免疫分型标记物和CD43在非特指弥漫性大B细胞淋巴瘤中的表达及临床意义

目的 探讨免疫分型标记物和CD43在非特指弥漫性大B细胞淋巴瘤(DLBCL NOS)中的表达及其临床意义.方法 收集120例DLBCL NOS临床病理资料进行分析.采用免疫组化法检测CD10、bcl-6、MUM-1和CD43的表达,根据Hans分型将其分为GCB型和non-GCB型.结果 120例DLBCL,NOS中GCB型和non-GCB型分别为38例和82例,Hans分型与DLBCL NOS预后无关(P＞0.05).120例DLBCL NOS中CD43阳性33例(27.5％),CD43表达与性别、临床分期和免疫分型均无关(P＞0.05),与年龄(P=0.036)和生存状态(P=0.004)有关.结论 DLBCL NOS预后差与CD43阳性表达有关,与Hans分型无关.     

抗CD20单抗联合CHOP方案治疗弥漫性大B细胞淋巴瘤的多中心临床研究

目的：观察抗CD20单抗联合环磷酰胺、长春新碱、阿霉素及泼尼松治疗初诊的弥漫性大B细胞淋巴瘤(DLBL)的临床疗效。方法：200204-200302， 52例病人进入本研究。化疗采用标准的CHOP方案：环磷酰胺600 mg/m2（第1天），长春新碱1.4 mg/m2（第1天），阿霉素25 mg/m2（第1天）和泼尼松60 mg/d（第1～5天），每3周1个疗程，共6个疗程。利妥昔单抗静脉滴注剂量为375 mg/m2，每周或每3周输注1次，连续4次或6次。结果：在50例患者中，60%获得完全反应(CR)，总有效率(OR)为100%。50例患者共随访了2~30周，患者16周的疾病无进展生存(PFS)率为87.3%。主要不良反应为输注相关的不良反应（32%）和化疗相关的血液学毒副反应（20%）。结论：利妥昔单抗联合CHOP方案可有效用于治疗新诊断的弥漫性大B细胞性淋巴瘤具有较高的缓解率，不良反应较少。     

Clinical Significance of the t(14;18) And BCL2 Overexpression in Follicular Large Cell Lymphoma

Follicular large cell lymphoma (FLCL) is an aggressive disease that responds to anthracy-cline-containing chemotherapy much like diffuse large B-cell lymphoma (DLBCL). Since the t(14; 18) and/or bcl2 protein expression are less common in FLCL than in its low-grade counterparts, we sought to determine whether these features were predictive of survival as in DLBCL. We studied 50 patients with FLCL who were treated with curative intent. The t(14; 18) was found by cytogenetic analysis in 56% of the patients and bcl2 protein was expressed by the tumor cells in 73%, but neither was predictive of survival. However, abnormalities of chromosome 17p and the presence of trisomy 21 were adverse predictors of survival, as were a number of clinical features. We conclude that neither the absence of the t(14; 18) nor the lack of bcl2 expression explain the good response of a subset of patients with FLCL to curative therapy.     

Translocation (14;19)(q32;q13.1) in a Young Patient who Developed a Large Cell Lymphoma after an Initial Diagnosis of CLL

A translocation (14;19)(q32;q13.1) was found in a 31 year old man with a large cell lymphoma which had evolved from chronic lymphocytic leukaemia (CLL). Molecular analysis showed a monoclonal proliferation of B cells with rearrangement of the immunoglobulin (Ig) heavy and kappa light chain genes, and of the bcl-3 gene on chromosome 19q. Nine cases with t(14;19) from the literature were reviewed; B cell lymphoma had been diagnosed in eight and acute biphenotypic leukaemia in one of these cases. Four had transformed from CLL to a more aggressive disease, as in the present case. Two out of seven patients as well as the present one, with t(14;19) and CLL were young (less than 40). The t(14;19) is usually associated with other cytogenetic abnormalities; in our case a (15;16)(q15;p13) translocation was found and appears to be an additional nonrandom aberration in t(14;19) disorders.     

