Clinical significance of disease‐specific MYD88 mutations in circulating DNA in primary central nervous system lymphoma

Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell‐free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell‐free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor‐derived DNA and cell‐free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor‐derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell‐free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell‐free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell‐free DNA and could be used as non‐invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL.     

Rapid detection of the MYD88 L265P mutation for pre- and intra-operative diagnosis of primary central nervous system lymphoma

The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is a disease-specific mutation of primary central nervous system lymphoma (PCNSL) among the central nervous system tumors. Accordingly, this mutation is considered a reliable diagnostic molecular marker of PCNSL. As the intra-operative diagnosis of PCNSL is sometimes difficult to achieve using histological examinations alone, intra-operative detection of the MYD88 L265P mutation could be effective for the accurate diagnosis of PCNSL. Herein, we aimed to develop a novel rapid genotyping system (GeneSoC) using real-time polymerase chain reaction (PCR) based on microfluidic thermal cycling technology. This real-time PCR system shortened the analysis time, which enabled the detection of the MYD88 L265P mutation within 15 min. Rapid detection of the MYD88 L265P mutation was performed intra-operatively using GeneSoC in 24 consecutive cases with suspected malignant brain tumors, including 10 cases with suspected PCNSL before surgery. The MYD88 L265P mutation was detected in eight cases in which tumors were pathologically diagnosed as PCNSL after the operation, while wild-type MYD88 was detected in 16 cases. Although two of the 16 cases with wild-type MYD88 were pathologically diagnosed as PCNSL after the operation, MYD88 L265P could be detected in all eight PCNSL cases harboring MYD88 L265P. The MYD88 L265P mutation could also be detected using cell-free DNA derived from the cerebrospinal fluid of two PCNSL cases. Detection of the MYD88 L265P mutation using GeneSoC might not only improve the accuracy of intra-operative diagnosis of PCNSL but also help the future pre-operative diagnosis through liquid biopsy of cerebrospinal fluid.     

Liquid biopsy of cerebrospinal fluid for MYD88 L265P mutation is useful for diagnosis of central nervous system lymphoma

The current standard of diagnosing central nervous system (CNS) lymphoma is stereotactic biopsy, however the procedure has a risk of surgical complication. Liquid biopsy of the CSF is a less invasive, non-surgical method that can be used for diagnosing CNS lymphoma. In this study, we established a clinically applicable protocol for determining mutations in MYD88 in the CSF of patients with CNS lymphoma. CSF was collected prior to the start of chemotherapy from 42 patients with CNS lymphoma and matched tumor specimens. Mutations in MYD88 in 33 tumor samples were identified using pyrosequencing. Using 10 ng each of cellular DNA and cell-free DNA (cfDNA) extracted from the CSF, the MYD88 L265P mutation was detected using digital PCR. The conditions to judge mutation were rigorously determined. The median Target/Total value of cases with MYD88 mutations in the tumors was 5.1% in cellular DNA and 22.0% in cfDNA. The criteria to judge mutation were then determined, with a Target/Total value of 0.25% as the cutoff. When MYD88 mutations were determined based on these criteria, the sensitivity and specificity were 92.2% and 100%, respectively, with cellular DNA; and the sensitivity and specificity were 100% with cfDNA. Therefore, the DNA yield, mutated allele fraction, and accuracy were significantly higher in cfDNA compared with that in cellular DNA. Taken together, this study highlights the importance of detecting the MYD88 L265P mutation in cfDNA of the CSF for diagnosing CNS lymphoma using digital PCR, a highly accurate and clinically applicable method.     

