Quantitation of vancomycin and its crystalline degradation product (CDP-1) in human serum by high performance liquid chromatography

Mantle cell lymphoma (MCL) patients represent a difficult problem, sometimes to establish the diagnosis but mostly because of their refractoriness to standard lymphoma treatments. Which treatments to apply and to whom is not yet defined. In this study, we attempted to analyze the clinical features, to identify the major prognostic factors, and to evaluate the outcome of 121 MCL patients treated in our institution between 1979 and 1997. Clinical data, treatment modalities, and International Prognostic Index (IPI) score were evaluated. Median age was 63 years. Patients usually presented with advanced stage disease (87%), disseminated lymph nodes (57%), bone marrow involvement (79%), but with a good performance status (PS) (81%). Lymphocytosis >4000/microl and/or peripheral blood involvement was present in 36% of cases, and gastrointestinal disease in 18%. The t(11;14)(q13;q32) and/or bcl-1 rearrangement was detected in 47/57 studied cases. Median overall survival (OS) was 3.12 years and a longer survival was significantly associated with younger age (<70 years), good PS (<2), localized disease (stage I-II), fewer than two extra-nodal sites, absence of spleen or peripheral blood involvement, normal serum LDH and beta2-microglobulin levels, and hemoglobin level greater than 12 g/dl. However, the IPI failed to identify patients with longer OS and in a multiparametric analysis, only older age, hemoglobin less than 12 g/dl, poor PS, and blood involvement were associated with a poorer outcome. Treatment modalities had no impact on survival with 75% of patients relapsing or progressing. Our data showed that the poor outcome of MCL patients is mainly related to adverse patient characteristics, a highly disseminated tumor, and some unknown parameters associated with the refractoriness to standard therapy.     

Prognostic factors for survival of non-Hodgkin's lymphoma patients treated with high-dose chemotherapy and autologous bone marrow transplantation

Prognostic factors to identify patients with high-risk non-Hodgkin's lymphoma (NHL) have recently been developed. We retrospectively investigated the relation between prognostic factors and treatment outcome after autologous bone marrow transplantation (ABMT). From 1984 to 1994, 80 consecutive patients with NHL responding slowly to or relapsing after front-line therapy were treated with high-dose chemotherapy and ABMT. Prognostic factors at the time of diagnosis and of ABMT were related to clinical outcome after ABMT. The cumulative 5-year overall survival (OS) was 51%, progression-free survival (PFS) 41%, and relapse-free survival (RFS) 53%. Absence of B symptoms and intermediate-grade malignancy at first presentation of disease were independently related to prolonged OS (P = 0.02 and P < 0.01, respectively) and prolonged PFS (P = 0.005 and P = 0.01, respectively). At the time of ABMT, first PR or CR, normal LDH levels and tumour stage I + II were associated with prolonged OS (P = 0.0005, P = 0.03 and P = 0.004, respectively). A Coiffier index of 0 or 1, first PR or CR and no extranodal disease involvement were related to prolonged PFS (P = 0.0002, P = 0.005 and P = 0.07, respectively). Treatment-related deaths occurred in 10% of patients. Assessment of disease status, LDH level, tumour stage, extranodal disease involvement and Coiffier index at the time of ABMT is respectively efficient in predicting treatment outcome after ABMT.     

原发结内外周T细胞淋巴瘤19例临床特征及预后分析

目的 分析原发结内外周T细胞淋巴瘤(PTCL)的临床特点、治疗和预后.方法 回顾性分析19例原发结内PTCL患者的临床资料、治疗反应以及预后因素.结果 19例患者中位发病年龄54岁,男女比例2.17∶1,其中94.7%(18/19)为Ⅲ～Ⅳ期,84.2%(16/19)有B症状,84.2%(16/19)有结外器官受累,57.9%(11/19)有骨髓浸润.化疗完全缓解(CR)率36.8%(7/19),2年总生存(OS)率47.4%,2年无进展生存(PFS)率25%.预后分析显示,结外侵犯数量(EN)≥2个、美国东部肿瘤协作组(ECOG)体能状态评分≥2分、国际预后指数(IPI)评分＞2分以及β2-微球蛋白(βrMG)升高为不良预后因素.结论 原发结内PTCL是一类高度侵袭的异质性T细胞淋巴瘤,化疗效果差,多项因素提示不良预后.     