The Impact of COVID-19 on Academic Cancer Clinical Trials in Canada and the Initial Response from Cancer Centers

The COVID-19 pandemic resulted in temporary holds placed on new trial startups, patient recruitment and follow up visits for trials which contributed to major disruptions in cancer center trial unit operations. To assess the impact, the Canadian Cancer Clinical Trials Network (3CTN) members participated in regional meetings and a survey to understand the impact of the pandemic to academic cancer clinical trials (ACCT) activity, cancer trial unit operations and supports needed for post-pandemic recovery. Trial performance and recruitment data collected from 1 April 2020–31 March 2021 was compared to the same period in previous years. From 1 April–30 June 2020, patient recruitment decreased by 67.5% and trial site activations decreased by 81% compared to the same period in 2019. Recovery to reopening and recruitment of ACCTs began after three months, which was faster than initially projected. However, ongoing COVID-19 impacts on trial unit staffing and operations continue to contribute to delayed trial activations, lower patient recruitment and may further strain centers’ capacity for participation in academic-sponsored trials.     

Clinical Impact of t(14;18) in Diffuse Large B-cell Lymphoma

Objective: Recent studies have suggested that t(14;18) is present in a significant proportion of diffuse large B-cell lymphomas (DLBCLs). However, the prognostic significance of this translocation and its relationship with BCL-2 protein expression remains controversial. Our study aimed to investigate the predictive power of t(14;18) and BCL-2 protein expression in the prognosis of DLBCLs. Methods: Biopsy specimens from 106 DLBCLs were analyzed using interphase fluorescence in situ hybridization (FISH). Immu...     

CDKN2 (MTS1/p16INK4A) Gene Alterations in Adult T-Cell Leukemia/Lymphoma

p16^INK4A is a cyclin-dependent kinase inhibitor (CDKI), and regulates the cell cycle negatively. Recently, p16^INK4A protein was shown to be encoded by the CDKN2 gene, which is identical to multiple tumor suppressor gene 1 (MTS1) on chromosome 9p21, where genetic alterations occur frequently in many malignant tumors. As the loss of p16^INK4A function by genetic alterations leads to inappropriate progression of the cell cycle, the CDKN2 gene has been investigated intensively as a new candidate tumor suppressor gene in many malignant tumors. Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy associated with human T-cell lymphotrophic virus type 1 (HTLV-1). As the development to ATL is believed to require not only HTLV-1 infection but also accumulation of genetic alterations, we investigated the relationship between alterations in the CDKN2 gene and ATL. Alterations in the CDKN2 gene were detected in approximately 15 to 20% of ATL patients. Interestingly, most of the patients with CDKN2 gene alterations had the aggressive form of ATL. The CDKN2 gene appears to be the major tumor suppressor gene on chromosome 9p21, and alteration in this gene may play an important role during late stages in the transformation process induced by HTLV-1.     

MYC/BCL2双表达大B细胞淋巴瘤中PD-L1的表达及其临床意义CSCD

目的探讨MYC/BCL2双表达大B细胞淋巴瘤(DEL)与程序性细胞死亡受体-配体1(PD-L1)mRNA、蛋白表达的相关性及其临床意义。方法收集90例弥漫大B细胞淋巴瘤(DLBCL)病例,采用免疫组织化学染色检测MYC、BCL2蛋白并分组,双标记染色法检测各组病例的肿瘤细胞或微环境细胞中PD-L1表达;实时荧光PCR技术(Real-time PCR,qPCR)检测DEL组与non-DEL组PD-L1 mRNA相对表达量;收集临床病理资料并随访,对实验数据进行统计学分析。结果90例样本中28例为DEL,肿瘤细胞和微环境中PD-L1+分别为22例和26例。DEL组肿瘤细胞和微环境中PD-L1+分别为14例和9例;肿瘤细胞和微环境细胞PD-L1蛋白表达与DEL存在相关性(P<0.05);PD-L1 mRNA相对表达量在DEL与non-DEL组间存在显著差异(P=0.012);DEL组中PD-L1+与IPI评分和B症状的出现有关(P=0.007、0.021);Kaplan-Meier显示DEL中PD-L1+、肿瘤微环境PD-L1阳性(mPD-L1+)与患者预后相关(P=0.005、0.001)。结论DEL患者PD-L1 mRNA及蛋白表达都明显上调且与患者不良预后相关,PD-L1可作为DEL患者不良预后评估的危险因素。     

