Proteolytic activity of human non-Hodgkin's lymphomas

This study was conducted to assess the net proteolytic activity of human non-Hodgkin's lymphomas (NHLs). We have compared the extracellular matrix (ECM)-degradative abilities of human NHLs, reactive lymphoid hyperplasias, and established lymphoid cell lines using Matrigel invasion and elastin degradation assays. The inhibition studies allowed identification of the classes of proteinases involved in ECM degradation. Our results indicate that lymphocytes and other leukocytes derived from both human NHLs and reactive lymphoid hyperplasias are capable of Matrigel penetration, but only cells derived from the high-grade human NHLs degrade elastin in vitro. Established lymphoid cell lines (both malignant and Epstein-Barr virus immortalized) do not produce MMP-9, do not penetrate the Matrigel, and do not degrade elastin. Moreover, in human NHLs, elastolytic activity is blocked by metalloproteinase inhibitors, while inhibitors of the other classes of proteolytic enzymes have only minor effects. This study identifies metalloproteinases as the most important class of proteinases involved in ECM degradation by NHLs. The previous studies suggest that, within this class, MMP-9 represents the key enzyme that plays a role in the biological aggressiveness of human NHLs.     

Practical role of molecular diagnostics in non-Hodgkin's lymphomas

Molecular techniques are becoming increasingly important in the analysis of NHL, both for diagnostic purposes and in order to evaluate prognosis accurately. The increasing number of techniques available renders evaluation of their relative roles important and a review of their informativity in NHL at diagnosis timely. Molecular equivalents of chromosomal translocations generate either a qualitative change due to the expression of a chimaeric, relatively tumour specific, protein, such as the NPM-ALK associated with the t(2;5) in ALCL or a quantitative change in the extent, stage or site of expression of a full length protein, due to its juxtapositioning to and deregulation by an Ig or TCR gene. The latter represents errors of the somatic recombination process which lymphoid precursors undergo. In NHL, this category includes BCL1/CCND1, BCL2, BCL6 and MYC. The molecular characteristics, the functional consequences and the main clinical correlations of each of these abnormalities is reviewed. At diagnosis, immunological detection of the deregulated 'protooncogene' may well provide the simplest, most appropriate screening technique for CCND1 and NPM-ALK induced ALK expression. BCL6 abnormalities demonstrate similarities to BCL2 and MYC and a combination of immunophenotypic, FISH, Southern blot and PCR techniques are useful in their characterization. For the approximately 50% of NHL without one of the above markers, identification of a clonal Ig or TCR rearrangement can provide a useful 'pan' B or T molecular equivalent, provided that the limitations of the detection techniques are appreciated. Appropriate use of these techniques will transform our ability to classify, stratify and eventually treat in a risk adapted manner, patients with NHL.     

Treatment of localized non-Hodgkin's lymphomas of the head and neck

BACKGROUND: Localized non-Hodgkin's lymphomas of the head and neck are generally treated with radiotherapy with or without chemotherapy, although the results of treatment of localized non-Hodgkin's lymphomas with of treatment of localized non-Hodgkin's lymphomas with chemotherapy alone appear to be favorable. It is unclear if and when combined modality therapy should be used. METHODS: The authors reviewed the records of 53 patients with Stage I or II non-Hodgkin's lymphoma of the head and neck, who were treated with radiotherapy alone (13 patients), chemotherapy according to the cyclophosphamide, doxorubicin, vincristine, prednisone- (CHOP) regimen (27 patients), or a combination of both treatments (13 patients). RESULTS: A complete remission was achieved in 43 (81%) patients. The 5-year survival for all patients was 78%. A significant difference (P = 0.03) in 5-year relapse-free survival was observed between Stages I and II disease, of 92 and 60%, respectively. Extensive tumor was a significantly poor prognostic factor (P = 0.04) with a 5-year relapse-free survival of 52 versus 84% for patients with nonextensive lymphoma. Eight relapses occurred; in five patients, a local relapse was the first presentation. Although salvage radiotherapy was successful in these five patients, a distant relapse developed in three. No relapses were observed in previously irradiated areas. CONCLUSIONS: Our results suggest that radiotherapy alone is the appropriate treatment for nonextensive Stage I intermediate grade non-Hodgkin's lymphoma of the head and neck. For extensive Stage I or II non-Hodgkin's lymphomas, chemotherapy is preferable. The value of combined modality therapy remains unclear.     

