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S E Coupland

Publications and source records attributed to S E Coupland.

At least 19 recordsLinked to original sources
PubMed2006

Primary lymphoma of the lacrimal sac: an EORTC ophthalmic oncology task force study.

AIM: To define the clinical and histopathological characteristics of primary lacrimal sac lymphoma in a predominantly white population. METHODS: Specimens of lacrimal sac lymphoma and follow up data were solicited from members of the Ophthalmic Oncology Task Force of the European Organization for Research and Treatment of Cancer (EORTC) and the European Ophthalmic Pathology Society (EOPS). Specimens were stained with haematoxylin and eosin and an immunohistochemical panel against leucocyte antigens was applied. Diagnosis was reached by consensus of five experienced pathologists according to the World Health Organization classification system. The histopathological findings were correlated with the clinical data. RESULTS: Of 15 primary lacrimal sac lymphomas, five (33%) were diffuse large B cell lymphoma (DLBCL), five (33%) were extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma), three were classified as "transitional MALT lymphoma," being in transition from MALT lymphoma to DLBCL, and two were unclassified B cell lymphomas. Nine of the patients were female, and the median age at the time of diagnosis was 71 years (range 45-95 years). The most frequent presenting symptoms were epiphora (85%), swelling in the region of the lacrimal sac (79%), and dacryocystitis (21%). All but one patient presented in stage I. Systemic spread occurred in three of nine patients (33%). The 5 year overall survival was 65%. CONCLUSIONS: DLBCL and MALT lymphoma are equally common in the lacrimal sac in contrast with the remaining periorbital and/or orbital region where MALT lymphoma predominates.

Aged↗
PubMed2005

Pharmacokinetics and efficacy of ifosfamide or trofosfamide in patients with intraocular lymphoma.

BACKGROUND: The prognosis of intraocular lymphoma (IOL) is poor, and the optimal treatment has not yet been defined. The study assesses ifosfamide (IFO) and trofosfamide (TRO) for treating IOL. PATIENTS AND METHODS: We prospectively evaluated the efficacy and aqueous penetration of intravenous IFO, oral TRO and their active 4-hydroxy (4-OH) metabolites in 10 patients with IOL. Doses varied from 1500 to 2000 mg/m2/day on days 1-3 for IFO and from 150 to 400 mg/day (continuous or intermittent administration) for TRO. Four patients had newly diagnosed disease, and six had relapsed after pretreatment. RESULTS: All patients responded to first treatment with IFO or TRO, and both of two patients responded to re-treatment with IFO on ocular relapse. Progression-free survival from the first treatment with IFO or TRO was > or = 6-18 months. In six of six patients, 4-OH metabolites were detected in the aqueous humor at a concentration of 0.32-1.56 microM immediately after IFO infusion with an aqueous/serum ratio of 0.19-0.54. 4-OH metabolites could be detected in one of three patients at a concentration of 7.2 microM 3-16 h after ingestion of TRO. CONCLUSIONS: IFO and TRO are active in IOL. IOL patients evidence aqueous penetration of 4-OH metabolites after intravenous administration of IFO.

Aged↗
PubMed2005

[Characterization of an experimental venous thrombus model with MRI, phlebography and histology].