Detection of L265P MYD‐88 mutation in a series of clonal B‐cell lymphocytosis of marginal zone origin (CBL‐MZ)

Clonal B‐cell lymphocytosis of marginal zone origin (CBL‐MZ) is a recently described entity characterized by the presence of clonal B cells in the blood and/or bone marrow (BM) with morphologic and immunophenotypic features consistent with marginal zone derivation in otherwise healthy individuals. CBL‐MZ is commonly associated with paraproteinemia, usually immunoglobulin M (IgM), raising diagnostic difficulties from Waldenstrom macroglobulinemia (WM). The aim of the present study was to determine the presence of MYD‐88 L265P mutation in a well‐characterized series of CBL‐MZ to identify cases that may in fact represent WM. Fifty‐three CBL‐MZ cases were retrospectively evaluated. MYD‐88 L265P mutation was determined by allele‐specific polymerase chain reaction in blood and/or BM mononuclear cells. Almost half of the CBL‐MZ cases (49%) were associated with paraproteinemia mainly of the IgM type (65%). MYD‐88 L265P mutation was identified in 10 cases (19%). These cases may truly represent WM, whereas 43 cases (81%) are still classified as CBL‐MZ. Mutated cases were all associated with paraproteinemia compared with 37% of the nonmutated ones (P < .0001). In addition, mutated cases displayed more frequently CD38 and CD25 positivity (P = .002 and P = .005, respectively). Moreover, cases without paraproteinemia presented more frequently with lymphocytosis, irrespective of the presence of the MYD‐88 mutation (P = .02). The present study demonstrates that MYD‐88 L265P mutation may represent the only sensitive marker for the differentiation of CBL‐MZ from probable WM. However, further studies are warranted to better define the biological significance of MYD‐88 L265P mutation and to clarify whether the presence of the mutation establishes WM diagnosis or that it can also be present in borderline cases associated with paraproteinemia.     

Mutations found in cell‐free DNAs of patients with malignant lymphoma at remission can derive from clonal hematopoiesis

Cell‐free DNA (cfDNA) analysis to detect circulating tumor DNA has been focused on monitoring malignant lymphomas. However, clonal hematopoiesis of indeterminate potential (CHIP)‐associated mutations can also be detected by cfDNA analysis. Our aim is to investigate the origin of mutations detected in cfDNA among B‐cell lymphoma patients. MYD88/CD79B, DNMT3A, and TP53 were chosen as genes of interest, representing each of the following categories: lymphoma driver genes, CHIP‐related genes, and genes shared between lymphoma and CHIP. Seventy‐five B‐cell lymphoma patients were included in this retrospective study. Serum cfDNAs at time of complete metabolic response (CMR) were sequenced for TP53 (N = 75) and DNMT3A (N = 49). MYD88 p.L265P and CD79B p.Y196C/H mutations were analyzed in diffuse large B‐cell lymphoma (DLBCL) patients whose tumor samples were available (N = 29). Two and seven mutations in TP53 and DNMT3A, respectively, were detected in cfDNA at CMR. These mutations were detected in either bone marrow mononuclear cells (BMMC) or PBMC. Although four DNMT3A mutations were also detected in tumors, median variant allele frequencies in the tumors (<1.0%) were significantly lower than those in both BMMC (6.1%) and serum (5.2%) obtained before the therapy. Conversely, five MYD88 and three CD79B mutations detected in tumors were confirmed in cfDNA before therapy, but not in BMMC nor in cfDNA at CMR. Thus, all TP53 and DNMT3A mutations detected in cfDNA at remission seemed to originate from CHIP rather than from residual disease. Results of liquid biopsy should be carefully interpreted, especially in genes shared between lymphomas and CHIP.     

Characteristics of Waldenström Macroglobulinemia in Korean Patients According to Mutational Status of MYD88 and CXCR4: Analysis Using Ultra-Deep Sequencing