Features of the lateralization of speech function in stutterers as a function of the sex of the subjects

BACKGROUND: To analyze the response to eradicative therapy and prognostic factors in 52 patients with primary gastrointestinal lymphoma (PGIL) diagnosed at a single institution in a 13 year period. PATIENTS AND METHODS: The main clinical, biological and evolutive data were recorded. Pathologic diagnosis of PGIL was made according to the Working Formulation. Clinical stage was determined by the Ann Arbor system modified by Mushoff. The results of therapy as well as the influence of such characteristics on complete remission (CR), disease-free survival (DFS) and overall survival (OS) were studied. RESULTS: Mean age of the series was 53 years (SD 15). Thirty patients were males. HIV infection preceded PGIL diagnosis in 10 cases. Seventeen had bad performance status (ECOG 2-4) and 30 B symptoms. The PGIL localization was gastric in 31 cases and 29 had a low grade malignant lymphoma. B phenotype was demonstrated in 98% and 22 patients presented advanced stages (IIE2-IV). Treatment was radical surgery followed by intensive chemotherapy in 32 cases, intensive chemotherapy alone in 17, and surgical resection in 3. CR was obtained in 34 patients and 6 of them relapsed. The projected DFS from CR at 9 years was 72% and OS was 26%. CR and survival were not influenced by PGIL localization and treatment type. The main unfavourable prognostic factors were advanced stage (CR and OS), B symptoms (DFS and OS) and advanced ECOG score (CR, DFS and OS). Previous HIV infection had an independent prognostic influence on both CR and OS. CONCLUSIONS: In patients with PGIL, the achievement of CR, DFS and survival have been independent of the type of eradicative treatment used. Performance status, B symptoms and clinical stage have been the main prognostic factors. HIV infection carried an independent prognostic significance.     

Mantle cell lymphoma: correlation of clinical outcome and biologic features with three histologic variants

PURPOSE: Clinical data and histologic material were retrospectively analyzed in 46 cases of previously untreated mantle cell lymphoma (MCL) to more fully characterize the clinical response pattern of these lymphomas and to determine whether growth pattern significantly affected clinical outcome. MATERIALS AND METHODS: The histologic pattern was classified as diffuse (61%), nodular (13%), and mantle zone (26%) in accordance with stated criteria. RESULTS: Bone marrow infiltration was detected in 69% of cases; the frequency of involvement correlated with histologic pattern, being most common in diffuse variants and least common in mantle zone variants. Other sites of extranodal involvement were observed in 50% of cases. Cyclin-D1 staining revealed nuclear positivity in 23 of 25 patients (92%) and no difference was observed between the various histologic patterns. Rearrangement at the bcl-1 major translocation cluster (MTC) was detected in seven of 21 cases, without regard for histologic pattern. Complete response rates to doxorubicin-based regimens showed a striking correlation with histologic pattern. Seventy-three percent of patients with a mantle zone pattern attained a complete response compared with only 25% of patients with a nodular pattern and 19% with a diffuse pattern. Three-year survival rates were 100%, 50%, and 55% for patients with mantle zone, nodular, and diffuse histologic patterns, respectively. CONCLUSION: We conclude that (1) diffuse and nodular MCL are associated with a poor treatment response and a poor overall survival rate; (2) the mantle zone variant exhibits the clinical attributes of a low-grade lymphoma; and (3) the poor survival rates of patients with nodular and diffuse MCL suggest that these variants be classified as intermediate-grade lymphomas. However, the trend of the time to treatment failure curve does not indicate that current regimens can cure MCL.     