Molecular Cloning of 19p13 Breakpoint Region in Infantile Leukemia with t(11;19)(q23;p13) Translocation

We studied the breakpoint regions involved in t(11;19)(q23;p13) translocation associated with infantile leukemias. Southern blot analysis with the partial cDNA clone for the MLL gene at 11q23 which we had isolated previously detected gene rearrangements in all three cell lines and three leukemia samples from the patients with t(11;19) translocation, indicating that these breakpoints were clustered within the 8.5 kb Bam HI germline fragment detected by the probe. To study the breakpoint region, a genomic library of one of the cell lines, KOCL-33, was made. We have isolated the der(19) allele containing the breakpoint as well as the germline alleles at 19p13 and 11q23. Using the genomic probes on chromosome 19 near the breakpoint, Southern blot analysis was performed. The breakpoints at 19p13 of the two other cell lines and the three leukemia samples were not located within 36 kilobases of the KOCL-33 breakpoint, although pulsed-field gel electrophoresis showed that the breakpoints of all three cell lines were on the same Nru I fragment of 230 kilobases. These results showed that the breakpoints at 19p13 were not clustered like those at 11q23 in t(11;19) translocation.     

Favorable Pharmacodynamic Features and Superior Anti-Leukemic Activity of B43 (Anti-CD 19) Immunotoxins Containing Two Pokeweed Antiviral Protein Molecules Covalently Linked to each Monoclonal Antibody Molecule

Standard immunotoxin production procedures using whole IgG as the MoAb moiety yield a heterogeneous mixture of 180 kDa, 210 kDa, and 240 kDa immunotoxin species with 1 to 1, 1 to 2, and 1 to 3 MoAb to toxin ratios. This heterogeneity makes it impossible to precisely deliver a predetermined immunotoxin dose to target cells and impairs the accuracy of pharmacologic studies. In this report, we describe the preparation and characterization of B43(anti-CD19)-pokeweed antiviral protein (PAP) immunotoxins containing either one or two 30 kDa PAP toxin molecules covalently linked to each 150 kDa B43 monoclonal antibody molecule. Compared to the 180 kDa immunotoxin, the 210 kDA immunotoxin displayed greater in vitro chemical stability, resulted in higher systemic exposure levels in vivo, and was a more effective anti-leukemic agent in a SCID mouse model of human B-lineage acute lymphoblastic leukemia. Taken together, the results of this study recommend the clinical evaluation of 210 kDa B43-PAP as a potentially more effective immunotoxin against relapsed B-lineage ALL.     

Effects of the Intermolecular Toxin-Monoclonal Antibody Linkage on the In Vivo Stability, Immunogenicity and Anti-Leukemic Activity of B43 (Anti-CD19) Pokeweed Antiviral Protein Immunotoxin

We have successfully constructed highly potent and selective anti-CD19 PAP immunotoxins using each of the three crosslinking agents, SPDP, LC-SPDP, or SMPT, to generate an intermolecular bridge between the B43 MoAb and PAP toxin moieties. These immunotoxins were selectively immunoreactive with and cytotoxic against CD19' B-lineage ALL cells. In this report, we compared (a) in vivo chemical, immunological, and biological stability, (b) in uiuo immunogenicity, and (c) in vivo anti-leukemic activity of various B43-PAP immunotoxin constructs. Our data recommend the use of SPDP and SMPT rather than LC-SPDP for generation of B43(anti-CD19)-PAP immunotoxins as clinical anti-leukemic agents. To our knowledge, this is the first comparative analysis of the in vivo pharmacokinetic features, immunogenicity, and anti-leukemic activity of anti-CD19 PAP immunotoxins that were prepared with different heterobifunctional crosslinking agents.     

