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The native chimeric human-mouse anti-CD20 antibody IDEC-C2B8 (rituximab) is therapeutically applied in relapsed non-Hodgkin's lymphoma (NHL). The purpose of this study was to evaluate the distribution and pharmacokinetics of iodine-131 labelled rituximab in humans for radioimmunotherapy of relapsed CD20-positive NHL. Thirty-five patients with relapsed NHL were administered 20-40 mg rituximab labelled with 250 MBq (131)I. Biodistribution was determined by the gamma camera whole-body scans, whole-body probe measurements and the analysis of serial blood and urine samples. Dosimetry was performed using the MIRDOSE 3 program. Antibody administration was well tolerated. The whole-body activity showed a mono-exponential decrease with a wide range of effective half-lives, the mean value (88 h) being significantly longer than the half-life of its murine counterpart, tositumomab. This led to appropriately higher dose factors for the whole body and organs. Activity was excreted mainly through the kidneys. Normal organs showed decreasing ratios of organ to whole-body activity over time, whereas the tumour tissue presented different kinetics, with increasing ratios of tumour to whole-body activity as evidence for specific antibody binding. It is concluded that (131)I-labelled rituximab is suitable for pretherapeutic dosimetry. Due to the wide range of whole-body and organ dose factors, individual dosimetry is necessary for radioimmunotherapy with (131)I-labelled rituximab. The therapeutic activities of (131)I-labelled rituximab required to deliver similar doses should be lower than those of its murine counterpart.
Eur J Nucl Med Mol Imaging 2002 Oct
PMID:Biodistribution and kinetics of (131)I-labelled anti-CD20 MAB IDEC-C2B8 (rituximab) in relapsed non-Hodgkin's lymphoma. 1227 7

Cyclin D1 overexpression is a valuable marker for the diagnosis of mantle cell lymphoma (MCL). We used a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) method to quantify levels of cyclin D1, CD20, and cyclophilin A mRNA in manually microdissected, paraffin-embedded tissue sections using an ABI 7700 qRT-PCR system. The study group included 21 cases of MCL and 37 cases of other types of B-cell non-Hodgkin's lymphoma. Cyclin D1 mRNA copy number was normalized to CD20 and cyclophilin A mRNA and evaluated statistically by analysis of variance. The relative cyclin D1 levels were similar whether normalized to CD20 or cyclophilin A, indicating that CD20 levels are stable and can be used as a B-cell-specific normalizer. Statistically significant differences were found in the median levels of cyclin D1 mRNA (expressed as % CD20 mRNA) among cases of MCL (87.6), small lymphocytic lymphoma (9.9), follicular lymphoma (2.4), diffuse large B-cell lymphoma (5.9), marginal zone B-cell lymphoma (39.8), and Burkitt lymphoma (7.1) (P < 0.05). We conclude that qRT-PCR can be used to quantify cyclin D1 mRNA levels in archival tissue sections. Normalization of cyclin D1 to a B-cell-specific marker more accurately reflects overexpression by MCL than other methods that normalize using constitutively expressed mRNA species.
J Mol Diagn 2002 Nov
PMID:Determination of cyclin D1 and CD20 mRNA levels by real-time quantitative RT-PCR from archival tissue sections of mantle cell lymphoma and other non-Hodgkin's lymphomas. 1241 87

Diagnosis of a second HIV-associated non-Hodgkin lymphoma (HIV-NHL) is rare, but additional cases may occur as aggressive therapy for both HIV and NHL improves. An 11-year-old presented with a second primary HIV-NHL following remission for 9 years. Analysis of the tumor demonstrated presence of EBV and HIV with absence of CMV, HHV-8, and HHV-6. Although microscopic disease was present only in CSF, analysis of peripheral blood and bone marrow by PCR was positive. The patient underwent a stem cell transplant, but within 3 months, his disease recurred. Analysis for residual disease and viruses in similar cases may provide information in understanding pediatric HIV-NHL.
Pediatr Pathol Mol Med
PMID:Molecular analysis and pathology of a second pediatric HIV-associated Burkitt lymphoma. 1253 69