INTRODUCTION: Several magnetic resonance (MR) techniques designed to demonstrate the characteristic signal intensity of blood degeneration products of thrombi have been suggested, but the effect of thrombus organization on the MR display, in particular with regard to its temporal evolution, remains to be determined. It is the purpose of this study to develop a stagnation thrombus model in rabbits and to characterize thrombus at different ages with two (MR) imaging techniques, phlebography and histology. MATERIALS AND METHODS: Venous stagnation thrombi were induced in the external jugular veins of rabbits using a minimally invasive radiological technique to produce artificial embolic vascular occlusion and hypercoagulability. Twenty-five animals were divided into 5 groups of 5 animals, and each group underwent 1.5 T MR imaging at 1, 3, 5, 7 and 9 days after thrombus induction using a T1-weighted magnetization-prepared rapid gradient-echo sequence (MP-RAGE: TR 10.4 msec, TE 4.0 msec, FA 15 degrees ) and a T2-weighted fast low-angle shot sequence (FLASH: TR 54 msec, TE 18 msec, FA 15 degrees ). The thrombus length was measured on the T1-weighted images. Thrombus conspicuity, signal intensity, and heterogeneity on T2* weighted images were described using visual scales. Radiographic venography and histology served as reference methods. RESULTS: Thrombi were successfully induced in all animals. The overall thrombus length decreased from 43 +/- 9 (day 1 after induction) to 23 +/- 4 mm (day 9). On 3D-reconstructions of the T1-weighted images, the visible portion of the true thrombus length relative to the overall thrombus length was 0.16 +/- 0.3 (day 1), 0.24 +/- 0.3 (day 3), 0.38 +/- 0.5 (day 5), 0.06 +/- 0.1 (day 7) and 0.00 (day 9). Sixteen of 25 thrombi were detectable with the T2*-weighted technique. The overall thrombus signal intensity decreased with the age of the thrombus from day 1 to day 9. The histological evaluation showed that the rabbit thrombi closely resemble human thrombi morphologically. CONCLUSIONS: The thrombus model closely resembles the human venous stagnation thrombus of different organizational stages. With state-of-the-art MRI techniques, thrombi were only partially displayed with the visibility depending on thrombus age. The model may be suitable for evaluating new and potentially more effective MRI techniques for improved thrombus visualization.

Animals↗
PubMed2005

Plasmacellular differentiation in extranodal marginal zone B cell lymphomas of the ocular adnexa: an analysis of the neoplastic plasma cell phenotype and its prognostic significance in 136 cases.

AIM: To determine (a) the expression of plasma cell related antigens in extranodal marginal zone B cell lymphomas (EMZL) of the ocular adnexa; and (b) the prognostic value of plasmacellular differentiation in these tumours. METHODS: A consecutive case series of 136 ocular adnexal EMZL obtained from three ocular pathology centres over 20 years was analysed retrospectively. An extensive immunohistochemical panel, including the plasma cell related antigens VS38c, CD38, CD138, multiple myeloma oncogene-1-protein (MUM1/IRF4), and CREB binding protein (CBP) was performed. EMZL were defined as "plasmacellular differentiated" on the basis of morphological features, evidence of cytoplasmic immunoglobulin, negativity for BSAP/PAX5, and expression of at least one of the investigated plasma cell related antigens. Controls included normal or hyperplastic lymphatic tissues. Detailed clinical data were collected for most patients, and compared with the results of immunohistochemistry. The end points considered for statistical analysis were development of local tumour recurrence, development of systemic disease, and lymphoma related death. RESULTS: 57 (42%) of the 136 ocular adnexal EMZL showed a plasmacellular differentiation; 45 of these plasmacytoid cases were primary tumours. In contrast with most admixed normal plasma cells, which displayed co-expression of MUM1/IRF4, Vs38c, CD38, CD138, and CBP, the plasmacellular differentiated EMZL tumour cells demonstrated co-expression of all five plasma cell related antigens in only six of 57 (11%) plasmacellular differentiated ocular adnexal EMZL. The most commonly expressed plasma cell related antigen was MUM1/IRF4, immunoreactivity being seen in 56/57 (98%) plasmacellular differentiated EMZL examined. Although the association of plasmacellular differentiation in primary ocular adnexal EMZL and disseminated disease was statistically significant on univariate analysis (p = 0.042), this was weaker on multivariate analysis. CONCLUSION: Plasmacellular differentiated tumour cells in EMZL demonstrate an aberrant immune profile for plasma cell related antigens when compared with normal plasma cells. On multivariate analysis, plasmacellular differentiation in ocular adnexal EMZL was not significantly associated with local recurrence, the development of systemic disease, or with lymphoma related death.

ADP-ribosyl Cyclase↗
PubMed2004

[Lymphoproliferative lesions of the ocular adnexa. Differential diagnostic guidelines].