Prognosis and management strategies of lymphatic neoplasias in the elderly. I. Aggressive non-Hodgkin's lymphomas

Lymphomas belong to the class of malignant diseases with the fastest increasing incidence. High-grade non-Hodgkin's lymphomas (NHL) display a peak of incidence in the age group above 65. In the last few years, age has been recognized as a major risk factor for overall survival of high-grade NHL patients, and numerous attempts have been made to analyze the contribution of factors to the age-related worsening of prognosis in this disease, e.g. the biology of the disease on the one hand, and age-specific comorbidity or degree of cytotoxicity, reluctance in diagnosis and treatment and socioeconomic factors on the other. Furthermore, age-adapted treatment protocols have been designed and tested for their practicability and efficacy in the elderly. Very recently, large randomized prospective clinical trials have been carried out which support the idea that treatment with a curative intent is warranted even in the very elderly and that a successful attempt to cure requires the use of full-dose anthracycline-containing regimens closely similar to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). In addition, progress has been made in systematically defining maximally tolerated doses of the cytotoxic drugs and in specifically testing anthracyclines with reduced cardiotoxicity with an efficacy similar to that of doxorubicin, and further in investigating the advantage of applying hematopoietic growth factors and/or cardioprotective drugs in this older population. In limited stages of disease, three cycles of CHOP chemotherapy followed by involved field irradiation may be superior to radiotherapy and prolonged chemotherapy and may produce highly satisfying cure rates.     

Application of form features in digital cell analysis of non-Hodgkin's lymphomas

The form of a biological cell nucleus can be characterized by the well-known circularity factor, which is derived from the area of an object and its circumference. More sophisticated form features are introduced, which are calculated from the curvature of an object ("bending energy") or from invariant moments. To investigate the sensitivity of the various form features on controlled changes of form and the behaviour under rotation and scaling, algebraic curves similar to the form of real nucleus profiles are generated. Analysis of the shape characteristics of biological cells requires an extraction of the boundaries of the nuclei. This was performed by an edge detection algorithm using eight gradient masks followed by a contour tracing procedure with feedback. The suitability of the introduced form features for classification of different nucleus profiles of non-Hodgkin's lymphomas (NHL) was tested using a Bayes classifier.     

Diagnostic and prognostic value of interleukin-6 in malignant non-Hodgkin's lymphomas

Sixty six patients with non-Hodgkin's lymphomas (NHL) were studied, interleukin-6 (IL-6) was revealed in the blood sera of 33 patients. IL-6 was revealed more frequently in patients with high-grade malignant (p < 0.05) than in those with low-grade malignancy. The largest group of IL-6 positive patients included NHL patients with diffuse large B-cell lymphoma and angioimmunoblastic lymphoma. The marked relationship was found between the serum IL-6 levels and the stage of disease: the serum IL-6 level was significantly lower in untreated patients with Stages II and III disease than in those with end-stage (IV) NHL. IL-6 significantly decreased upon remission, comparable with its level before the initiation of treatment. Analysing the association of prognosis of disease with the serum IL-6 showed that in the group of patients with good (The SNLG index < 2) and intermediate (2 < SNLG index < by 2.6) prognosis, the concentration of this cytokine was significantly lower than in those with poor prognosis (SNLG index > 2.6). There was a significant decrease of the total survival rates of NHL with serum IL-6 found. Therefore, IL-6 is a good prognostic marker in NHL and associated with the activity of a malignant process. Additionally, the increased serum IL-6 levels correlated with NK activities positively and with serum IL-4 levels negatively.     

Burkitt-like lymphomas in AIDS patients: characterization within a series of 103 human immunodeficiency virus-associated non-Hodgkin's lymphomas. Burkitt's Lymphoma Study Group

