The absence of CD20 messenger RNA in recurrent cutaneous B-cell lymphoma following rituximab therapy

BACKGROUND: Rituximab has been used to treat relapsed low-grade or advanced non-Hodgkin's lymphoma since 1997, targeting the CD20 antigen expressed by B cells. Single-agent rituximab therapy is safe and well tolerated. Recurrences showing a loss of CD20 expression following rituximab therapy have been reported. METHODS: Four patients with CD20-positive cutaneous B-cell lymphoma received rituximab therapy with subsequent recurrences. The biopsies were assessed for cytoplasmic CD20 expression; CD20 messenger RNA was also assessed where tissue was available. RESULTS: Cutaneous relapses occurring within 1.5-3 months following the last dose of rituximab were CD20 negative. In three cases, subsequent relapses showed renewed expression of CD20. Those biopsies demonstrating a loss of surface and cytoplasmic CD20 by immunohistochemistry also showed no evidence of messenger RNA for CD20 using an in situ polymerase chain reaction-based methodology. CONCLUSIONS: Rituximab may be associated with the emergence of CD20-negative B-cell clones, potentially rendering a tumor insensitive to this drug. Conversely, following cessation of the drug, a re-expression of CD20 within the neoplastic cells may occur allowing therapeutic intervention with this monoclonal antibody. The loss of CD20 expression appears to be a direct effect of the drug on CD20 messenger RNA synthesis.     

Association of Tamoxifen (TAM) and TAM Metabolite Concentrations with Self-Reported Side Effects of TAM in Women with Breast Cancer

The positive effects of tamoxifen (TAM) on breast cancer recurrence and survival as well as on overall mortality have led to its use as the predominant adjuvant therapy among women with breast cancer. However, the association of TAM intake with undesirable side effects has been reported in numerous studies. This analysis was carried out to assess whether the concentrations of TAM or TAM metabolites, N -desmethyltamoxifen ( N -DMT) and 4-hydroxytamoxifen (4-OHT), were associated with self-reported side effects of TAM. Participants were 99 breast cancer patients who had been taking TAM for at least 30 days. Each participant completed a questionnaire that was used to ascertain whether she experienced certain specific symptoms while taking TAM. In addition, each woman provided a blood sample that was used to measure plasma concentrations of TAM, N -DMT, and 4-OHT by high performance liquid chromatography. Results of the analysis showed that women who experienced at least one TAM-related side effect had significantly higher levels of TAM than women not experiencing any TAM-related side effects. Furthermore, women who reported experiencing visual problems had significantly higher levels of both TAM and N -DMT compared to those women who reported experiencing no visual problems. The levels of 4-OHT were negatively associated with the occurrence of vaginal discharge. The results of this study suggest that the self-reported occurrence of certain symptoms during TAM treatment is related to TAM metabolism. Future studies should assess subgroups of women with specific TAM and TAM metabolite profiles to determine whether alternate, equally effective therapies would decrease their risk of experiencing certain undesirable side effects.     

Evaluation of pelvic and breast examination skills of interns in obstetrics and gynecology and internal medicine

OBJECTIVE: The purpose of this study was to evaluate the pelvic and breast examination skills of a group of interns who were entering obstetrics and gynecology and internal medicine and to determine whether previous experience predicts performance. STUDY DESIGN: This was a prospective study that, with the use of an examination with a standardized format of 26 skills, assessed the performance of 10 interns who were entering internal medicine and 9 interns who were entering obstetrics and gynecology. chi(2) analysis and Fisher exact tests were used. RESULTS: There was no significant difference in overall performance on the pelvic and breast examinations between the two groups. The obstetrics and gynecology interns performed significantly better (P<.05) on the three skills that assessed professional conduct. There was considerable variability within each group. There was no correlation between previous clinical experience and performance on the skills assessment, nor was there a correlation between perceived competence and actual performance. CONCLUSIONS: Previous clinical experience does not predict performance in a standardized assessment of pelvic and breast examination skills nor does it account for the great variability in competence levels in interns who are entering obstetrics and gynecology and internal medicine.     

Simultaneous acceleration of the cell cycle and suppression of apoptosis by splice variant delta-6 of the candidate tumour suppressor LUCA-15/RBM5

BACKGROUND: The short arm of chromosome 3 is thought to include one or more tumour suppressor genes (TSGs), since carcinoma of various tissues display deletions in this region. Many genes mapping to this region have recently been identified, including the LUCA-15/RBM5 gene. RESULTS: In this study we report the cloning from human bone marrow library of a splice variant of LUCA-15 which lacks exon 6, resulting in a frameshift and producing a truncated protein of 150 amino acids instead of 815 amino acids. This variant is widely expressed at a low level in normal tissues and is expressed at increased levels in T-leukaemic cell lines. Over-expression of this splice variant after electroporation both shortened the cell cycle and inhibited CD95-mediated apoptosis in CEM-C7 T-cells. In marked contrast, over-expression of the full length LUCA-15/RBM5 suppressed cell proliferation both by inducing apoptosis and by extending the G1 phase of the cell cycle. CONCLUSION: These results, taken together with previous observations from ourselves and others, suggest that LUCA-15 is involved in the control of both apoptosis and the cell cycle. Since oncogenesis often relies on separate changes in molecules regulating apoptosis on the one hand, and proliferation, on the other, the discovery of a candidate tumour suppressor gene which affects both processes simultaneously is likely to be of major significance.     

The treatment of immune glomerular disease

Conclusions Although the outcome of severe forms of glomerulonephritis has improved over recent years, there has to be a realistic sense of disappointment related to the lack of immunologically specific treatment available, reflected in the overall similarity of the management of these patients. The sense of disappointment is heightened by the lack of properly conducted trials containing an adequate number of subjects to answer the relatively simple questions posed in everyday nephrological practice. With the advent of the more specific immunological therapies outlined above and the development in some diseases of particular immunopathogenetic markers, there are reasons for an optimistic view of the future; this must be tempered by the hope that new forms of therapy will be properly assessed.     

Service Increment for Teaching (SIFT): a review of its origins, development and current role in supporting undergraduate medical education in England and Wales

OBJECTIVES: To describe the ways in which total resources available for the Service Increment for Teaching (SIFT) have been determined and related to numbers of undergraduate medical students; and the development and current arrangements for allocating SIFT to the providers of service support for teaching. DESIGN: The derivation of SIFT from excess costs of teaching hospitals over general hospitals is described. The official principles of organizing SIFT to reimburse the service costs of teaching undergraduate medical students are explained. The crucial development that is examined is the change from SIFT being a global subsidy to being related to educational contracts. This development has facilitated both the specification of standards and innovative uses of SIFT. These are illustrated with examples. SETTING: Hospital and Community Health Services and Primary Care in the National Health Service (NHS) in England and Wales. SUBJECTS: Medical students. RESULTS: There is often confusion caused by SIFT being intended to cover the service costs of teaching but not having been derived in this way. This causes problems in deciding what providers should be paid through contracts for teaching of different kinds. CONCLUSIONS: The new contractual basis has enabled medical schools to use contracts to improve the clinical teaching of undergraduate medical students in the NHS. These developments may offer useful models for other countries.