The ocular adnexal lymphomas represent the malignant end of the spectrum of lymphoproliferative lesions which occur in the conjunctiva, eyelids, lacrimal gland and orbit. The new "W.H.O. Classification of Tumours of Haemopoietic and Lymphoid Tissues" is the most suitable for subdividing the ocular adnexal lymphomas, whereby the extranodal marginal zone B-cell lymphoma (EMZL) represents the most common lymphoma subtype. Management of patients with ocular adnexal lymphomas includes a systemic medical examination to establish the clinical stage of the disease. Most patients have stage IE disease and current recommended therapy for this is radiotherapy, while disseminated disease is treated with chemotherapy. Despite usually demonstrating an indolent course, EMZLs are renowned for recurrence in extranodal sites, including other ocular adnexal sites. Furthermore, Blastic transformation of EMZL with a corresponding aggressive clinical course has been described. Long-term follow-up with half-yearly examinations are therefore recommended. Major prognostic criteria for the ocular adnexal lymphomas include the age of the patient, anatomical location of the tumour, stage of the disease at first presentation, serum lactate dehydrogenase level at the time of diagnosis, lymphoma subtype as determined using W.H.O. lymphoma classification and the tumour cell growth rate. The clinical symptoms and histopathological findings of the differential diagnosis of lymphoproliferative lesions of the ocular adnexa are discussed.

Adult↗
PubMed2004

[Primary intraocular lymphoma].

Primary intraocular lymphoma (PIOL) is a rare extranodal Non-Hodgkin lymphoma (NHL), involving the retina, the subretinal space, vitreous body and/or optic nerve. The majority of PIOL are diffuse large cell B-cell lymphomas according to the new W.H.O. lymphoma classification with an immunophenotype suggesting an origin from germinal centre cells. PIOL occurs independently or together with primary central nervous system lymphoma (PCNSL), and often presents in the form of a steroid-resistant uveitis. PIOL is one of the most challenging intraocular tumours to diagnose. Cytological examination of vitreal aspirates remains the gold standard for exclusion of neoplastic disease in patients with idiopathic uveitis. Various techniques, particularly the polymerase chain reaction analysing clonal rearrangements of the immunoglobin heavy chain or the T-cell receptor genes, prove to be useful adjuncts. Chorioretinal biopsies increase the chances of diagnosing or excluding a PIOL involving the retina and choroid. Furthermore, they allow exact subtyping of the malignant lymphoma when present, enabling exclusion of an ocular manifestation of a systemic lymphoma. Currently, most PIOL/PCNSL are treated with systemic chemotherapy. Ocular recurrences are often treated with radiotherapy, and increasingly with intraocular methotrexate. Although the prognosis of patients with PCNS/PIOL remains poor, newer methods enabling earlier diagnosis establishment and treatment are gradually increasing overall survival.

Antineoplastic Agents↗
PubMed2002

Iron-oxide-enhanced magnetic resonance imaging of atherosclerotic plaques: postmortem analysis of accuracy, inter-observer agreement, and pitfalls.