We have earlier shown that attenuated measles virus (MV) has therapeutic potential as a replicating oncolytic virus in models of non-Hodgkin's lymphoma (NHL). In the current study, we investigated whether we could obtain replicating MVs capable of entering CD20(+) target cells through an interaction between a single-chain (scFv) anti-CD20 antibody and the CD20 antigen, a target of considerable clinical relevance in NHL. We replaced the H envelope glycoprotein of MV by an H-scFv anti-CD20 fusion protein with and without a protease-cleavable linker. Biochemical analysis of purified virions confirmed that the modified H proteins were incorporated into the viral particles with efficiency similar to unmodified H. Experiments employing CHO cells and CHO cells expressing human CD20 indicated that the MVH alpha CD20 viruses were able to replicate well in CHOCD20 but not CHO cells. MVH alpha CD20 or a nonmodified control MV were administered systemically to immunodeficient mice bearing bilateral human tumor xenografts, one side with and the other side without CD20 expression. Growth of CD20(+) tumors was retarded by MVH alpha CD20 as compared with the control virus. The viruses had equivalent effects on the CD20(-) tumors. Thus we have demonstrated that the entry of a replicating oncolytic virus can be mediated through an interaction between a highly clinically relevant single-chain antibody and its target antigen, and we have shown that this interaction enhances in vivo oncolytic activity.
Mol Ther 2003 Jan
PMID:An oncolytic measles virus engineered to enter cells through the CD20 antigen. 1257 19

Until recently, gallium-67 scintigraphy (GS) has been the best available functional imaging modality for evaluating patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). The diagnostic accuracy of GS in detecting lymphoma is based on optimisation of the imaging protocol, knowledge of potential physiological and benign sites of (67)Ga uptake, and the Ga avidity characteristics of the individual lymphoma. As (67)Ga is a tumour viability agent, the role of GS is primarily at follow-up. A residual mass persisting on CT after treatment poses a common clinical dilemma: it may indicate the presence of viable lymphoma, which requires further treatment, or it can be benign, consisting of only fibrotic and necrotic tissues. GS can successfully differentiate between these conditions. Routine follow-up with GS may allow early diagnosis of recurrence and early institution of treatment. Reversion of a positive GS to a negative test, and the rapidity with which this occurs has a high predictive value for the outcome of the individual patient. Lymphoma showing a normal GS early during treatment has a better prognosis than lymphoma with persistence of pathological findings. Other tumour-seeking single-photon emitting agents, such as thallium-201, technetium-99m methoxyisobutylisonitrile and indium-111 octreotide, have been investigated in lymphoma, primarily as an alternative to GS in specific clinical settings, but are of limited value. The role of radioimmunoscintigraphy is gaining importance in conjunction with radioimmunotherapy. Fluorine-18 fluorodeoxyglucose (FDG) imaging of lymphoma using either dedicated or camera-based PET systems is gradually replacing GS for assessment of lymphoma. FDG overcomes some of the limitations of GS while sharing its tumour viability characteristics. The extensive clinical knowledge and experience accumulated over three decades with GS in lymphoma provides a solid background as well as a model for the assessment of new functional imaging techniques.
Eur J Nucl Med Mol Imaging 2003 Jun
PMID:Gallium-67 scintigraphy: a cornerstone in functional imaging of lymphoma. 1264 87

The last 25 years have seen major changes in the imaging investigation and subsequent management of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL); accurate staging is vital for prognostication and treatment in both, and particularly in HD. The choice of imaging modality for staging depends on its accuracy, impact on clinical decision-making, and availability. Modern CT scanners fulfil most of the desired criteria. The advent of CT scanning, along with the development of ever more effective chemotherapeutic regimens, has resulted in the virtual demise of bipedal lymphangiography (LAG) as a staging tool in patients with lymphoma. It has rendered superfluous a battery of other tests that were in routine use. This contribution reviews the evidence for the use of CT in preference to LAG. CT accurately depicts nodal enlargement above and below the diaphragm, has variable sensitivity for intra-abdominal visceral involvement and is generally outstanding in depicting the extent of disease, especially extranodal extension. Despite the advances in CT technology, there are still areas where CT performs less well (e.g. disease in normal-sized lymph nodes, splenic and bone marrow infiltration). The influence of technical factors, such as the use of intravenous contrast medium, is discussed. In some instances, CT is not the imaging modality of choice and the place of newer techniques such as MRI and endoscopic ultrasound will be reviewed.
Eur J Nucl Med Mol Imaging 2003 Jun
PMID:Computerised tomography in the staging of Hodgkin's disease and non-Hodgkin's lymphoma. 1270 30