BackgroundLittle is known about the mutational frequency of myeloid differentiation factor 88 (MYD88) and C-X-C chemokine receptor type 4 (CXCR4) and the corresponding characteristics in Asian individuals afflicted with Waldenström macroglobulinemia (WM). We investigated the characteristics of WM according to mutational status of MYD88/CXCR4, and attempted to determine the lineage commitment among hematopoietic cells by MYD88^L265P single-cell sequencing on bone marrow (BM) smear slides.Materials and MethodsCXCR4 mutations (muts) were detected using ultra-deep sequencing using target capture. Mutational burden of MYD88 was assessed using real-time polymerase chain reaction. Single-cell sequencing for MYD88 was performed on lymphocytes, plasmacytoid lymphocytes, plasma cells, and neutrophils using laser microdissection.ResultsAmong 31 patients, the frequencies of MYD88/CXCR4 muts were as follows: MYD88 wild type (WT) CXCR4^WT (6 patients, 19.4%), MYD88^L265PCXCR4^WT (19 patients, 61.4%), MYD88^L265PCXCR4^mut (6 patients, 19.4%; 1 frameshift and 5 nonsense muts). Immunoglobulin M levels of MYD88^L265CXCR4^WT patients were significantly higher than those of MYD88^WTCXCR4^WT patients (P = .024). Tumor burden in BM was highest in patients with MYD88^L265PCXCR4^mut (82.0%), followed by MYD88^L265PCXCR4^WT (52.8%) and MYD88^WTCXCR4^WT (14.2%) (P < .001). The quantity of MYD88-mutated DNA tended to correlate with tumor burden in BM (correlation coefficient 0.647; P = .009). MYD88^L265P was detected in plasma cells, plasmacytoid lymphocytes, and lymphocytes but not neutrophils.ConclusionThe frequency of MYD88/CXCR4 muts in Korean and Caucasian patients with WM was similar, however 5 of the 6 CXCR4 muts were nonsense—a proportion higher than reported frequencies in Caucasian individuals. Ultra-deep sequencing was capable of detecting CXCR4 muts not detectable using Sanger sequencing, suggesting a possible replacement of the B-cell sorting.     

Gene expression profiling of primary vitreoretinal lymphoma

The characteristics of tumor cells of primary vitreoretinal lymphoma (PVRL) have not been defined, although researches have shown that most cases are of diffuse large B‐cell lymphoma (DLBCL). To determine the subtype and biological characteristics of tumor cells of PVRL, we performed a gene expression profiling analysis. RNA was extracted from the vitreous fluid of 7 PVRL patients and from nodal samples of 10 DLBCL patients: 6 of germinal center B‐cell (GCB) type and 4 of activated B‐cell (ABC) type determined by Hans’ criteria. Six PVRL samples showed gene expression profiles that were similar to each other. The patterns were different from those of the ABC‐type nodular DLBCL but relatively close to those of the GCB‐type nodular DLBCL. Interestingly, all of the 6 examined PVRL samples had either MYD88^L265P or mutation in the immunoreceptor tyrosine‐based activation motif (ITAM) region of CD79B. Five PVRL patients with similar gene expression profiles were treated with a standardized regimen: intravitreal administration of methotrexate (MTX) followed by six courses of systemic high doses of MTX. As a result, 2 patients had CD79B mutations and showed early central nervous system (CNS) progression. Patients without CNS progression did not have this mutation. In conclusion, PVRL had unique genetic features: an expression pattern different from ABC‐type and relatively close to GCB‐type DLBCL. CD79B mutations showed potential to serve as prognostic markers for CNS progression.     

The use of droplet digital PCR in liquid biopsies: A highly sensitive technique for MYD88 p.(L265P) detection in cerebrospinal fluid

The gold standard for diagnosis of central nervous system lymphomas still regards a stereotactic brain biopsy, with the risk of major complications for the patient. As tumor cells can be detected in cerebrospinal fluid (CSF), CSF analysis can be used as an alternative. In this respect, mutation analysis in CSF can be of added value to other diagnostic parameters such a cytomorphology and clonality analysis. A well‐known example of targeted mutation analysis entails MYD88 p.(L265P) detection, which is present in the majority of Bing Neel syndrome and primary central nervous system lymphoma (PCNSL) patients. Unfortunately, tumor yield in CSF can be very low. Therefore, use of the highly sensitive droplet digital PCR (ddPCR) might be a suitable analysis strategy for targeted mutation detection. We analyzed 26 formalin fixed paraffin embedded (FFPE) samples (8 positive and 18 negative for MYD88 p.(L265P) mutation) by ddPCR, of which the results were compared with next generation sequencing (NGS). Subsequently, 32 CSF samples were analyzed by ddPCR. ddPCR and NGS results on FFPE material showed 100% concordance. Among the 32 CSF samples, 9 belonged to patients with lymphoplasmacytic lymphoma (LPL) and clinical suspicion of Bing Neel syndrome, and 3 belonged to patients with PCNSL. Nine of these samples tested positive for MYD88 p.(L265P) (8 LPL and 1 PCNSL). This study shows that sensitive MYD88 mutation analysis by ddPCR in CSF is highly reliable and can be applied even when DNA input is low. Therefore, ddPCR is of added value to current diagnostic parameters, especially when the available amount of DNA is limited.     

