Rituximab: mechanisms and applications.
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Antibodies, Monoclonal↗
Biomedical subjects
P W Johnson
Publications and source records attributed to P W Johnson.
BAG-1 immunostaining and survival in early breast cancer.
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Breast Neoplasms↗
A randomized trial of amifostine as a cytoprotective agent in patients receiving chemotherapy for small cell lung cancer.
A randomized trial was conducted to determine whether administration of Amifostine with chemotherapy for small cell lung cancer could decrease the toxicity. 84 patients with small cell lung cancer of favourable prognosis (limited disease, performance status 0-1; limited disease with performance status 2 but normal sodium and alkaline phosphatase, or extensive disease with performance status 0-1, normal sodium and alkaline phosphatase) received treatment with Ifosfamide 3 g/m(2)intravenously, Carboplatin (Glomerular filtration rate + 25) x6 mg intravenously, Etoposide 50 mg orally, twice daily, for 7 days, every 3 weeks. Patients were randomized to receive amifostine 740 mg/m(2)immediately prior to the intravenous drugs (n = 42) or to receive chemotherapy alone (n = 42). The two groups were similar with respect to baseline prognostic factors. There was no significant difference in the occurrence of grade III or IV neutropenia or thrombocytopenia between the two groups, nor in the response rate or overall survival, for which the median was 11 months in the chemotherapy only group and 14 months in the group treated with amifostine. This study has not shown a protective effect from the use of amifostine with this regimen and there does not appear to be any effect upon the efficacy of treatment.
Adult↗
Comparison of measurement accuracy between two types of wrist goniometer systems.
Studies have shown that wrist goniometers are prone to measurement errors, particularly due to crosstalk. This study compared two wrist goniometer systems: a commonly used biaxial, single transducer (System A) and a biaxial, two-transducer (System B). Wrist angles, range of movement and crosstalk results were compared. With the wrist in 90 degrees of pronation, eight subjects were placed in 20 different wrist postures between -40 degrees and 40 degrees of flexion/extension and between -10 degrees and 20 degrees of deviation. Relative to System B, System A had larger measurement errors and was more prone to crosstalk. There may be two sources of crosstalk: (1) intrinsic crosstalk associated with the design, application and twisting of the goniometer transducer when on the wrist, and (2) extrinsic crosstalk associated with the anatomy and complex movement of the wrist joint. It appears that the majority of the radial/ulnar crosstalk measured with System A was intrinsic crosstalk due to the twisting of the goniometer transducer.
Adult↗
The therapeutic use of antibodies for malignancy.
The idea of using the specificity of antibodies to target malignant cells was put forward very soon after the discovery of techniques to generate monoclonal reagents. The responses seen with mouse anti-idiotype in patients with B-cell lymphomas indicated the potential of this approach, but it was some years before key technical obstacles were overcome and the more widespread application of these therapies became possible. Whilst they were originally conceived as having an immunotherapeutic effect, it has become clear that recruitment of immune effectors is only one component of successful antibody therapy, and their action upon the cellular target, either blocking or agonistic, is also critical. The development of immunoconjugates to deliver toxins or radiation is a further extension of the approach, and here again the intracellular effect of antibody ligation appears to be crucial. This presentation will address the central theme of antibody treatments for malignancy that are now reaching the clinic, and will use these examples to highlight ways in which antibodies may be acting in vivo.
Abatacept↗
Development and application of a quantitative, specific assay for Cryptosporidium parvum oocyst detection in high-turbidity environmental water samples.
Chlorine-resistant Cryptosporidium parvum oocysts in drinking water play an important role in the epidemiology of cryptosporidiosis. Current methods of detecting these organisms in water are insensitive, labor-intensive, highly subjective, and severely limited by sample turbidity. We describe here an alternative technique utilizing electrochemiluminescence (ECL) technology for detecting C. parvum oocysts in environmental water samples. This method is quantitative, reproducible, and requires only minimal sample processing. Currently, the ECL assay can detect as few as one oocyst in one milliliter of concentrated test sample with sample turbidity of up to 10,000 nephelometric turbidity units. Water and sewer samples collected during a cryptosporidiosis outbreak were tested by ECL assay. Cryptosporidium parvum oocysts were found in the source water at the time of outbreak, and a sharply decreasing level of oocysts in sewer samples was observed over a three-month period following the outbreak.