This review considers in detail the descriptive and aetiological epidemiology of Hodgkin's disease and non-Hodgkin's lymphoma (NHL), with attention to histological subcategories when the literature allows. The aetiology of Hodgkin's disease remains only partially understood. There is evidence that Epstein-Barr virus (EBV) may be involved in the causation of some cases, and clinical immune deficiency is a risk factor for a few, but the evidence is not entirely consistent and other factors may also be important in causing the EBV-associated cases of Hodgkin's disease. The cause of EBV-unassociated cases remains obscure. For NHL, although it has been shown that some cases are related to immune deficiency and chronic antigenic stimulation, and especially to EBV in the context of immune deficiency, the causation of the majority of cases remains unknown. The increasing incidence of NHL, other than that related to AIDS, is also essentially unexplained. Epidemiological investigation of the aetiology of NHL and Hodgkin's disease is making steady progress, however, and there remain leads to be followed that may result in a better understanding and hence prevention.
Eur J Nucl Med Mol Imaging 2003 Jun
PMID:Epidemiology of Hodgkin's disease and non-Hodgkin's lymphoma. 1273 87

Positron emission tomography (PET) has now gained a place in the management of patients with cancer, including those with Hodgkin's disease and non-Hodgkin's lymphoma. Restaging studies and those addressing the monitoring of response to treatment are especially in focus. Most of the knowledge gained has been achieved with dedicated BGO-based PET technology, but there are a number of developments that will impact on the use of this metabolic imaging technique in the investigation of patients with lymphoma. The challenges ahead are determined by the need for high-quality whole-body imaging associated with increased patient throughput and the need to investigate the role of new labelled ligands. The latter are likely to yield new insights into tumour cell characterisation, tumour behaviour and tumour outcome assessment. The study of new radiolabelled ligands will impose further demands for rapid dynamic data acquisition and accurate tracer quantification. Current and future developments in PET technology range from the use of new detector materials to different detector geometries and data acquisition modes. The search for alternatives to BGO scintillation materials for PET has led to the development of PET instruments utilising new crystals such as LSO and GSO. The use of these new detectors and the increased sensitivity achieved with 3D data acquisitions represent the most significant current developments in the field. With the increasing demands imposed on the clinical utilisation of PET, issues such as study cost and patient throughput will emerge as significant future factors. As a consequence, low-cost units are being offered by the manufacturers through the utilisation of gamma camera-based SPET systems for PET coincidence imaging. Unfortunately, clinical studies in lymphoma and other cancers have already demonstrated the limitations of this technology, with 20% of lesions <15 mm in size escaping detection. On the other hand, the recent development of combined PET/CT devices attempts to address the lack of anatomical information inherent with PET images, taking advantage of further improvement in patient throughput and hence cost-effectiveness. Preliminary studies using this multimodality imaging approach have already demonstrated the potential of the technique. Although the potential exists, certain technical issues with PET/CT require refinement of the methodology. Such issues include organ movement (such as respiratory motion), which strongly influences the image fusion of a rapidly acquired CT scan with the slower acquisition of a PET dataset, and the derivation of CT-based attenuation coefficients in the presence of contrast agents or metallic implants. The application of the technology for radiotherapy planning also poses a number of associated challenges. Finally, the development of dedicated PET systems based on planar detector arrangements with new detector components has the potential to improve clinical throughput by over 100%, but clinical trials using such systems have still to be carried out in order to establish the associated whole-body image quality.
Eur J Nucl Med Mol Imaging 2003 Jun
PMID:Impact of technology on the utilisation of positron emission tomography in lymphoma: current and future perspectives. 1274 30