Intensive therapy with peripheral stem cell transplantation in 16 patients with mantle cell lymphoma

BACKGROUND: Despite improved detection of mantle cell lymphoma (MCL), results of its treatment with conventional therapies remain disappointing and the survival rate poor. The role of high-dose chemotherapy has recently been investigated but no potential benefit has been clearly established. We report here our experience with MCL patients treated with intensive chemotherapy and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Of the 16 MCL patients who received high-dose chemotherapy and ASCT beginning in 1989, six were treated in first-line and 10 in sensitive relapse. Twelve of 16 patients received regimens which included total body irradiation. All patients received peripheral blood stem cells (PBSC) with the exception of one, who underwent bone marrow transplantation. RESULTS: Three patients died of toxic effects of treatment, Three months after transplant, seven achieved complete response, (CR) and two partial responses (PR), two were stable and two had progressed. With a median follow-up after transplant of 22 months, five of the six surviving patients were without progression, and three were in CR. The median times for event-free survival (EFS) and overall survival (OS) were, respectively, 249 and 317 days. The expected three-year EFS and OS were 24%. The median survival after diagnosis was only 29 months. None of the criteria appeared to be significantly associated with a better outcome, but first-line intensification and a short delay after initial diagnosis may be favorable. CONCLUSION: In this study we were not able to confirm the hypothetical benefit of high-dose chemotherapy and PBSC transplantation in mantle cell lymphoma, even though this approach may be promising in a subgroup of patient.     

Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma

PURPOSE: Diffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (Hyper-CVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation. PATIENTS AND METHODS: Forty-five patients were enrolled; 25 patients were previously untreated, 43 patients had Ann Arbor stage IV disease, and 42 patients had marrow involvement. Forty-one patients had diffuse histology, two patients had nodular, and two patients had blastic variants. RESULTS: Hyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplantation induction chemotherapy. All patients who went on to undergo transplantation achieved CRs. For the 25 previously untreated patients, the overall survival (OS) and event-free survival (EFS) rates at 3 years were 92% (95% confidence interval [CI], 80 to 100) and 72% (95% CI, 45 to 98) compared with 25% (95% CI, 12 to 62; P = .005) and 17% (95% CI, 10 to 43; P = .007), respectively, for the previously treated patients. When compared with a historic control group who received a CY, DOX, VCR, and prednisone (CHOP)-like regimen, untreated patients in the study had a 3-year EFS rate of 72% versus 28% (P = .0001) and a better OS rate (92% v 56%; P = .05). Treatment-related death occurred in five patients: all were previously treated and two received allogeneic transplants. CONCLUSION: The Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL.     

Phenoloxidase-dependent cytotoxic mechanism in ascidian (Styela plicata) hemocytes active against erythrocytes and K562 tumor cells

The distinction between mantle cell lymphoma (MCL) and other low-grade B-cell neoplasms is important because MCL has a more aggressive clinical course. In bone marrow biopsy specimens, this distinction can be especially difficult. We examined 70 bone marrow biopsy specimens involved by various B-cell lymphoid neoplasms to assess the utility of cyclin D1 immunostaining in distinguishing MCL from other B-cell lymphoproliferative disorders. We used a cocktail of two monoclonal anti-cyclin D1 antibodies and a heat- and sonication-induced epitope retrieval procedure. The neoplasms assessed included MCL (32 cases), small lymphocytic lymphoma/chronic lymphocytic leukemia (18 cases), follicular lymphoma (11 cases), hairy cell leukemia (5 cases), splenic marginal zone lymphoma (2 cases), and small lymphocytic lymphoma with plasmacytoid differentiation (2 cases). The diagnosis of MCL in bone marrow was confirmed by review of the original diagnostic biopsy specimens along with additional data, such as immunophenotypic or molecular studies. Most MCL (23/32; 72%) cases expressed cyclin D1 protein. In contrast, one case of small lymphocytic lymphoma/chronic lymphocytic leukemia (1/18; 6%) and one case of hairy cell leukemia (1/5; 20%) expressed cyclin D1 protein. These findings demonstrate that immunostaining for cyclin D1 protein expression is useful in distinguishing MCL from other B-cell lymphoid neoplasms in the bone marrow.     