Animals↗
Identification of a novel human BCL-X promoter and exon.
BCL-XL is a key anti-apoptotic BCL-2 family protein that is widely expressed in human cancer cells and is induced in response to diverse survival signals. The translation initiation codon for BCL-XL is located in BCL-X exon II and previous analyses have indicated that BCL-XL RNAs initiate close to the start of exon II or additionally contain a non-coding first exon (exon IA) spliced to exon II. Using 5' RACE we have now identified a novel BCL-X non-coding exon (exon IB) which is spliced directly to exon II in place of exon IA. Exon IB-containing RNAs encoded BCL-XL and were detected in non-malignant lymphocytes and lymphoma cells from lymph node biopsies and were expressed at significant levels in cell lines derived from ovarian, colon and breast cancers. We identified two TATA-box sequences upstream of exon IB and demonstrated that surrounding genomic sequences contained strong promoter activity in lymphoma cells (approximately 300-fold active relative to controls). We have therefore identified a powerful new BCL-X promoter and a novel exon that contributes to BCL-XL expression.
Base Sequence↗
Positive and negative selection to reduce tumour contamination in peripheral blood stem cell harvests.
Peripheral blood progenitor cells used during high dose treatments for malignancy may be contaminated with tumour cells that could later contribute to recurrence. CD34+ selected harvests still contain tumour cells and an additional negative selection may be capable of reducing this contamination. We have assessed a two-stage technique in which a CD34+ selection is followed by a tumour specific depletion stage using a B cell or breast cancer specific antibody panel. Initial small-scale selections on 11 patients with NHL and breast cancer showed that cell loss was greatest following the CD34+ selection with a median yield of 38.8 per cent (range 17. 2-56.4 per cent). The addition of the depletion stage resulted in a minimal loss of CD34+ cells with a yield for this step of 94.2 per cent (range 77.5-99.3 per cent). Clinical scale selections were performed on seven patients with CLL and a median of 2.8x10(6)/kg CD34+ cells (range 1.5-6.1x10(6)/kg) were collected. Cell recovery was 53.3 per cent following CD34+ selection and 76.9 per cent following the tumour specific depletion stage, resulting in a final product containing a median of 1.0x10(6)/kg CD34+ cells (range 0. 55-2.0x10(6)/kg). All unmanipulated harvests were heavily contaminated with tumour cells (median contamination 10.2 per cent, range 2.0-83.1 per cent) as measured by flow cytometry and a median 4.7 log (range 3-5 log) tumour cell purge was produced following two-stage selection. Six of the patients have received cells manipulated in this way with median engraftment times of neutrophils>0.5x10(9)/l=16 days (range 13-20 days) and platelets>20x10(9)/l=16.5 days (range 11-42 days). At a median follow-up of 25 months, these transplanted patients remain well and in molecular complete remission.
Adult↗
Postural analysis of paramedics simulating frequently performed strenuous work tasks.
Paramedics who perform emergency rescue functions are highly susceptible to musculoskeletal injuries. Through an interview and survey process firefighters, many of whom are cross-trained paramedics in a consortium of 14 suburban fire departments, identified and rated tasks that were perceived to be both strenuous and frequently performed. The objective of the current study was to describe the working postures and the forces applied as firefighter/paramedics (FF/Ps) simulated specific roles within the following tasks identified by the survey: (1) transferring a patient from a bed to a stretcher using bedsheets, (2) transferring a patient from the ambulance stretcher to a hospital gurney, (3) carrying a victim down a set of stairs and around a landing using a stairchair, (4) carrying a victim down a set of stairs and around a landing using a backboard, and (5) carrying a victim down a set of stairs using a stretcher. Ten two-person teams of FF/Ps participated and were videotaped to obtain postural data for the upper and lower extremities as they performed each role in the simulated two-person tasks. Trunk postures were obtained using lumbar motion monitors. Static hand forces were estimated using a hand-held dynamometer at the most physically demanding points for each role within each task. The postural and force data were averaged across subjects performing identical roles to quantify the postures assumed by the FF/Ps at the most strenuous moments during task performance. Based on these analyses we concluded that: (1) when transferring victims from a bed to a stretcher the FF/P on the bed was able to maintain an upright and more stable posture by standing as opposed to kneeling, (2) an interface board should be used to reduce the frictional forces when transferring victims from a bed to a stretcher or from a stretcher to a gurney, thereby reducing the need to lift the victim with flexed torsos and/or shoulders, and (3) equipment and training that encourages the FF/P in the leader role to walk facing forward during victim transport, especially when descending stairs, potentially results in safer transit.