PURPOSE: Burkitt-like lymphoma (BLL) is a tumor with morphologic features intermediate between Burkitt's lymphoma (BL) and large-cell lymphoma, but its relationship with these lymphomas is currently unclear. We have therefore analyzed its characteristics within a large series of human immunodeficiency virus (HIV)-associated lymphomas. MATERIALS AND METHODS: Clinical, histologic, immunophenotypic, and molecular analyses were performed on 103 patients with AIDS lymphomas. RESULTS: Nineteen cases (18.4%) were identified as BLL. They were monoclonal B-cell proliferations, as evaluated by immunoglobulin (Ig) gene rearrangement analyses, and had rearrangement of the c-myc oncogene in 68% of cases but not the bcl-2 gene, in contrast to a previous study on non-HIV-associated BLL. This molecular pattern was therefore identical to that of typical BL, suggesting that they represented tumors of similar origin. However, some features could clearly differentiate BLL from BL and were similar to those seen in the diffuse large-cell immunoblastic lymphomas (DLC-IBL) group. These included a greater frequency of Epstein-Barr Virus (EBV) infection (79% v 48%, P = .04), an upregulation of CD39 (50% v 0%, P = .0007) and CD70 (75% v 15%, P = .003) activation antigens and of the CD11a/LFA-1 adhesion molecule (83% v30%, P = .05), and, finally, a lower CD4 count (mean, 119/microL v 270/microL, P = .04). CONCLUSION: BLL is a frequent entity among AIDS lymphomas and should be considered as a morphologic variant of BL in the context of severe immunodepression that occurs in HIV-infected patients.     

Usefulness of an immunohistochemical panel in paraffin-embedded tissues for the differentiation of B-cell non-Hodgkin's lymphomas of small lymphocytes

Diagnosis of small B-cell lymphomas is sometimes difficult without fresh tissue for flow cytometry (FC) or immunohistochemistry (IHC). Therefore, we examined the usefulness of a paraffin section IHC panel consisting of antibodies to CD5, CD10, CD20, CD23, CD43, and cyclin D1. We tested 55 formalin-fixed small B-cell lymphomas, including 16 small lymphocytic lymphomas (SLLs), 10 mantle cell lymphomas (MCLs), 25 follicle center lymphomas (FCLs), and 4 mantle zone lymphomas (MZLs). Seventeen cases had B5-fixed sections that were stained in the same manner. The findings were correlated with FC immunophenotyping when available. All of the SLLs and 90% of the MCLs expressed CD5 by IHC, with occasional weak expression in some MCLs. All of the FCLs and MZLs lacked CD5 expression. These results were comparable to those obtained by FC. CD43 expression was seen in 100% of the SLLs, 90% of the MCLs, and 75% of the MZLs. CD23 expression was seen in 94% of the SLL; of these, 100% also showed expression of CD23 by FC. Cyclin D1 was detected in all of the MCLs by IHC but also in 3 of the 16 SLLs. CD23 was absent in all of the MCLs. CD10 expression was present in 21 (95%) of 22 FCLs. All of the 17 cases fixed in B5 showed a decreased immunoreactivity for CD5 in the neoplastic cells. In contrast, CD10 immunoreactivity was judged better in B5-fixed sections. We concluded, therefore, that anti-CD5 and -CD10 were useful tools in the differential diagnosis of B-cell lymphomas of small lymphocytes and that a paraffin-section IHC panel consisting of antibodies to CD5, CD10, CD20, CD23, CD43, and cyclin D1 was a useful ancillary technique that compared favorably with FC.     

Cytolytic (TIA-1+) tumor infiltrating lymphocytes in B cell non-Hodgkin's lymphomas. SWOG Central Repository Members

TIA-1 is a monoclonal antibody (mAb) that identifies cytolytic cells. We studied eleven B cell non-Hodgkin's lymphomas (NHL) of low grade, eleven B cell NHL of intermediate-high grade, and 10 benign lymphoid hyperplasias (BLH) to investigate potential differences in the number of host cytolytic tumor infiltrating lymphocytes (TILs). Frozen sections were immunostained with TIA-1 mAb and the number of immunoreactive cells (TIA-1+) per mm2 of tissue was quantitated within reactive or neoplastic lymphoid follicles or random areas of diffuse NHL. The number of TIA-1+ cells/mm2 was significantly higher in intermediate and high grade B cell NHL than in low grade NHL or BLH with means +/- se of 1377.8 +/- 173, 866.2 +/- 92.3 and 774.1 +/- 76.2, respectively (p < 0.0183 and p < 0.0125). There was no significant difference between BLH and low grade NHL. The increased number of TIA-1+ TILs in B cell NHL of intermediate and high grade suggests the possibility of a host cytolytic immune response versus the tumor. Paradoxically, B cell tumors of worst biological outcome contained more cytolytic TILs. Functional defects of host cytolytic TILs in NHL patients should be investigated in future studies.     