INTRODUCTION: Contrast-enhanced magnetic resonance (MR) imaging using ultra small superparamagnetic iron oxide (USPIO) particles is a new noninvasive modality for imaging inflammatory atherosclerotic plaques. We determined the accuracy, interobserver agreement, and potential sources of error of this technique by means of postmortem MR imaging of aortic preparations. MATERIAL AND METHODS: Anesthetized atherosclerotic Watanabe heritable hyperlipidemic (WHHL) rabbits were studied after administration of different dosages of intravenous USPIO (DDM 43/34, IDF Berlin, Germany) and different postcontrast time intervals. A (n = 5) received 0 micromol Fe/kg. B (n = 5) received 50 micromol Fe/kg, 8-hour postcontrast interval. C (n = 5) received 50 micromol, 24 hours. D received 200 micromol, 48 hours. The aortas were removed and 3-mm segments prepared for postmortem examination by MR imaging using a T2-weighted gradient-echo sequence (TR/TE/FA; 41 milliseconds/11 milliseconds/15 degrees ), radiography (mammography), and histology (iron staining). USPIO accumulation was defined as the presence of 20 iron-positive cells per microscopic view (x100 magnification). Two independent readers analyzed the MR images and rated their confidence level for a positive MRI finding, defined as a focal signal loss, on a 5-point scale. The results were evaluated by receiver-operator characteristic (ROC) analysis. RESULTS: Of a total of 621 vessel segments technically acceptable for evaluation, 534 were histologically negative and 87 positive. Accuracy, expressed as the area under the ROC curve, was 0.85 for reader 1 and 0.88 for reader 2. Interobserver agreement was 0.67. False-positive findings were established by at least one reader for 121 of the 621 segments, false-negative findings for only 15 segments. Calcifications and mural thrombi were identified as potential sources of error of the method. CONCLUSION: Postmortem USPIO-enhanced MR imaging of atherosclerotic plaques showed a high accuracy and good interobserver agreement in the animal model used here. Further optimization of the method should aim at reducing the rather high percentage of false-positive results.

Animals↗
PubMed2001

Expression of Fas and Fas ligand in uveal melanoma: biological implication and prognostic value.

The interaction between Fas and Fas ligand is one possible immune escape mechanism used by tumour cells. In the present study, melanoma tissue from 103 patients who underwent enucleation for malignant uveal melanoma (iris melanomas excluded) was stained by immunohistochemistry with monoclonal antibodies specific for Fas, Fas ligand, CD3, CD8, and CD68. Histological and clinical data for these tumours were assessed. Both Fas and Fas ligand were detected in uveal melanomas. Cells of the monocyte/macrophage lineage rather than T-cells were the predominant group of tumour-infiltrating cells. The metastasis-free 5-year survival rates in the univariate analyses were considerably lower in patients with tumours that lacked Fas ligand expression (< 35% of the tumour cells), in the presence of more than 50 CD8-positive cells in 20 high-power fields and in the presence of more than 100 CD3-positive cells in 20 high-power fields. Fas and Fas ligand expression was associated with scleral infiltration. After adjustment for scleral infiltration, the predictive value of both Fas and Fas ligand expression was markedly decreased. In addition, the CD3- and CD8-positive cell count was positively associated with the histological cell type. Cox proportional hazards models showed that the presence of CD3- and CD8-positive cells was not an independent prognostic factor after adjusting for histological cell type. This preliminary observation deserves further investigation, which may shed more light on the immune escape mechanisms of this tumour and thus enable novel therapeutic strategies. The clinical relevance of this observation is limited, as more predictive parameters have been described for uveal melanoma.

Adolescent↗
PubMed2001

Contribution of lymphatic drainage system in corneal allograft rejection in mice.

PURPOSE: To modulate aqueous outflow via the uveoscleral pathway and to determine its influence on corneal graft survival in mice. METHODS: BALB/c mice received corneal transplants from C3H mice and were placed randomly in three treatment groups: saline, pilocarpine or latanoprost. Three further groups received adjuvant systemic and topical corticosteroids. The kinetics of infiltrating lymphocytes, neutrophils and macrophages in the transplants was investigated in an additional 96 animals. Cytokine expression in the submandibular lymph nodes and spleen was investigated using in-situ hybridization and RNAse protection assay. Tracer experiments were conducted using 99mTC colloidal albumin Nanocoll; count rates were determined in the submandibular lymph nodes, spleen and blood following both subconjunctival and intracameral injection. RESULTS: Neither pilocarpine nor latanoprost had any influence on aqueous outflow or allograft survival in mice. Neutrophils and macrophages dominated the infiltrating cells 11 days postoperative in both treated and untreated grafts. On postoperative day 13, a greater increase in lymphocytes than in other cell groups was observed in allogeneic grafts. Following allogeneic transplantation, 1% of lymphocytes in ipsilateral submandibular lymph nodes were positive for IFN-gamma. Tracer studies revealed a 16% aqueous outflow via the uveoscleral routes following intracameral injection of Nanocoll; this was increased by 97% with subconjunctival injection. CONCLUSION: Our data confirm the existence of functional lymphatic drainage via the uveoscleral pathway and conjunctiva in the mouse. Cells within the ipsilateral submandibular lymph node respond to stimuli upstream. This reaction could potentially be manipulated to improve graft survival.