Allied Health Personnel↗
Biomechanical analyses of paramedics simulating frequently performed strenuous work tasks.
Firefighters performing emergency rescue functions are at an elevated risk of musculoskeletal injuries. The objective of the current study was to analyze the biomechanical stresses placed on the body based on simulations of the following strenuous and frequently performed emergency rescue tasks: (1) transferring a patient from a bed to a stretcher using bedsheets, (2) transferring a patient from the ambulance stretcher to a hospital gurney, (3) carrying a victim down a set of stairs and through a landing using a stairchair, (4) carrying a victim down a set of stairs and through a landing using a backboard, and (5) carrying a victim down a straight set of stairs using a stretcher. Postural data were analyzed using the University of Michigan's Three-Dimensional Static Strength Prediction Program and the relative risk of low back disorder (LBD) was quantified using the trunk motion model published by Marras et al. (1993, spine 18, 617-628). Peak compression values and the probabilities from the Marras et al. (1993) model indicated that the most hazardous tasks performed as part of this simulation included pulling a victim from a bed to a stretcher, the initial descent of a set of stairs when using the stretcher, and lifting a victim on a backboard from the floor. Overall, the two models were well correlated in their assessment of the task components modelled (r = 0.78). These data indicate where engineering changes to equipment regularly used by emergency rescue personnel would have the greatest impact in reducing the risk of musculoskeletal injury.
Allied Health Personnel↗
Clinical trials of antibody therapy.
Much of the 25 years since Kohler and Milstein first described making monoclonal antibodies (mAbs) has been spent trying to develop these reagents to treat human disease. Until recently, progress has been frustratingly slow and by 1994 only one mAb, anti-CD3 (OKT3), had been licensed for clinical use. In the past five years, however, the situation has changed dramatically, with numerous mAbs now showing clinical potential, and a further seven approved for human treatment. Furthermore, all indications are that this upward trend will continue, with a quarter of all new biological products currently undergoing clinical development being antibody based.
Animals↗
A phase II study to evaluate the combination of fludarabine, mitoxantrone and dexamethasone (FMD) in patients with follicular lymphoma.
BACKGROUND: 'Molecular response' is being investigated as a therapeutic goal in follicular lymphoma (FL). High response rates in FL with the fludarabine combination 'FMD' have been associated with 'molecular remission'. A phase II study of FMD in FL was therefore conducted. PATIENTS AND METHODS: Fifty-four patients, ten of whom were newly diagnosed received FMD. Forty-four percent of the previously treated patients had 'chemoresistant' disease. Treatment comprised: fludarabine 25 mg/m2 days 1-3, mitoxantrone 10 mg/m2 day 1, and dexamethasone 20 mg days 1-5. Blood/bone marrow was collected for quantitation of t(14;18) by 'real-time' PCR. RESULTS: The overall response rate was 37 of 54 (69%), complete responses being seen in 11 patients (20%), with no difference between newly diagnosed and the previously treated patients. However, the response rate in 'chemosensitive' relapse was 84% compared to 44% in patients in whom the last prior regimen had failed. Molecular responses were seen in 17 of 25 and PCR negativity in 8 of 25, although molecular and clinical responses did not always correlate. Toxicity was moderate, 19 patients required admission. However, in 6 of 12 patients, subsequent G-CSF mobilised stem cell harvests failed. CONCLUSIONS: FMD was well tolerated but with a lower than expected response rate. Molecular responses were seen in the majority of responding patients however, 'molecular remission' was rare.