长链非编码RNA BCAR4在弥漫性大B细胞淋巴瘤患者中的表达及其临床意义

目的探讨长链非编码RNA(LncRNA)BCAR4在弥漫性大B细胞淋巴瘤(DLBCL)患者中的表达及其临床意义。方法以90例DLBCL患者为观察组,以同期90例淋巴反应性增生(RLH)患者为对照组。采用实时荧光定量PCR(QRT-PCR)检测2组血液LncRNA BCAR4含量,并分析其与DLBCL病理特征及患者预后的关系。结果DLBCL患者血清BCAR4表达水平(4.25±0.23)明显高于RLH患者(1.12±0.07)(P<0.05)。肿瘤较大、分期较高、存在B症状、国际预后指数(IPI)较高的DLBCL患者LncRNA BCAR4表达水平明显更高(P<0.05);高表达lncRNA BCAR4的DLBCL患者中位无进展生存时间(16.15±2.24个月)显著短于低表达者(33.06±3.22个月)(P<0.05)。多因素Cox回归分析显示,高表达的lncRNA BCAR4与高IPI指数是DLBCL患者预后不良的独立危险因素(P<0.05)。结论lncRNA BCAR4在DLBCL患者中表达水平较高,并与患者的肿瘤大小、分期、是否存在B症状、IPI指数及预后有关。     

Multicenter Study of the Seroprevalence of Antibodies against Covid-19 in Patients with Lymphoma: An Analysis of the Oncological Group for the Treatment and Study of Lymphomas (Gotel)

The new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) coronavirus has generated a pandemic, in which there are population groups at higher risk and who are potentially fatal victims of the disease. Cancer patients have been considered a group with special susceptibility, particularly patients with lung tumour involvement and haematological neoplasms. The Spanish Lymphoma Oncology Group (GOTEL) carried out a multicenter study of SARS-CoV-2 seroprevalence in patients with lymphoma. Results: A total of 150 patients were included between 22 May and 11 June 2020. The mean age was 65 years (range 17–89), 70 women (46.5%) and 80 men (53, 5%). At the time of diagnosis of lymphoma, 13 cases were stage I (9%), 27 (18%) stage II, 37 (24.5%) stage III, and 73 (48.5%) stage IV, while 6.6% had a primary extranodal origin. A total of 10 cases with positive serology for SARS-CoV-2 were identified, which is a prevalence of 6% in this population. None of the patients required intensive care unit management and all fully recovered from the infection. Conclusion: IgG antibody seroprevalence in lymphoma patients appears similar to that of the general population and does not show greater aggressiveness.     

Stimulation of Bruton's Tyrosine Kinase (BTK) and Inositol 1,4,5-Trisphosphate Production in Leukemia and Lymphoma Cells Exposed to Low Energy Electromagnetic Fields

We examined the effects of low energy electromagnetic field (EMF) exposure on the BTK kinase activity in B18-2 ([Btk-, rBTK(wt)] DT40) chicken lymphoma B cells and NALM-6 leukemic pre-B cells. Exposure of B18-2 cells to EMF resulted in activation of BTK within 1 to 15 minutes in 8 of 8 independent experiments with stimulation indexes ranging from 1.2 to 13.3. While in some experiments the BTK stimulation was transient, in others the BTK activity continued to be significantly elevated for up to 4 hours. Similarly, exposure of NALM-6 cells to EMF resulted in activation of BTK within 30 minutes in 7 of 7 experiments with stimulation indexes ranging from 1.2 to 7.4. Stimulation of BTK activity in EMF exposed cells was associated with enhanced phosphoinositide turnover and increased inositol- 1,4,5-tri-sphosphate (IP3) production in 7 of 13 experiments with DT40 cells and 7 of 13 experiments with NALM-6 cells. The likelihood and magnitude of an IP3 response after EMF exposure were similar to those after BCR ligation on DT40 cells and CD 19 ligation on NALM-6 cells. These results confirm and extend our previous studies regarding EMF-induced biochemical signaling events in B-lineage lymphoid cells.     