New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project

Increasing knowledge about the biology of the non-Hodgkin's lymphomas has led to new approaches in classification. Rather than grouping lymphomas simply based on cell size, cell shape, and growth pattern, it is now possible to identify distinctive clinicopathologic entities. In many cases, the existence of specific immunologic and/or genetic features has confirmed the existence of these distinctive types of lymphoma. Since patients will be given these diagnoses by pathologists, it is important that clinicians be knowledgeable with regard to their clinical characteristics. The findings for the 13 most common lymphoma types that will be encountered in clinical practice are presented here.     

The morphologic spectrum of non-Hodgkin's lymphomas with BCL1/cyclin D1 gene rearrangements

BCL1/PRAD1 gene rearrangements involving the cyclin D1 gene are a feature of about 70% of centrocytic/mantle-cell lymphomas (CC/MCL) but are identified in only a small proportion of other B-cell non-Hodgkin's lymphomas. Of 37 lymphomas found to have BCL1/cyclin D1 (PRAD1, CCND1) gene rearrangements, 30 fit the morphologic and immunophenotypic criteria for typical CC/MCL. Seven cases with morphologic features atypical for CC/MCL were identified. CD5+ monoclonal B cells were documented in all these cases. Six cases were subsequently stained for cyclin D1 protein, and all showed nuclear positivity. Five cases had variably sized foci of cells with moderately abundant pale cytoplasm resembling parafollicular/monocytoid B cells, marginal zone cells, hairy cells, or even proliferation centers. Transformed-appearing cells were also present in some lymphomas. In one case, striking follicular colonization created a markedly nodular growth pattern mimicking a follicular lymphoma. A sixth case had a marked predominance of small, round lymphocytes at some sites, mimicking a small lymphocytic lymphoma. Five of these six cases also had areas more typical of CC/MCL. The seventh case was a CD5-positive splenic marginal zone-like lymphoma (SMZL) with plasmacytic differentiation and circulating villous lymphocytes consistent with a splenic lymphoma with villous lymphocytes (SLVL). These cases illustrate the morphologic spectrum of small B-cell lymphoid neoplasms that have BCL1/cyclin D1 gene rearrangements and overexpression of cyclin D1. Despite the BCL1 translocation and cyclin D1 overexpression, the splenic lymphoma with plasmacytic differentiation was definitely not a CC/MCL and fit the clinicopathologic entity of SMZL/SLVL. The other six cases are best considered CC/MCL variants based on a combined morphologic, immunophenotypic, and genotypic evaluation. Genotypic or immunophenotypic studies to identify cyclin D1 rearrangements and overexpression, although not pathognomonic, are useful in recognizing these variant CC/MCL cases, which can mimic almost any of the other well-described but more indolent low-grade B-cell lymphomas and leukemias. Some of the variant CC/MCL cases had features in common with the CD5+ cyclin D1+ SMZL/SLVL, suggesting a possible relationship between these two otherwise distinct entities.     

Distinctions between treatment outcomes and their implications for treatment evaluation.

Maintains that treatment outcomes are distinguished as ultimate, instrumental, and intermediate in terms of the role that they play in the treatment process. Ultimate outcomes signal the achievement of treatment objectives and are the criteria for treatment success. Instrumental outcomes are those that are assumed to be sufficient conditions for attainment of other outcomes without further intervention. Intermediate outcomes are those viewed as generally facilitative of continued treatment or as necessary preconditions for employment of a particular interventive technique. These distinctions between outcomes are proposed to facilitate a more discriminating view of the treatment process and, as a result, contribute to the design of evaluative studies, particularly those investigating the effectiveness of interventive approaches. (46 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Phase II trial of paclitaxel by 24-hour continuous infusion for relapsed non-Hodgkin's lymphomas: Southwest Oncology Group trial 9246