Adult↗
The emerging role of radioimmunotherapy in haematological malignancies.
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Animals↗
A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response.
Follicular lymphoma (FL) cells express CD20 and are associated in most cases with the t(14;18) chromosomal translocation. A multicentre study was undertaken between January 1997 and January 1998 to assess the complete response rate (CR) and overall response rate (RR) to rituximab, a chimaeric anti-CD20 monoclonal antibody. Seventy patients with previously treated FL received rituximab (375 mg/m2/week x4, by intravenous infusion). Restaging studies were performed 1 and 2 months after therapy. Molecular monitoring for the presence of cells harbouring the Bcl-2/JH gene rearrangement in the peripheral blood (PB) and bone marrow (BM) was performed before and after treatment using a two-step semi-nested polymerase chain reaction (PCR) assay. The overall RR was 32/70 (46%), being highest in patients who had received only one previous treatment (12/15, 80%). However, only two patients achieved a CR. The median duration of response was 11 months. Thirteen of 21 evaluable 'PCR-positive' patients (62%) became 'PCR-negative' in PB and/or BM samples 1 month after rituximab, although this did not correlate with clinical response. Treatment was generally well tolerated, although one patient developed Stevens-Johnson syndrome. Rituximab was shown to be active in FL, and in some cases PB and/or BM became PCR negative. Studies in combination with cytotoxic chemotherapy to increase the CR rate are warranted.
Adult↗
Autologous stem cell transplantation for malignancy: a systematic review of the literature.
A systematic review of the literature was undertaken to assess what published evidence is currently available to support the increasing use of autologous stem cell transplantation (ASCT), and to evaluate the published data with regard to the comparative cost of high-dose and conventional therapy. The review aimed to identify all published, randomized controlled trials (RCTs) comparing high-dose therapy (HDT) with ASCT versus conventional chemotherapy (CC) in acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, and breast, lung, testicular and ovarian cancer. The review also aimed to identify all studies that had compared the cost of the two treatment strategies. Reports were identified by systematic searches of Cancerlit, Embase and Medline, and handsearching of several conference proceedings. Where possible, pooled odds ratios (ORs) were calculated according to the fixed-effect model. A total of 18 randomized trials were identified in acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, and breast, lung and testicular cancer. Trials were generally small and no disease site had sufficient information to determine reliably whether high-dose therapy with autologous transplant is more effective than CC. Five studies were identified that compared the cost of the two treatments. These found the cost of HDT to be between one and four times higher than that of CC. Further randomized trials are required. Where appropriate, these should include economic assessment and assessments of long-term toxicity.
Antineoplastic Agents↗
European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma.
PURPOSE: Mantle-cell lymphoma (MCL), immunocytoma (IMC), and small B-cell lymphocytic lymphoma (SLL) are B-cell malignancies that express CD20 and are incurable with standard therapy. A multicenter phase II study was conducted to assess the toxicity and the overall response rates (RR) and complete response (CR) rates to rituximab (chimeric anti-CD20 monoclonal antibody). PATIENTS AND METHODS: Between January 1997 and January 1998, 131 patients with newly diagnosed MCL (MCL1; n = 34) and previously treated MCL (MCL2; n = 40), IMC (n = 28), and SLL (n = 29) received rituximab 375 mg/m(2)/wk for 4 weeks via intravenous infusion. Restaging studies were performed 1 and 2 months after treatment. An analysis of the duration of response was conducted in December 1998. RESULTS: Eleven patients were unassessable, including one who died of splenic rupture after the first infusion. The RR among the 120 assessable patients was 30% (36 of 120 patients). The RR by histology was as follows: MCL1, 38%; MCL2, 37%; IMC, 28%; and SLL, 14%. Ten patients, all with MCL, achieved CR. The median duration of response in MCL was 1.2 years. Immediate side effects were common and usually responded to adjustments in the infusion rate. There were 31 episodes of infection after treatment; most cases were mild. Cardiac arrhythmia and ophthalmologic side effects occurred in 10 and nine patients, respectively, including one case of severe loss of visual acuity. CONCLUSION: Single-agent rituximab has moderate activity in MCL and IMC but only limited activity in SLL. The duration of response in MCL was similar to that previously reported in follicular lymphoma. Its use in combination with cytotoxic chemotherapy to increase the CR rate is warranted in MCL and IMC.