Animals↗
PubMed2001

Alterations in expression of mucin, tenascin-c and syndecan-1 in the conjunctiva following retinal surgery and plaque radiotherapy.

PURPOSE: Disturbances of the ocular tear film layer and dry eye symptoms are common complications following retinal surgery and ocular tumour therapy. Examined were the histopathological changes of the conjunctiva following posterior segment surgery and plaque radiotherapy. METHODS: Biopsy specimens of the superior bulbar conjunctiva were obtained during cataract surgery between 2 weeks and 7 years following vitrectomy (n=92) or plaque radiotherapy for uveal melanoma (n=20) and from control subjects without previous ocular surgery (n=29). These were examined using conventional histology (HE, PAS, Van Gieson) and immunochemistry [APAAP, using antibodies directed against MUC1, MUC5AC, syndecan-1 and tenascin-C (TN-C)]. The histopathological changes were graded and statistical analysis was performed using Wilcoxon and Kruskal-Wallis rank sum tests. RESULTS: Conjunctival specimens of patients following vitrectomy or plaque radiotherapy for uveal melanoma demonstrated increased epithelial stratification, a significant decrease in the number of PAS- and MUC5AC-positive goblet cells, and distributional changes in expression of MUC1, syndecan- and TN-C within conjunctival epithelium or stroma. These alterations - in particular the goblet cell reduction and stromal fibrosis - were most prominent in those patients who had undergone radiotherapy. CONCLUSIONS: Posterior segment surgery can lead to morphological alterations of the conjunctiva and distributional changes in ocular mucins, which may cause dry eye symptoms.

Adult↗
PubMed2001

Secondary ocular involvement in systemic "memory" B-cell lymphocytic leukemia.

OBJECTIVE: Recently, B-cell chronic lymphocytic leukemia (B-CLL) has been subdivided into "naive" B-CLL and "memory" B-CLL on the basis of the presence of somatic mutations in the variable region of the immunoglobulin heavy chain gene (IgH). The aim of the current paper was to report the clinical, histopathologic, and molecular biologic findings of intraocular and ocular adnexal involvement in a patient with systemic B-CLL. DESIGN: Case report. INTERVENTION: Treatment consisted of systemic chemotherapy, conjunctival biopsies, and, ultimately, enucleation of the left eye. METHODS: Histopathologic findings of a bone marrow biopsy, the conjunctival biopsies, and the enucleated eye were compared. Further, extensive immunohistochemistry, polymerase chain reaction (PCR) for the detection of heavy chain (IgH) gene rearrangement, gene scan analysis, and DNA sequencing were performed on all tissues. RESULTS: The tumor manifestations in all specimens demonstrated similar morphologic and immunophenotypic characteristics, consistent with the diagnosis of B-CLL. Immunoglobulin-H PCR and gene scan analysis showed that the B-CLL infiltrates consisted of B cells derived from the same clone. DNA sequencing demonstrated the presence of eight somatic mutations in the variable region of IgH, consistent with "memory" B-CLL. CONCLUSIONS: Secondary ocular manifestations of B-CLL occur relatively commonly during disease progression. In the current case of memory B-CLL, ocular manifestation of the disease occurred 16 years after initial diagnosis, agreeing with clinical studies suggesting that a less aggressive course is seen in "memory" B-CLL than its counterpart, "naive" B-CLL. Somatic mutation analysis in the variable region of IgH in B-CLL should be part of routine staging investigations to aid the prediction of the individual clinical course in B-CLL patients and to determine new therapeutic strategies.

Antibodies, Monoclonal↗
PubMed2001

Long term outcome of ocular adnexal lymphoma subtyped according to the REAL classification. Revised European and American Lymphoma.