Molecular profiling of Chinese R-CHOP treated DLBCL patients: Identifying a high-risk subgroup

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive and heterogenous disease. Although most patients can be cured by immunochemotherapy, 30% to 40% patient will ultimately develop relapsed or refractory disease. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. We performed capture-based targeted sequencing on baseline samples of 105 DLBCL patients using a panel consisting of 112 lymphoma-related genes. Subsequently, 81 treatment-naïve patients with measurable disease and followed for over 1 year were included for survival analysis. Collectively, the most commonly seen mutations included IGH fusion (69%), PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (87.0% vs 50.0%, P = .009). For those with TP53 disruptive mutations, 91.7% patients were in the primary refractory group. Interestingly, BCL-2 somatic hypermutation was only seen in patients without primary refractory disease (P = .014). In multivariate analysis, BCL-2 amplification (hazard ratio [HR] = 2.94, P = .022), B2M mutation (HR = 2.99, P = .017) and TP53 mutation (HR = 3.19, P < .001) were independently associated with shorter time to progression (TTP). Furthermore, TP53 mutations was correlated with worse overall survival (P = .049). Next, we investigated mutation landscape in patients with wild-type (WT) TP53 (n = 58) and found that patients harboring MYD88 L265P had significantly inferior TTP than those with WT or non-265P (P = .046). Our study reveals the mutation spectrum of treatment-naive Chinese DLBCL patients. It also confirms the clinical significance of TP53 mutations and indicates the prognostic value of MYD88 L265P in TP53 WT patients.     

Activation of TAK1 by MYD88 L265P drives malignant B-cell Growth in non-Hodgkin lymphoma

Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88_L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenström''s macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88_L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88_L265P-expressing B cells. We report here that MYD88_L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88_L265P, IRAK and TRAF6 oligomerization and NF-κB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88_L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88_L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88_L265P.     

Mutational analysis of primary central nervous system lymphoma

Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signaling pathways such as NFKB, B cell differentiation and cell cycle control. Focused resequencing in the larger cohort revealed high mutation rates for genes already described as mutated in PCNSL such as MYD88 (38%), CD79B (30%), PIM1 (22%) and TBL1XR1 (19%) and for genes not previously reported to be involved in PCNSL tumorigenesis such as ETV6 (16%), IRF4 (14%), IRF2BP2 (11%) and EBF1 (11%). Of note, only 3 somatically acquired SNVs were annotated in the COSMIC database. Our results demonstrate a high genetic heterogeneity of PCNSL and mutational pattern similarities with extracerebral diffuse large B cell lymphomas, particularly of the activated B-cell (ABC) subtype, suggesting shared underlying biological mechanisms. The present study provides new insights into the mutational profile of PCNSL and potential targets for therapeutic strategies.     

Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88^L265P mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To investigate the clinical impact of genetic alterations in WM, we assembled a large cohort of 219 WMs and 12 LPLs dividing into two subcohorts: a training cohort, patients sequenced by a same targeted 29-gene next-generation sequencing (NGS) panel, and a validation cohort, patients sequenced by allele specific-PCR or other targeted NGS panels. In both training and validation subcohorts, MYD88^L265P and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4^NS/MS), cytogenetic complex karyotypes, and a family history of lymphoma/leukemia in first-degree relatives were associated with significantly worse clinical outcomes only or more in the validation subcohort. We further investigated the efficacy of various treatments and interaction with genetic factors in the entire cohort. Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival. Ibrutinib/BTKi showed potential benefit in relapsed/refractory patients and patients without CXCR4^NS/MS including those with TP53 mutations. In conclusion, genetic testing for MYD88^L265P, TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic.     