Reassessment of non-hodgkins's lymphoma with a "nodular" growth variant: a clinicopathologic study of follicular, mantle cell and marginal zone lymphomas prospectively diagnosed with multiparameter analyses

Although three subtypes of non-Hodgkin's lymphoma (NHL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), are now well recognized as independent categories, their biological behavior has not been fully compared. One of the reasons for this may be that subclassification by histological examination alone is often difficult since they all have a common variant of a "nodular" growth pattern and occasionally show similar cytological morphology. Recently, we reviewed patients with FL, MCL and MZL, who were prospectively diagnosed, using multiparameter analyses with unfixed fresh biopsy materials. Of 407 NHL patients, 101 (24.8%) belonged to these three categories and 80 could be followed; FL (n=27), MCL (n=27) and MZL (n=26). Twenty eight cases with diffuse large B-cell (DL-B) lineage lymphoma were selected as control at random. The frequency of the MCL patients with performance status (PS) 2 to 4 (41%) was significantly higher than MZL patients (4%) [P< 0.001]. The 3 year survival rate with FL, MCL, MZL and DL-B was 71.5%, 57.4%, 93.3% and 53.1%, respectively. The survival rate for MZL was significantly better than both FL (p = 0.048) and MCL (p = 0.0085). Significant differences were also found in the overall survival rates among the four risk groups as defined by the International Index [I2](low, low-intermediate, high-intermediate and high; 97.4%, 79.6%, 39.4% and 18.2%, respectively). A multivariate analysis revealed that the International Index may be a significant predictor for short survival (p=0.0001) in the patients with FL, MCL or MZL. These results suggest that MZL shows an apparently better prognosis than FL and MCL and is found to be a prognostically independent category. In contrast, the clinical outcome in MCL is the worst among the three subtypes and was closer to that of DL-B. The International Index can be applied to a wide spectrum of NHL, including MCL, MZL and FL, to and can predict prognosis in these cases.     

Homing receptor alpha4beta7 integrin expression predicts digestive tract involvement in mantle cell lymphoma

Appropriate staging and evaluation of residual disease is critical to improving the treatment of patients with lymphoma. The specific expression of homing receptors may determine the preferential dissemination pattern of tumoral cells. We investigated the expression of the mucosal homing receptor alpha4beta7 on tumoral cells from peripheral lymph node in patients with newly diagnosed mantle cell lymphoma (MCL) to check whether it is associated with gastrointestinal involvement. Expression of the alpha4beta1 integrin and the peripheral lymph node addressin CD62L were also examined. Thirteen MCL patients presenting with peripheral lymphadenopathy were studied. Expression of the mucosal homing receptor integrin alpha4beta7 by peripheral lymph node lymphoma cells was found to be frequent (5/13) and associated with gastrointestinal involvement (5/7). In contrast, lymphoma cells from patients without gastrointestinal involvement did not express alpha4beta7 (6/6) (P = 0.03). These data suggest that alpha4beta7 integrin is expressed by a subset of MCLs and that its expression may predict digestive tract involvement in MCL, furnishing a basis for recognizing two distinct clinical and phenotypic forms, ie, "digestive homing (or digestive primitive)" versus "peripheral" MCL. Further studies on more patients will be needed to understand the impact of biological differences on the prognosis of these two clinical forms.     