AIM: To classify ocular adnexal lymphomas according to the Revised European and American Lymphoma (REAL) classification and to determine any correlation between clinical features or histomorphological variables with the patients' outcome. METHODS: Conventional and immunohistology were performed on representative sections of 53 specimens of 46 patients with ocular adnexal lymphoma. The antibodies used were CD20, BCL-2, CD21, CD23, CD43, CD3, CD5, p53, cyclin D1, pan-cytokeratin, kappa, lambda, IgD, and IgM. The growth fraction of the tumours was determined using the MIB-1 antibody directed against the Ki-67 antigen. Clinical follow up data regarding the outcome were obtained from the treating physicians and/or hospital files. The Student's t test and log rank test were used for statistical analysis. RESULTS: The patient collective consisted of 29 females and 17 males with an age range of 32-89.7 years (average 63 years). Almost all specimens represented B cell non-Hodgkin's lymphomas: extranodal marginal zone lymphoma (EMZL) (n=38), diffuse large cell B cell lymphoma (n=8), lymphoplasmocytic lymphoma/immunocytoma (n=2), mantle cell lymphoma (n=2), follicle centre lymphoma (n=1), and plasmacytoma (n=1). One case of a secondary anaplastic large cell lymphoma of T cell type (T-ALCL) was diagnosed. The majority of the patients had stage I disease. A variety of therapeutic regimens was administered, the main form of treatment being radiotherapy. The average follow up time was 85 months. Complete remission was achieved in 24 patients (10 after excision alone, eight after radiotherapy alone, three after combined excision and radiotherapy, one after chemotherapy alone, and two after combined radiotherapy and chemotherapy). 12 patients died of causes related to lymphoma; in one patient the cause of death was unknown. Six patients had persistent tumour at final follow up and two patients were lost to follow up. The stage at presentation, as well as the lymphoma malignancy category, had a significant correlation with the final course of the disease (p=0.0001 and p=0.03, respectively). A significant correlation was also noted between the final outcome (p<0.05) and tumour cell expression for Ki-67 antigen and p53 protein. CONCLUSION: 67% of patients with ocular adnexal lymphoma had EMZL. The stage at presentation had a significant influence on the final outcome. MIB-1 and p53 expression by the tumour cells proved to be important immunohistochemical markers concerning the prognosis. It is suggested that, following thorough staging investigations, primary EMZL (stage I) (if accessible) should be treated with excisional biopsy and subsequent low dose radiotherapy. Primary diffuse large cell B cell lymphoma of the ocular adnexa requires at least similar therapeutic measures and regular intensive follow up.

Adult↗
PubMed2001

USPIO-enhanced direct MR imaging of thrombus: preclinical evaluation in rabbits.

PURPOSE: To test the hypothesis that ultrasmall superparamagnetic iron oxide (USPIO) particles may diffuse into nonendothelialized fresh thrombi and thus allow for direct magnetic resonance (MR) imaging of a thrombus. MATERIALS AND METHODS: Stagnation thrombi of different thrombus ages (1, 3, 5, 7, and 9 days) were induced in the external jugular veins of 25 rabbits. Direct MR imaging of thrombi was performed by using a fat-saturated T1-weighted gradient-echo sequence (three-dimensional [3D] magnetization prepared rapid acquisition gradient echo) before and 24 hours after intravenous administration of USPIO (particle size, 25 nm; 200 micromol per kilogram of body weight). Thrombus length on 3D reconstruction images was compared with that depicted on a radiographic venogram and with histologic findings (joint reference standard). In addition, T2*-weighted gradient-echo images were acquired and scored semiquantitatively. RESULTS: The hyperintensity of the thrombus segment depicted on T1-weighted images (thrombus length determined with 3D reconstruction images divided by true thrombus length) increased significantly after administration of contrast medium at a thrombus age of 3 days (0.6 +/- 0.4 [SD] to 0.8 +/- 0.4; P =.02), 5 days (0.1 +/- 0.1 to 1.0 +/- 0.1; P <.001), and 7 days (0 to 0.6 +/- 0.4; P =.02), but not at an age of 1 and 9 days. No significant change in the thrombus signal intensity was observed on T2*-weighted images. CONCLUSION: The animal model showed that direct MR imaging of the thrombus improved 24 hours after USPIO administration with a T1-weighted sequence. No improvement was seen with the T2*-weighted sequence.

