Management of metastatic breast cancer

Systemic treatment almost certainly prolongs the median survival of women with metastatic breast cancer, and it may prolong the survival of a small number of patients substantially. Even with conventional therapy, 10% or more patients may live into the second decade after recurrence. However, the disease cannot be eradicated, and the primary goal of treatment remains palliation and improvement of the quality of life. Because of the great variability in the pattern and course of the disease from one patient to another, therapy should be selected judiciously to maximize response and minimize toxicity. In some clinical situations, such as pathologic fractures and brain metastases, local therapies alone, such as surgery or irradiation, are the treatments of choice. Patients who will respond to endocrine therapy are well defined, and all patients with the characteristics of an endocrine responder deserve a chance at palliation with this modality alone because of its limited toxicity. A number of new forms of endocrine therapy with more specific targets at estrogen and progesterone receptor sites are now in clinical trials. When used appropriately, chemotherapy significantly improves patient quality of life despite its toxicity. No drug combinations, schedules, or doses have been shown to prolong survival or provide better net palliation than classic CMF (oral cyclophosphamide with intravenous methotrexate and 5-fluorouracil) or CAF (intravenous cyclophosphamide, doxorubicin, and 5-fluorouracil). Treatment with these combinations in excess of 6 to 9 months provides only marginal additional benefits and no survival advantage. The role of high dose chemotherapy with autologous bone marrow transplantation remains a promising area of investigation, but the available survival data are entirely compatible with the possibility that this modality will eventually prove inferior to conventional therapy. Many new cytotoxic agents with unique mechanisms of action are currently under investigation, including taxol, taxotere, Topotecan, and amonafide. Taxol may be the most promising therapy now available for patients whose disease has become refractory to doxorubicin. Biologic therapies using monoclonal antibodies against a specific oncogene or its product have entered clinical trials, and novel drug delivery systems using liposomes are under evaluation.

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Resumen El tratamiento sistémico casi ciertamente prolonga la supervivencia media de las mujeres con cáncer mamario metastásico y logra prolongar la sobrevida de un muy pequeño número de pacientes en forma muy sustancial. Aún con terapia convencional, 10% o más de las pacientes sobreviven hasta la segunda década después de una recurrencia. Sin embargo, la enfermedad no puede ser erradicada y el objetivo primario del tratamiento sigue siendo paliativo para mejorar la calidad de vida. Teniendo en cuenta la gran variabilidad del patrón y de la evolución de la enfermedad entre una y otra paciente, la terapia debe ser cuidadosamente seleccionada a fin de lograr la máxima respuesta y minimizar la toxicidad. En algunas situaciones clínicas, tales como las fracturas patológicas y las metástasis cerebrales, las solas modalidades de terapia local, tales como la cirugía o la irradiación, constituyen los tratamientos de elección. Las pacientes que puedan responder a la terapia endocrina están bien definidas, y todas las pacientes con las características de ser una de las que responda al manejo endocrino merece la oportunidad de paliación con esta modalidad, en virtud de su limitada toxicidad. Variadas y nuevas formas de terapia endocrina con miras más específicas en cuanto a receptores de estrógeno y de progesterona se encuentran en ensayo. Cuando la quimioterapia es utilizada en forma apropiada, ésta mejora significativamente la calidad de vida a pesar de su toxicidad. Ninguna combinación de drogas, programas o dosificaciones ha demonstrado prolongar la sobrevida o lograr mejor paliación que el régimen clásico CMF (ciclofosfamida oral con metotrexato IV y 5-fluorouracilo). El tratamiento con estas combinaciones por más de 6–9 meses provee apenas beneficios adicionales marginales y ninguna ventaja en cuanto a sobrevida. El papel de la quimioterapia de altas dosis con trasplante autólogo de médula ósea permanece como una promisoria área de investigación, pero la información sobre supervivencia hasta ahora disponible es enteramente compatible con la posibilidad de que esta modalidad llegue a demostrar ser inferior a la terapia convencional. Muchos nuevos agentes citotóxicos con mecanismos de acción únicos están siendo investigados en la actualidad. Estos incluyen el taxol, el taxotere, el Topotecan y el amonafide. El taxol puede ser la forma más promisoria de terapia actualmente disponible para pacientes cuya enfermedad se ha hecho resistente a la doxorubicina. Las terapias biológicas usando anticuerpos monoclonales contra un oncogene específico o su producto han ingresado a los ensayos clínicos y novedosos sistemas de administración de drogas, utilizando liposomas, también se hallan en proceso de investigación.