Successful treatment of two relapsed patients with t(11;19)(q23;p13) acute myeloid leukemia by CLAE chemotherapy sequential with allogeneic hematopoietic stem cell transplantation: Case reports

The prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) is poor, with a 3-year overall survival rate of 10%. Patients with translocation (t)(11;19)(q23;p13) have a higher risk of relapse and there is no optimal regimen for these patients. The present study treated two young patients with t(11;19)(q23;p13) AML, who relapsed after one or two cycles of consolidation, with a salvage treatment consisting of sequential cladribine, cytarabine and etoposide (CLAE) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Both neutrophil and platelet engraftments were achieved within 15 days, and no severe transplant-related complications and graft-versus-host diseases were observed. Following allo-HSCT, both patients achieved complete hematologic and cytogenetic remission. Decitabine was used for the prophylaxis of relapse. The two patients remained alive and disease-free for 100 days following allo-HSCT. The results presented here suggest that CLAE regimen sequential with allo-HSCT may be effective in treating patients with R/R AML, with t(11;19)(q23;p13). However, further studies and a larger sample size are required to validate the effectiveness of this treatment regimen.     

Clinical Features,Management, and Prognosis of an International Series of 161 Patients With Limited‐Stage Diffuse Large B‐Cell Lymphoma of the Bone (the IELSG‐14 Study)

Introduction.

The clinical features, management, and prognosis of stage I–II diffuse large B-cell lymphoma of the bone (PB-DLBCL) included in an international database of 499 lymphoma patients with skeletal involvement were reviewed.

Methods.

HIV-negative patients (n = 161) with diffuse large B-cell lymphoma of the bone (PB-DLBCL) after complete staging workup were considered. The primary objective of this study was to identify the most effective treatment modality; the secondary objectives were to define the contribution of irradiation fields and doses and the pattern of relapse.

Results.

Median age was 55 years (range, 18–99 years), with a male/female ratio of 1:2; 141 (87%) patients had stage I, 14 (9%) had B symptoms, 37 (23%) had bulky lesion, 54 (33%) showed elevated lactate dehydrogenase serum levels, and 25 (15%) had fracture. Thirteen (8%) patients received chemotherapy alone, 23 (14%) received radiotherapy alone, and 125 (78%) received both treatments. The response to the first-line treatment was complete in 131 of 152 assessed patients (complete response rate, 86%; 95% confidence interval [CI], 81%–91%) and partial in 7, with an overall response rate of 91% (95% CI, 87%–95%). At a median follow-up of 54 months (range, 3–218), 107 (67%) patients remained relapse-free, with a 5-year progression-free survival of 68% (SE: 4). Four (2.5%) patients had meningeal relapse; 119 patients were alive (113 disease-free), with a 5-year overall survival of 75% (SE: 4). Patients managed with primary chemotherapy, whether followed by radiotherapy or not, had a significantly better outcome than patients treated with primary radiotherapy, whether followed by chemotherapy or not. The addition of consolidative radiotherapy after primary chemotherapy was not associated with improved outcome; doses >36 Gy and the irradiation of the whole affected bone were not associated with better outcome.

Conclusion.

Patients with PB-DLBCL exhibit a favorable prognosis when treated with primary anthracycline-based chemotherapy whether followed by radiotherapy or not. In patients treated with chemoradiotherapy, the use of larger radiation fields and doses is not associated with better outcome. Central nervous system dissemination is a rare event in PB-DLBCL patients.