Animals↗
PubMed2001

New approaches to lymphoma diagnosis.

Recent years have brought an explosion of new diagnostic tools to the pathology of lymphomas, which have permitted more precise disease definition and recognition of factors that can predict prognosis and response to treatment. These new methods exploit both the biological features of normal lymphocytes as they progress through differentiation pathways and the genetic abnormalities that characterize malignant transformation. These features can be assessed in individual tumors with techniques that detect proteins (immunophenotyping), messenger RNA (in-situ hybridization), or changes in DNA [Southern blot, PCR, fluorescence in-situ hybridization (FISH), and gene sequencing]. Recently, the novel technology of "gene chips" or DNA microarrays has greatly enhanced the efficiency of analyzing expression of many genes simultaneously at the RNA level. Understanding the relationship of lymphoid neoplasms to their normal counterparts and the genetic events that lead to malignant transformation in lymphoid cells are essential for physicians caring for patients with lymphoma, since these are the basis of modern classification, diagnosis, and prognosis prediction. Although microarray technology is not ready for prime time in the daily diagnosis of lymphoma, practitioners should understand its potential and limitations. The vast majority of lymphoid neoplasms worldwide are derived from B lymphocytes at various stages of differentiation. The review by Harald Stein and colleagues present the events of normal B-cell differentiation that are relevant to understanding the biology of B-cell neoplasia. These include antigen receptor [immunoglobulin (Ig)] gene rearrangement, somatic mutations of the Ig variable region genes, receptor editing, Ig heavy chain class switch, and differential expression of a variety of adhesion molecules and receptor proteins as the cell progresses from a precursor B cell to a mature plasma cell. Most lymphoid neoplasms have genetic abnormalities, many of which appear to occur during the gene rearrangements and mutations that characterize normal B-cell differentiation. Dr. Riccardo Dalla Favera reviews the mechanisms of these translocations and other abnormalities, and their consequences for lymphocyte biology. The association of specific abnormalities with individual lymphomas is reviewed. Dr. Wing C. Chan reviews the technology and applications of DNA microarray analysis, its promises and pitfalls, and what it has already told us about the biology of lymphomas. Finally, what does this all mean? The applications, both current and future, of these discoveries to the diagnosis and treatment of patients with lymphoma are discussed by Dr. Nancy Lee Harris.

Cell Differentiation↗
PubMed2000

The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma.

Malignant uveal melanoma is the commonest primary intraocular tumour in adults. It metastasizes frequently and 50% of patients die within 10 years of diagnosis. The expression of cyclin D1, p53, and MDM2 in uveal melanoma and their relationship to metastasis-free 5-year survival was determined, in order to investigate whether these proteins help to distinguish those patients with a favourable prognosis from those with a poorer one. Ninety-six eyes enucleated for uveal melanomas were immunohistochemically analysed for the protein expression of cyclin D1 and related cell-cycle markers, p53 and MDM2. The evaluation of the specimens was undertaken by two independent pathologists without knowledge of the outcome. Statistical analysis of clinical, morphological, and immunohistological features was performed. A 'favourable outcome' was defined as survival of at least 5 years after diagnosis, without metastases (n=57). An 'unfavourable outcome' was defined as death from metastases within the first 5 years after diagnosis of uveal melanoma (n=39). Cyclin D1 positivity (>15% positive tumour cells) as well as p53 positivity (>15% positive tumour cells) was associated with an unfavourable outcome (for cyclin D1: odds ratio=4. 2, 95% confidence interval 1.5-11.8, p=0.006; for p53: odds ratio=3. 2, 95% confidence interval 1.1-9.3, p=0.03). In addition, cyclin D1 positivity was associated with the presence of extraocular extension of the tumour (p=0.01), with the mixed or epithelioid cell type (p=0. 02), and with the tumour cell MIB-1 positivity (p=0.0001). MDM2 immunoreactivity of the tumour cells showed a potential correlation with clinical outcome (odds ratio=2.1, 95% confidence interval 0.8-5. 8, p=0.13). Multiple logistic regression models showed that cyclin D1 positivity is an independent prognostic factor after control for other prognostic markers. The expression of cyclin D1 in uveal melanoma is associated with a more aggressive course and histologically unfavourable disease. This could serve as a further independent prognostic factor in uveal melanoma.