Somatostatin receptor (SSTR) scintigraphy and gallium-67 citrate ((67)Ga) scintigraphy have been used for visualisation of Hodgkin's lymphoma and non-Hodgkin's lymphoma. However, experience with B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type is very limited. The aim of this study was to prospectively compare the (67)Ga scintigraphy results with those obtained by (111)In-DOTA- dPhe(1)-Tyr(3)-octreotide ((111)In-DOTA-TOCT) and (111)In-DOTA-lanreotide ((111)In-DOTA-LAN) scintigraphy in patients with proven MALT-type lymphoma. Comparative scintigraphic examinations using (67)Ga, (111)In-DOTA-TOCT and (111)In-DOTA-LAN were performed in 18 patients (11 female and 7 male, median age 64+/-15 years) with histologically verified MALT-type lymphomas of various origin. Planar and single-photon emission tomography imaging acquisitions were performed after injection of a mean dose of 185+/-26 MBq (67)Ga and 165+/-20 MBq (111)In-DOTA-TOCT or (111)In-DOTA-LAN. All scintigraphic results were correlated with other conventional examinations including gastroscopy, colonoscopy, endosonoscopy, ophthalmologic investigation, CT of the thorax and abdomen and bone marrow biopsy. This comparative study showed that (67)Ga scintigraphy found abnormalities in 10 of 16 patients (63%) and detected 18 of 31 clinically involved sites (58%), but was false positive in three patients. (111)In-DOTA-TOCT found abnormalities in 9 of 15 patients (60%) and detected 15 of 27 clinical lesions (56%); it was false positive in two patients. (111)In-DOTA-LAN scintigraphy showed abnormalities in 7 of 11 patients (64%) and found 12 of 22 clinical lesions (55%). False-positive (111)In-DOTA-LAN scan results were found in two patients. For supra-diaphragmatic lesions, (67)Ga scintigraphy detected 12 of 16 sites (75%). (111)In-DOTA-TOCT scintigraphy revealed 7 of 15 lesions (47%). (111)In-DOTA-LAN showed 6 of 12 positive sites (50%). For infra-diaphragmatic involvement, the sensitivities of (67)Ga, (111)In-DOTA-TOCT and (111)In-DOTA-LAN were 40%, 67% and 60%, respectively. It is concluded that MALT-type lymphoma can be visualised by (67)Ga, (111)In-DOTA-TOCT and (111)In-DOTA-LAN scintigraphy. Although there were no statistically significant differences in patient-related and site-related sensitivities when using (67)Ga compared with (111)In-DOTA-TOCT and (111)In-DOTA-LAN, the sensitivity of (67)Ga tended to be superior to that of (111)In-DOTA-TOCT and (111)In-DOTA-LAN for supra-diaphragmatic lesions but inferior for infra-diaphragmatic involvement. In selected cases, the combination of (67)Ga and (111)In-DOTA-LAN or (111)In-DOTA-TOCT may increase the diagnostic efficiency in patients with MALT-type lymphoma.
Eur J Nucl Med Mol Imaging 2003 Aug
PMID:111In-DOTA- dPhe1-Tyr3-octreotide, 111In-DOTA-lanreotide and 67Ga citrate scintigraphy for visualisation of extranodal marginal zone B-cell lymphoma of the MALT type: a comparative study. 1276 34

Immunomedics and Amgen are developing the unconjugated form of the anti-CD22 humanized monoclonal antibody, epratuzumab, for the potential treatment of lymphoma, non-Hodgkin's lymphoma (NHL) and certain autoimmune conditions. Immunogenics is also developing the radioisotope-linked (90Y) form of epratuzumab. The monoclonal antibody is currently undergoing phase III clinical trials for the potential treatment of aggressive lymphoma. By January 2003, epratuzumab had received Orphan Drug status in the US for its potential in the treatment of NHL.
Curr Opin Mol Ther 2003 Apr
PMID:Technology evaluation: epratuzumab, Immunomedics/Amgen. 1277 11


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