PURPOSE: The Southwest Oncology Group (SWOG) recently conducted a multiinstitutional phase II trial to determine the complete response (CR) and partial response (PR) rates, toxicities, and progression-free and overall survivals of patients with relapsed non-Hodgkin's lymphomas (NHLs) treated with a 24-hour continuous infusion of paclitaxel at a dose of 175 mg/m2. PATIENTS AND METHODS: Sixty-six patients with relapsed NHL who had received minimal prior therapy (one prior chemotherapy regimen for intermediate- to high-grade NHL [44 patients] or one or two prior regimens for low-grade NHL [22 patients]) were premedicated with dexamethasone, diphenhydramine, and cimetidine and then treated with continuous intravenous infusion paclitaxel over 24 hours every 21 days. RESULTS: Eleven of 66 patients (17%) achieved rigorously documented objective remissions, including two CRs (3%) and nine PRs (14%). In addition, another five patients (8%) achieved apparent PRs on a single computed tomographic (CT) scan. Responses were brief, lasting a median of 3 months (5 months for indolent lymphomas and 3 months for intermediate- to high-grade lymphomas). Grade 4 or 5 granulocytopenia was the only common serious toxicity, and occurred in 42 of 66 patients (64%). CONCLUSION: Paclitaxel is generally well tolerated when given as a continuous infusion of 175 mg/m2 over 24 hours, despite predictable granulocytopenia. However, single-agent paclitaxel has modest clinical efficacy compared with other available treatments for relapsed NHL.     

Prognostic implications of proliferating cell nuclear antigen (PCNA), AgNORs and P53 in non-Hodgkin's lymphomas

We investigated the prognostic value of proliferating cell nuclear antigen (PCNA) and p53 oncoprotein expression and of nucleolar organiser region (NOR) scoring, in relation to classic clinicopathological parameters, in a series of non-Hodgkin's lymphomas (NHL). Paraffin embedded tissue from 91 patients with NHL was stained immunohistochemically with the monoclonal antibodies PC-10 (PCNA) and DO-1 (p53) and histochemically with the AgNOR technique. The median follow-up was 48 (4 to 193) months. The impact of PCNA and p53 expression and of AgNOR number on survival was tested using univariate as well as multivariate analysis, in order to circumvent the heterogeneity in histologic grade, type and therapy. Univariate analysis identified seven variables related to overall survival: histologic type and grade, clinical stage, chemotherapy, p53 labelling index (LI), PCNA LI and AgNOR score, whereas only one parameter i.e. histologic grade influenced disease-free survival. In multivariate analysis stage, PCNA LI and AgNOR score predicted independently overall survival. PCNA was also the only independent predictor of post-relapse survival and histologic grade the most important indicator of disease-free survival. In conclusion, PCNA expression and AgNOR number may be better predictors of overall and post-relapse survival than histologic grade. The latter remains the most valuable prognostic indicator of disease-free survival.     

Reproducibility and prognostic value of histopathological classifications of malignant lymphomas. Prolegomena for the 1st international classification proposed by WHO. Group of the non-Hodgkin's Malignant Lymphoma Classification Project

Different histopathologic classifications have been used in the study of malignant lymphomas. The clinical relevance (reproducibility, prognostic value) has not been precisely studied. The "non-Hodgkin's lymphoma classification project" has been organized to study a cohort of 1,403 cases in 9 sites around the world consisting of consecutive patients seen between 1988 and 1990 in order to have a good follow-up. The reproducibility of the up-dated Kiel and the ILSG (REAL) classifications between the 5 visiting expert hematopathologists was pretty good, at least 85% for the majority of the entities. According to survival curves, the lymphomas can be stratified in 4 different groups. Comparison with the international prognostic index demonstrate that for therapeutic strategy both histopathology and index should be used. The results bring a good support to the project of the WHO to propose the first international classification of lymphomas based on both forme classifications.     

Suggestions for Handling Military Reports.

Comments that Dr. Sherman Ross raises several questions in his discussion on "Military Reports--Published or Not Published?" in the October 1954 American Psychologist. Some of the questions can be answered, at least from the point of view of the present writer, and the answers reflect the present practice of Psychological Abstracts. Military reports were originally issued to disseminate information to a restricted group within the Armed Services, When these reports contained material of more general scientific or professional interest, which became more common following World War II, the authors and issuing agencies were perfectly willing to make them available, but they were issued in bibliographical irregular forms. Further, little attention has been paid to conformance to bibliographic custom. The documents appeared with cryptic and usually lengthy contract numbers, with authorship concealed in a maze of names of approvers, supervisors, superapprovers, coordinators, etc. Such documents could not be easily handled by the ordinary bibliographic methods and they were, at least in part for this reason, neglected. But there is an increasing bibliographic sophistication being shown by issuing agencies which makes possible certain categorizations. The author makes 3 recommendations regarding such records. He also mentions that he is in agreement that the question of dealing bibliographically with military reports is difficult. (PsycINFO Database Record (c) 2010 APA, all rights reserved)