Adolescent↗
PubMed2000

[Lymphatic system and differentiation of B and T lymphocytes].

Most malignant tumours are classified according to their cellular origins. With regard to the classification of the malignant lymphomas, however, the application of this concept was not possible for a long period. Attitudes towards this changed rapidly with the discovery and description of the various cellular components of lymphoid tissue, and with the development of methods, which reliably distinguish the cells of the lymphoid system from each other. It has become apparent that the cellular origin of most lymphomatous diseases determines their respective morphological and clinical characteristics and, therefore, represents a sound basis for the classification of most lymphomas. This principle of classifying malignant lymphomas was initially applied by the Kiel Classification. Since itsí publication, further scientific discoveries have enabled us to close the gaps in our knowledge regarding the development of lymphoid tissue and cells. These advances were incorporated in the REAL Classification, and, subsequently, in the new WHO Classification. It is obvious, therefore, that an understanding of the malignant lymphomas and their classification requires a basic understanding of the differentiation of the cells of the lymphoid system. Consequently, a description of the components, the development and of the various developmental stages of the lymphoid cells will be briefly reviewed here, serving as a basis for the following chapters, which will summarise the characteristics of the different lymphomas. As the majority of the malignant lymphomas arise from B- and T-cells, these cell types will be concentrated upon in this review.

B-Lymphocytes↗
PubMed2000

[Clinico-pathologic forms of peripheral T-and NK-cell lymphomas].

Malignant lymphomas, originating from peripheral T or NK cells, are rare tumours in Europe and account for less than 10% of all malignant lymphomas. In this review, the salient features of the more frequently occurring entities derived from T or NK cells will be presented. Nasal NK/T cell lymphoma is mainly found in the nose and paranasal sinuses and often, but not always, display an angiocentric growth pattern leading to coagulation necrosis. The tumor cells consistently express CD56, CD2 and the EBER molecules encoded by the Epstein-Barr virus. Clonal T cell receptor gene rearrangements are often absent indicating, in the majority of cases, a derivation of these tumors from NK cells. Enteropathy-type intestinal T-cell lymphomas often arise in patients with celiac disease and have a dismal prognosis. The tumour cells express T cell antigens, CD103 and cytotoxic molecules, but are negative for CD4. Approximately 20% of the cases display CD56 mostly in combination with CD8. Recently, an early purely intraepithelial form of this tumour was identified. Histologically these cases resemble celiac disease, however the intraepithelial lymphocytes often exhibit an abnormal immunophenotype with absent CD8 and T-cell-receptor protein expression, and, they are clonal by molecular analysis. Clinically, the patients suffer from refractory sprue or ulcerative jejunitis. The prognosis is bad with the patients often dying from malnutrition or an invasive tumour-forming T-cell lymphoma. Angioimmunoblastic T-cell lymphoma is defined by characteristic morphological findings (atypical lymphoid cells in part with pale cytoplasm, arborizing high endothelial venules and large FDC-meshworks) as well as clinical features (systemic symptoms, signs of a dys-regulated immune response). Peripheral T-cell lymphomas, that do not fit into a distinct entity, are classified in the REAL and the new WHO classifications as peripheral T-cell lymphomas unspecified. These display a broad morphological spectrum (including the T-cell lymphomas of different cell sizes, Lennert's lymphoma and T-zone lymphoma of the Kiel-classification) and in general are clinically aggressive.

Antigens, CD↗