Disease‐specific mutations in mature lymphoid neoplasms: Recent advances

Mature lymphoid neoplasms (MLN) are clinically and pathologically more complex than precursor lymphoid neoplasms. Until recently, molecular characterization of MLN was mainly based on cytogenetics/fluorescence in situ hybridization, allele copy number, and mRNA expression, approaches that yielded scanty gene mutation information. Use of massive parallel sequencing technologies has changed this outcome, and now many gene mutations have been discovered. Some of these are considerably frequent in, and substantially specific to, distinct MLN subtypes, and occur at single or several hotspots. They include the V600E BRAF mutation in hairy cell leukemia, the L265P MYD88 mutation in Waldenström macroglobulinemia, the G17V RHOA mutation in angioimmunoblastic T‐cell lymphoma and peripheral T‐cell lymphoma, not otherwise specified, and the Y640F//D661Y/V/H/I//N647I STAT3 mutations in T‐cell large granular lymphocytic leukemia. Detecting these mutations is highly valuable in diagnosing MLN subtypes. Defining these mutations also sheds light on the molecular pathogenesis of MLN, furthering development of molecular targeting therapies. In this review, we focus on the disease‐specific gene mutations in MLN discovered by recent massive sequencing technologies.     

The value of bone marrow biopsy for staging of patients with primary CNS lymphoma

BackgroundIn patients with presumed primary CNS lymphoma (PCNSL), a systemic manifestation is found only in a small minority. Although bone marrow biopsy (BMB) is recommended for staging, its diagnostic value is unclear.MethodsA retrospective analysis of 392 patients with presumed PCNSL from 3 university hospitals and 33 patients with secondary CNS lymphoma (SCNSL) and initial CNS involvement from a multicenter Germany-wide prospective registry was performed.ResultsA BMB was performed and documented in 320/392 patients with presumed PCNSL; 23 had pathologic results. One harbored the same lymphoma in the brain and bone marrow (BM), 22 showed findings in BM discordant to the histology of brain lymphoma; n = 12 harbored a low-grade lymphoma in the BM, the other showed B-cell proliferation but no proof of lymphoma (n = 5), monoclonal B cells (n = 3), or abnormalities not B-cell-associated (n = 2). In the group of SCNSL with initial CNS manifestation, 32/33 patients underwent BMB; 7 were documented with bone marrow involvement (BMI); 1 had concordant results in the brain and BM with no other systemic manifestation. Six had additional systemic lymphoma manifestations apart from the brain and BM.ConclusionsIn only 2 out of 352 (0.6%) patients with CNS lymphoma (320 presumed PCNSL and 32 SCNSL), BMB had an impact on diagnosis and treatment. While collected in a selected cohort, these findings challenge the value of BMB as part of routine staging in presumed PCNSL.     

Salvage chemoimmunotherapy with rituximab,ifosfamide and etoposide (R‐IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high‐dose methotrexate‐based chemotherapy

Despite a high proportion of patients with primary CNS lymphoma (PCNSL) experiences failure after/during first‐line treatment, a few studies focused on salvage therapy are available, often with disappointing results. Herein, we report feasibility and activity of a combination of rituximab, ifosfamide and etoposide (R‐IE regimen) in a multicentre series of patients with PCNSL relapsed or refractory to high‐dose methotrexate‐based chemotherapy. We considered consecutive HIV‐negative patients ≤75 years old with failed PCNSL treated with R‐IE regimen (rituximab 375 mg/m², day 0; ifosfamide 2 g/m²/day, days1–3; etoposide 250 mg/m², day 1; four courses). Twenty‐two patients (median age 60 years; range 39–72; male/female ratio: 1:4) received R‐IE as second‐line (n = 18) or third‐line (n = 4) treatment. Eleven patients had refractory PCNSL, and 11 had relapsing disease. Twelve patients had been previously irradiated. Sixty (68%) of the 88 planned courses were actually delivered; only one patient interrupted R‐IE because of toxicity. Grade 4 hematological toxicity was manageable; a single case of grade 4 non‐hematological toxicity (transient hepatotoxicity) was recorded. Response was complete in six patients and partial in three (overall response rate = 41%; 95%CI: 21–61%). Seven patients were successfully referred to autologous peripheral blood stem cell collection; four responders were consolidated with high‐dose chemotherapy supported by autologous stem cell transplant. At a median follow‐up of 24 months, eight responders did not experience relapse, two of them died of neurological impairment while in remission. Six patients are alive, with a 2‐year survival after relapse of 25 ± 9%. We concluded that R‐IE is a feasible and active combination for patients with relapsed/refractory PCNSL. This regimen allows stem cell collection and successful consolidation with high‐dose chemotherapy and autologous transplant. Copyright © 2012 John Wiley & Sons, Ltd.     

Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors

Data on relapsed primary central nervous system lymphoma (PCNSL) are limited. We have evaluated the clinical characteristics and outcome of relapsed PCNSL patients from two German trials. Patients with relapsed disease after primary treatment were studied. Primary therapy consisted of high-dose methotrexate-based chemotherapy in all patients. Treatment for relapse was not predetermined. After a median follow-up of 22.5 months, 52 (36%) patients with relapse were identified among 143 patients with complete remission (CR) after primary treatment. The median disease-free survival was 10.25 (3–47.5) months. The median age at relapse was 59 years. Forty-four of 51 evaluable patients relapsed within the CNS, 6 systemically and one both cerebrally and systemically. The median survival time after first relapse was 4.5 (0.5–40.5) months. Karnofsky performance status (KPS) at relapse (P = 0.004), site of relapse (isolated systemic versus other, P = 0.049) and treatment for relapse (versus no treatment, P = 0.001) were independent prognostic factors for survival after relapse in multivariate analysis. Survival of patients with relapsed PCNSL is poor despite high response rates to salvage therapy. Good KPS, isolated systemic relapse and treatment for relapse were significantly associated with longer survival.     

弥漫性大B细胞淋巴瘤中MYD88基因突变及其临床病理相关性分析

背景与目的：MYD88基因在弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）中有一定突变率,但其临床病理相关性目前研究报道甚少。该研究旨在分析DLBCL中MYD88基因突变的发生率及与临床病理参数的相关性。方法：收集121例DLBCL患者的临床病理资料,采用免疫组织化学法分析其免疫表型,采用PCR扩增及直接测序法检测MYD88 L265P位点突变情况,采用统计学方法分析MYD88突变与各临床病理参数的相关性。结果：121例DLBCL患者中,38例（31.4%）检测到MYD88 L265P突变。其中男性50例,女性71例,患者性别与该基因突变没有相关性（P=0.609）。年龄≥60岁组MYD88突变率为40.3%（25/62）,显著高于<60岁组（13/59,22.0%）（P=0.030）。MYD88突变主要发生在结外部位,其中最常见的是乳腺（12/13,92.3%）、男性生殖系统（10/11,90.9%）、女性生殖系统（5/6,83.3%）及中枢神经系统（4/6,66.7%）;结外DLBCL中的MYD88突变率（35/98,35.7%）显著高于结内者（2/20,10%）（P=0.024）。Non-GCB型DLBCL中MYD88突变率为39.7%（25/63）,显著高于GCB亚型（10/55,18.2%）（P=0.010）;结外DLBCL组中MYD88突变与免疫分型的相关性更加显著（P=0.003）,而结内组中两者无相关性（P=0.776）。Bcl-2蛋白阳性组（30/77,39.0%）及MYC/Bcl-2蛋白双表达组（19/46,41.3%）中MYD88突变率分别高于Bcl-2阴性组（5/40,12.5%）及非双表达组（16/70,22.9%）（P=0.003和0.034）。Ki-67增殖活性与MYD88基因突变显著相关［高增殖活性组为38.8%（33/85）,低增殖活性组为6.3%（2/32）］（P<0.001）。该基因突变与MYC蛋白及CD5表达均无相关性（P=0.581和0.759）。结论：MYD88 L265P突变好发于年龄≥60岁、non-GCB起源及特殊结外部位（如乳腺、中枢神经系统及生殖系统等）的DLBCL中,且具有较高增殖指数及MYC/Bcl-2蛋白双表达率;其预后相关性有待积累更多病例进一步分析。MYD88基因突变有望为揭示DLBCL发病机制及靶向治疗提供新的理论依据。     