Frequency and significance of anemia in non-Hodgkin's lymphoma patients

OBJECTIVES: Retrospective evaluation of anemia frequency and its prognostic value in patients with different subtypes of non-Hodgkin's lymphoma and comparison with other clinical characteristics. PATIENTS AND METHODS: Anemia was defined as a hemoglobin value less than or equal to 12 g/dl for all men and women over 50 years of age, and less than or equal to 11 g/dl for women under 50 years of age. The study included 1077 adult lymphoma patients treated between 1980 and 1995 with the following histologic subtypes: 127 patients with small lymphocytic or lymphoplasmacytoid, 62 with marginal zone, 50 with mantle-cell, 208 with follicular, 104 with T-cell lymphoma, 426 with diffuse large-cell and, finally, 73 patients with other high-grade lymphomas. RESULTS: Anemia was present in 341 patients (32%). It was an adverse prognostic factor (P < 0.0001) for overall survival (OS) and progression-free survival (PFS) but not for relapse-free survival (RFS). When patients with and those without bone marrow involvement were considered separately, anemia remained an adverse factor. Anemia was significantly associated with shorter PFS in small lymphocytic or lymphoplasmacytoid, mantle cell, diffuse large cell and high-grade lymphomas and with shorter OS in all histologic subgroups except marginal zone lymphoma. In multivariate analysis, anemia was a significant prognostic factor for OS and PFS for the population as a whole (P = 0.0001 and P = 0.0048, respectively) and in patients with bone marrow involvement (P = 0.007 and P = 0.005, respectively) but not in patients without bone marrow involvement. Finally, the addition of anemia to the International Prognostic Index led to an improvement for OS (P = 0.0004) and PFS (P = 0.0004). CONCLUSIONS: Anemia is an important adverse prognostic factor for the outcome of lymphoma patients, particularly in some histologic subgroups and in patients with bone marrow involvement.     

Negative regulation of Apo A-I gene expression by retinoic acid in rat hepatocytes maintained in a coculture system

Mantle cell lymphoma (MCL) is a subtype of B-cell non-Hodgkin's lymphoma recently recognised as a distinct disease entity. Little is known about the prognostic factors and optimal treatment of MCL. The aim of this study was to analyse retrospectively the clinical features and effect of treatment in 94 MCL patients diagnosed and treated in one centre between 1980 and 1996, and to find out different factors influencing the treatment results and prognosis. The median age of the patients was 66 years, and 77% were over 60 years old. Of the patients, 76% had advanced disease, the performance status (PS) was WHO 0-1 in 86%, and B symptoms were present in 35% of the cases. Bone marrow infiltration was found in 61% and overt leukaemia in 12% of the patients. Of the patients, 47% achieved complete remission with first- or second-line therapy. The median duration of remission, time to treatment failure (TTF), and survival were 28, 18, and 41 months, respectively. In multivariate analyses, age, stage and leukaemic disease were significantly associated with TTF, and age, stage, leukaemic disease and lactate dehydrogenase (LDH) with survival. Long-term prognosis is poor in MCL. None of the conventional chemotherapies seems curative. A prospective randomised trial should be made to evaluate the benefit of anthracycline-containing regimens in MCL.     

Newly designed computer controlled knee-ankle-foot orthosis (Intelligent Orthosis)

AIMS: Splenic marginal zone lymphoma (SMZL) is characterized by a micronodular infiltrate of the splenic white pulp, centred on pre-existing follicles, with a peripheral rim of 'marginal' zone B-cells, always accompanied by a variable degree of red pulp infiltration. These histological features can be closely mimicked by a variety of other small B-cell lymphomas when they involve the spleen, which makes recognition of SMZL difficult. We therefore have compared the histopathological and immunohistochemical features of other non-Hodgkin's lymphoma (NHL) types with those of SMZL. METHODS AND RESULTS: We selected cases of splenic involvement by different types of B-cell lymphoma, including mantle cell lymphoma (MCL), follicular lymphoma (FL), immunocytoma (IM) and lymphocytic lymphoma (B-CLL). A micronodular pattern and marginal zone differentiation were both found to be frequently present in FL and MCL, and with lesser frequency in IM and B-CLL. The main morphological feature useful for differential diagnosis was the cytological composition of the white pulp tumoral nodules. SMZL is distinguished by characteristic dimorphic cytology, different from the monomorphic cytology of MCL, and the distinctive mixture of centroblasts and centrocytes which is the rule in FL. B-CLL could also be identified on the basis of the polymorphic cytology including small lymphocytes and prolymphocytes, whereas cases diagnosed as IM show prominent plasmacytic differentiation, lacking the features of the other lymphoma types. Immunohistochemistry was particularly useful for the differential diagnosis. Thus the recognition of MCL was facilitated by the identification of cyclin D1 and CD43 reactivity, while FL could be recognized by the lack of IgD expression or the distinctive pattern of Ki67 staining found in SMZL. B-CLL cells were CD23+, CD43+. CONCLUSION: The results of this study provide morphological and immunohistological information useful in the recognition of the different varieties of NHLs when involving the spleen and the differential diagnosis of SMZL.     

BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors

In the present paper, we evaluate tolerability, outcome and prognostic factors in patients with poor prognosis non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) when uniformly treated with BCNU, etoposide, cytarabine and melphalan (BEAM) and autologous stem cell transplant (ASCT). On hundred and forty-eight patients with NHL (n = 112) or HD (n = 36) received BEAM followed by infusion of bone marrow (n = 55), peripheral blood stem cells (n = 79) or both (n = 14). Twenty-eight patients had low-grade lymphoma (LGL), 68 intermediate- and 16 high-grade lymphoma (IGL). Within the NHL group, 21 patients were in 2nd or subsequent complete remission (CR) at transplant, 34 had sensitive disease and 11 resistant disease; 46 patients were transplanted in 1st CR due to the presence of > or = 2 adverse prognostic features at diagnosis or to a slow CR. Of the HD patients at transplant 17 had active disease, 16 were in > or = 2 CR and three in 1st CR. The overall percentage of toxic deaths was 5.4%, while in the group of patients transplanted with PBSC it was only 1.3%. NHL patients: 78% were in CR following ASCT, including 25 out of 45 patients (56%) who were transplanted with active disease. Only two of the 11 patients transplanted with resistant disease achieved CR. Incidence of overall survival (OS) and disease-free survival (DFS) at 3 years was 65 and 75%, respectively. As far as histology was concerned, OS was significantly better for patients with LGL in comparison with IGL (88 vs 56%) (P = 0.002). DFS was significantly higher for patients transplanted in first CR or first partial remission (PR) than it was for those transplanted in a later CR or PR (86 vs 53%) (P = 0.02). Multivariate analysis for OS showed that histology, bulky disease, poor performance status at transplant and achievement of CR were independent prognostic factors. In addition, a high number of infused MNC was associated with poor DFS. HD patients: 30 (83%) were in CR after transplantation, with 25 maintaining CR at the end of the study. Only one of the four patients transplanted with resistant disease reached CR. Incidence of OS and DFS at 3 years was 78 and 81%. DFS was similar for patients transplanted with early or late relapse (95 and 93%). With multivariate analysis, the only independent variable for OS was CR after transplant. In conclusion, the present results demonstrate the efficacy and low toxicity of the BEAM regimen in high-risk lymphoma patients with sensitive disease. Other strategies should be investigated for patients with refractory lymphoma.     

Expression of CD44 (HCAM) in small lymphocytic and mantle cell lymphoma

Small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) are small B-cell lymphomas that share many morphological and immunophenotypic features, both expressing the T-cell antigen CD5. Because of this, there is speculation that these two lymphomas may have a common origin, both arising from the mantle zone of the lymph node. CD44 (HCAM), a glycoprotein "homing receptor," has been reported as a marker of small B-cell lymphomas for determining behavior as well as the nodal cell of origin. Intensity of CD44 expression also has been correlated with dissemination of lymphoma. We studied 50 cases with classic features of SLL (30 cases) or MCL (20 cases). Immunophenotypic analysis was performed on paraffin sections. All cases of MCL and SLL were CD20 positive; CD5 was expressed in 19 of 25 (76%) SLL and 11 of 15 (73%) MCL. Cyclin D1 was expressed in 11 of 17 (76%) MCL and no cases of SLL. CD43 coexpression was seen in 27 of 29 (93%) SLL and 17 of 19 (89%) MCL. CD23 was positive in 25 of 28 (89%) SLL and 2 of 20 (10%) MCL. Bcl-2 was positive in 18 of 22 (82%) SLL and 15 of 16 (94%) MCL. CD44 was positive with moderate to strong intensity in 11 of 30 SLL and 15 of 20 MCL. Peripheral blood involvement did not correlate with CD44 immunoreactivity. MCL tended to have intense CD44 immunoreactivity, whereas SLL tended to show weaker CD44 intensity. This trend in the intensity of CD44 in MCL suggests that CD44 may be helpful in distinguishing SLL from MCL and possibly elucidating the origin of these CD5-positive B-cell neoplasms.     

Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma

The prognostic significance of Bcl-2 protein expression and bcl-2 gene rearrangement in diffuse large cell lymphomas (DLCL) is controversial. Bcl-2 protein expression prevents apoptosis and may have an important role in clinical drug resistance. The presence of a bcl-2 gene rearrangement in de novo DLCL suggests a possible follicle center cell origin and perhaps a distinct clinical behavior more akin to low-grade non-Hodgkin's lymphoma (NHL). The purpose of this study was to determine the impact of Bcl-2 protein expression and bcl-2 gene rearrangement (mbr and mcr) on survival of a cohort of patients with DLCL who were uniformly evaluated and treated with effective chemotherapy. Patients included the original MACOP-B cohort (n = 121) and the initial 18 patients treated with the VACOP-B regimen (total = 139). All patients had advanced-stage disease, were 16 to 70 years old, and corresponded to Working Formulation categories F, G, or H. No patients had prior treatment, discordant lymphoma, or human immunodeficiency virus seropositivity. Paraffin sections from diagnostic biopsies were analyzed for bcl-2 gene rearrangement including mbr and mcr breakpoints by polymerase chain reaction and Bcl-2 protein expression by immunohistochemistry. With a median follow-up of 81 months, overall (OS), disease-free (DFS), and relapse-free survival (RFS) were measured to determine the prognostic significance of these parameters. Analyzable DNA was present in 118 of 139 (85%) cases, with 14 demonstrating a bcl-2 rearrangement (11 mbr, 3 mcr). All 14 of these bcl-2 gene rearrangement-positive cases were found in the 102 patients with a B-cell immunophenotype, but the presence of this rearrangement had no significant influence on survival. Bcl-2 protein expression was interpretable in 116 of 139 (83%) cases, with immunopositivity detected in 54 of 116 (47%). Using a cut-off of greater than 10% Bcl-2 immunopositive tumor cells for analysis, positive Bcl-2 protein expression was seen in 28 of 116 (24%) patients and the presence of this expression correlated with decreased 8-year OS (34% v 60%, P < .01), DFS (32% v 66%, P < .001), and RFS (25% v 59%, P < .001). Bcl-2 protein expression remained significant in multivariate analysis that included the clinical international prognostic index factors and immunophenotype (P < .02). In conclusion, although bcl-2 gene rearrangement status could not be shown to have an impact on outcome, Bcl-2 protein expression is a strong significant predictor of OS, DFS, and RFS in DLCLs.     

Rearrangements of the BCL6 gene and chromosome aberrations affecting 3q27 in 54 patients with non-Hodgkin's lymphoma

Chromosome aberrations affecting 3q27 are among the most frequent non-random abnormalities in non-Hodgkin's lymphomas (NHL), especially the diffuse, large cell type. Recently, an association between BCL6 rearrangement and frequent extranodal lesions, rare bone marrow infiltration and a favorable clinical outcome was reported. We performed molecular studies of the BCL6 gene in 54 patients with NHL. Twelve patients (22%) with rearranged BCL6 genes were selected for histological, clinical, molecular, and cytogenetic studies. Ten of these cases were diffuse, large cell type lymphoma, one a follicular lymphoma, and one a mantle cell lymphoma (MCL). All cases were of the B-cell type and this is the first time a rearranged BCL6 gene has been found in an MCL. Cytogenetic data for 10 cases were available and the partner sites of the 3q27 translocation were determined in 7 of 10 patients. These locations were variable, including 6p21.3, 9p22, and 14q11 in addition to the immunoglobulin loci 14q32 (IGH), 2p12 (IGK), and 22q11 (IGL). The heterogeneity in partner sites is distinct from other lymphoma subgroups and may suggest that the genetic events are not uniform among patients with BCL6 rearrangements.     