Adult↗
High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up.
PURPOSE: To evaluate the long-term results of high-dose therapy (HDT) in follicular lymphoma, with specific emphasis on the prognostic significance of polymerase chain reaction (PCR)-detectable Bcl-2/IgH rearrangements. PATIENTS AND METHODS: Between June 1985 and October 1995, 99 patients with follicular lymphoma received HDT as consolidation of second or subsequent remission. Bone marrow was treated in vitro with anti-B-cell antibodies and complement. RESULTS: Sixty-five patients remained alive, 49 treatment-failure free, with a median follow-up of 5.5 years (range, 1.5 to 12.5 years). Four "early" and 10 "late" deaths occurred from treatment-related causes; seven of the latter were due to secondary myelodysplasia (s-MDS) or secondary acute myeloblastic leukemia. Overall, 12 (12%) of the 99 patients developed s-MDS or acute myeloblastic leukemia. Kaplan-Meier estimates of freedom from recurrence (FFR) and survival rates at 5 years were 63% (95% confidence interval [CI], 52% to 72%) and 69% (95% CI, 58% to 78%), respectively. For all 99 patients, in multivariate analysis, absence of the Bcl-2/IgH rearrangement at the time of diagnosis (hazards ratio [HR], 0.39; P =.04) and three or fewer treatment episodes before HDT (HR, 0.03; P =.001) were significant prognostic factors for improved survival. For patients bearing Bcl-2/IgH rearrangements, in univariate and multivariate analyses, absence of a PCR-detectable Bcl-2/IgH rearrangement during follow-up was associated with a significantly lower risk of recurrence (adjusted HR, 0.13; P <.001) and death (HR, 0.25; P =.02), whereas the PCR status of the reinfused bone marrow did not correlate with outcome. CONCLUSION: Prolonged FFR can be achieved in patients with follicular lymphoma after HDT, but as yet there is no survival advantage compared with conventional treatment. These results confirm that elimination of cells bearing the Bcl-2/IgH rearrangement is highly desirable and should be attempted. The incidence of s-MDS is of increasing concern in this setting.
Adult↗
FLUDAP: salvage chemotherapy for relapsed/refractory aggressive non-Hodgkin's lymphoma.
The aim of this study was to investigate the combination of fludarabine phosphate, dexamethasone, cytosine arabinoside and cis-platinum (FLUDAP) in the treatment of patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). This regimen comprises: dexamethasone 100 mg/d continuous infusion (cont. inf.) d1-3; cytosine arabinoside (ara-C) 1 g/m2/d cont. inf. d 2,3; fludarabine phosphate 30 mg/m2 short inf. 4hr prior to each 24hr ara-C inf.; cis-platinum 50 mg/m2 4hr inf. at the start of each 24hr ara-C inf. G-CSF (lenograstim, Granocyte) is given at 263 microg s.c. daily from day 7 until the neutrophil count reaches 1.0x10(9)/l. The regimen repeats at 21 day intervals. A total of 33 patients were registered (median age 47 years; 24 males, 9 females); the majority (73%) were refractory to their previous treatment and most had advanced disease by Ann Arbor stage. Thirteen (39%) of the 33 enrolled patients (52% of the 25 fully evaluable patients who received at least 2 courses of FLUDAP) responded to treatment. A maximum response of complete remission was achieved in 5 patients, good partial remission in 3, and partial remission in 5. Twelve patients went on to successful stem cell supported intensification therapy. Median survival times were higher in the responding patients, and in those patients transplanted post-FLUDAP. The toxicity associated with the FLUDAP regimen was generally predictable; frequently reported severe events included haematological toxicity and infection. In conclusion, the FLUDAP regimen shows promise as a salvage regimen and increases the available therapeutic options in the treatment of recurrent/refractory aggressive NHL.
Adult↗