伴MYD88 L265P突变的脾边缘区淋巴瘤临床特征分析

目的 分析伴MYD88 L265P突变的脾边缘区淋巴瘤(splenic marginal zone lymphoma,SMZL)患者的临床特征.方法 回顾性分析本中心SMZL患者队列,将MYD88 L265P突变型患者的临床特征与野生型以及华氏巨球蛋白血症(Waldenstr?m macroglobulinemia,W...     

Comparing central nervous system (CNS) and extra‐CNS hemangiopericytomas in the Surveillance,Epidemiology, and End Results program

BACKGROUND:

Hemangiopericytomas (HPCs) are rare tumors in the central nervous system (CNS) and in extra‐CNS sites. The authors of this report used the Surveillance, Epidemiology, and End Results (SEER) Program to study prognostic factors in patients with HPC.

METHODS:

The SEER database was analyzed for patients who were diagnosed with HPC tumors from 1973 to 2007. Patients were stratified into CNS and extra‐CNS groups. Univariate and multivariate analyses were performed for the overall survival (OS) endpoint using major demographic factors (age, race, and sex) and disease factors (tumor site).

RESULTS:

In total, 655 patients with HPC were stratified into a CNS group (n = 199) and an extra‐CNS group (n = 456). The patients with extra‐CNS HPC were statistically older (mean age, 53 years vs 49 years; P = .008) and were more likely to have larger tumors (median greatest dimension, 7.0 cm vs 5.2 cm; P < .001). Patients who had CNS tumors had better OS and cause‐specific survival (CSS) compared with patients who had extra‐CNS tumors (P < .001 for both). Negative predictors of OS on multivariate analysis included extra‐CNS tumor site (hazard ratio [HR], 1.6; P = .005) and older age (ages 40‐59 years: HR, 2.08; P = .032; ages 60‐79 years: HR, 3.9; P < .001; aged ≥80 years: HR, 7.7; P < .001).

CONCLUSIONS:

The current analysis demonstrated that patients with extra‐CNS HPCs had worse OS and CSS than patients with CNS HPCs. Cancer 2012. © 2012 American Cancer Society.     

初治弥漫大B细胞淋巴瘤患者MYD88基因突变的临床特征及预后分析

目的:探讨MYD88基因突变对初治弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）的临床特征及预后的影响。方法:收集2013年1月至2015年1月空军军医大学第二附属医院血液科的74例初治DLBCL患者,回顾分析MYD88突变组（MYD88mut）和MYD88野生组（MYD88wt）患者的临床特征及治疗效果。结果:74例DLBCL患者中,MYD88mut组和MYD88wt组患者性别、年龄、ECOG评分、LDH、Ann Arbor分期、结外侵犯及IPI评分比较差异无统计学意义。MYD88mut组主要为ABC亚型（75.00%）。12例MYD88mut突变均为错义突变,其中8例氨基酸改变为L265P。MYD88mut组2周期R-CHOP方案完全缓解率（complete remission,CR）为41.67%,部分缓解率(partial remission,PR)为33.33%,客观有效率(objective effective,OR)为75.00%。MYD88wt组分别为77.42%、11.29%和88.71%。2组比较,2周期CR率具有统计学差异（P=0.030 4）。生存分析结果显示,MYD88mut组及MYD88wt组患者5年OS分别为54.98%与73.53%,PFS分别为48.61%与66.54%,2组比较,OS及PFS均具有统计学差异（P=0.003 4,P=0.031 9）。结论:MYD88突变主要存在于DLBCL的ABC亚型,且MYD88突变提示其预后不良。