A DR17-restricted T cell epitope from a secreted Mycobacterium tuberculosis antigen only binds to DR17 molecules at neutral pH

Mantle cell lymphoma (MCL) was first described as a distinct biological entity on the basis of its association with the t(11;14)(q13;q32) resulting in over-expression of the cyclin D1 gene. Recognition of the morphological, immunophenotypic and clinical characteristics of MCL has enabled the accurate diagnosis of this entity and appreciation of its poor prognosis. Most published series of patients with MCL have used anthracycline-containing regimens. In contrast the British National Lymphoma Investigation (BNLI) group have treated 65 patients with MCL with non-intensive 'low-grade lymphoma' therapy. The median overall survival of 57 months and progression-free survival of 24 months compares favourably with the more intensively treated series. Although the disease was generally more aggressive than other low-grade lymphomas, some patients were asymptomatic and had indolent disease. When compared to 1853 patients with non-MCL low-grade lymphomas entered on the BNLI database, patients were found on average to be older (P=0.02), to have more extranodal disease (P<0.00001), and a higher proportion to have a raised ESR (P=0.02) and a low serum albumin (P=0.002). Multivariate analysis of significant prognostic markers in all BNLI low-grade lymphomas failed to identify MCL as an independent prognostic factor.     

Prognostic significance of bone marrow trephine and peripheral blood smears in 55 patients with mantle cell lymphoma

Bone marrow trephine and peripheral blood smears taken at diagnosis of 55 cases of well-documented mantle cell lymphomas were reviewed in order to analyse the leukaemic involvement in this non-Hodgkin's lymphoma: its incidence, morphological characteristics and prognostic significance. A median survival of 36 months was found. The median age was 61 and the male to female ratio was 4:1. Morphologically 7 cases presented with a mantle zone pattern, all the others had a diffuse pattern. Involvement of the bone marrow was found in 58% and a trend for prolonged survival in patients with a negative trephine was seen. An absolute lymphocytosis above 10,000 mu l was found at diagnosis in 5 cases (10%) and had a statistically significant impact on survival. An additional 5 cases developed frank leukaemia during the course of the disease and died within 1 to 6 months of this evolution, suggesting that marked lymphocytosis is more a terminal event associated with an extremely poor prognosis than a presenting symptom. Finally we identified an additional parameter with statistically prognostic significance, namely, the presence of atypical cells in the peripheral blood even in the absence of an increased lymphocytosis.     

Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiologic features

Conventional chromosome analysis (CCA) and interphase fluorescence in situ hybridization (FISH) was performed in 42 patients with mantle-cell lymphoma (MCL), with BCL1 rearrangement. The t(11;14)(q13;q32) or 11q abnormalities were detected by CCA in 34 cases, 20 of which had additional aberrations. A normal karyotype was observed in 8 cases. Probes detecting the chromosome aberrations that were observed in at least 3 cases by CCA, ie, +12, 13q14 deletion, and 17p deletion, were used for interphase FISH analysis. FISH detected total or partial +12, 13q14 deletion and 17p- in 28.5%, 52.4%, and 26% of the cases, respectively. The presence of these anomalies was not a function of karyotype complexity. Based on the results of CCA/FISH, three groups of increasing karyotype complexity were recognized: group 1, including 11 patients without detectable aberrations in addition to BCL1 rearrangement; group 2, including 14 patients with 1 to 2 additional anomalies; and group 3, including 17 patients with three or more additional anomalies. Clinical parameters associated with shorter survival were male sex (P =.006) and primary lymph-node involvement compared with primary bone marrow involvement (P =.015). Trisomy 12 was the only single cytogenetic parameter predictive of a poor prognosis (P =.006) and the best prognostic indicator was the derived measure of karyotype complexity (P <.0001), which maintained statistical significance in multivariate analysis (P<.0001). We arrived at the following conclusions: 13q14 deletion occurs at a high incidence in MCL; 17p deletion and total/partial +12 are relatively frequent events in MCL, the latter aberration being associated with a shorter survival; and the degree of karyotype complexity has a strong impact on prognosis in this neoplasia.