCL6 in diffuse large B-cell lymphoma

The BCL6 （B-Cell Lymphoma 6） gene is a proto-onco- gene that is often expressed in diffuse large B-ceU lymphomas （DLBCLs）. BCL6 loss of function can kill DLBCL cells, demonstrating that BCL6 is necessary for the survival of DLBCL cells and could be a therapeutic target. In this study, we found that BCL6 protein levels were consistently upregulated in DLBCL tissues, whereas its mRNA levels varied randomly in tissues, suggesting that a post-transcriptional mechanism was involved in BCL6 regulation. We used bioinformatics analysis to search for miRNAs, which potentially target BCL6, and identified specific targeting sites for miR-10a in the 3＇-untranslated region （3＇-UTR） of BCL6. We fur- ther identified an inverse correlation between miR-10a levels and BCL6 protein levels, but not mRNA levels, in DLBCL tumor tissue samples. By overexpressing or knocking down miR-10a in DLBCL cells, we experi- mentally validated that miR-10a directly recognizes the 3＇-UTR of the BCL6 transcript and regulated BCL6expression. Furthermore, we demonstrated that nega- tively regulating BCL6 by miR-10a suppressed the pro- liferation and promoted apoptosis of DLBCL cells.