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Résumé Le traitement par voie systémique prolonge la survie médiane des patientes ayant un cancer métastatique du sein et peut également prolonger, sans doute, la survie d'un petit nombre d'autres patientes quel que soit le dégréé de sévérité de la maladie. Même avec une thérapeutique conventionnelle, 10% ou plus des patientes peuvent espérer survivre plus de 10 ans après leur récidive. La maladie ne peut, dans ce cas cependant, être enrayée et le but de la thérapeutique restera palliatif et d'améliorer la qualité de vie. En raison de la grande variabilité du type et de l'évolutivité de la maladie d'une patiente à l'autre, chaque protocole thérapeutique se doit d'être élaboré de façon à maximaliser la réponse tout en minimisant la toxicité. Dans certaines situations cliniques, telles les fractures pathologiques ou les métastases cérébrales, les thérapeutiques locales, telles la chirurgie ou l'irradiation, sont de modalités thérapeutiques de choix. On connaît aussi une catégorie de patientes qui répondent bien au traitement hormonal, qui devraient toutes être traitées par cette modalité étant donnée le peu de toxicité. Un certain nombre de ces traitements hormonaux sont actuellement l'objet d'essais thérapeutiques. Utilisée judicieusement la chimiothérapie améliore de façon significative la qualité de vie, et ce souvent, malgré sa toxicité. Aucune combinaison de médicaments ni de régimes ou de doses ne se sont montrés plus efficaces pour prolonger la survie ou améliorer le confort mieux que la classique association CMF (cyclophosphamide per os, methotrexate et 5-Fluorouracil par voie intraveineuse) ou la CAF (cyclophosphamide, doxorubicine, 5-fluorouracil par voie intraveineuse). Un traitement par ces combinaisons pendant plus de 6–9 mois n'apporte guère d'avantages, sans prolonger la survie pour autant. Le rôle de la chimiothérapie à hautes doses combinée avec la greffe de moelle osseuse était une voie prometteuse mais pour le moment, il semble exister de preuves en faveur de son infériorìté par rapport aux traitements conventionnels. D'autres nouvelles substances cytotoxiques, faisant intervenir d'uniques mécanismes d'actions, sont actuellement en cours d'évaluation. Ces nouveaux médicaments comprennent le taxol, le taxotère, le Topotécane, et l'amonafide. Le taxol est probablement celuì qui a le plus d'intérêt, semble-t'il, e cas de résistance à la doxorubicine. Des traitements biologiques, utilisant des anticorps spécifiques dirigés contre tel on tel oncogèn ou son produit, ainsi que de nouveaux systèmes d'apport des médicaments sont également au stade d'évaluation clinique.

     

Characterization of a YAC containing part or all of the Norrie disease locus

It has been shown from pulsed-field gel electrophoresis (PFGE)that the monoamine oxidase genes A and B (MAOA & MAOB) andDXS7 loci are physically very close. We have therefore extendedstudies on their relationship through the characterisation ofa 650 kb YAC isolated using L1.28 (recognising the DXS7 locus)as a probe. Restriction mapping of the YAC indicates that itcontains both MAOA and MAOB genes in addition to the DXS7 locus.The map derived from the YL1.28-YAC is compatible both withthe map from an independently derived YAC carrying MAOA andB genes and with the long range genomic map for the region.A series of subclones prepared from a 'phage library (lambdaDASH II) of the YAC have been characterised and have been employedto determine the end point of the deletion of a Norrie disease(NDP) patient who has been shown to lack both DXS7 and MAO codingsequences. The pattern of retention of subclones in the deletionpatient place the end point of the deletion within 30–130kb of the proximal end of the YAC. By combining the data withestablished recombination analysis, we provide evidence thatall or part of the NDP lies in the interval of approximately250kb within the YAC.     

Identifying potential indicators of the quality of end-of-life cancer care from administrative data.

PURPOSE: To explore potential indicators of the quality of end-of-life services for cancer patients that could be monitored using existing administrative data. METHODS: Quality indicators were identified and assessed by literature review for proposed indicators, focus groups with cancer patients and family members to assess candidate indicators and generate new ideas, and an expert panel ranking the meaningfulness and importance of each potential indicator using a modified Delphi approach. RESULTS: There were three major concepts of poor quality of end-of-life cancer care that could be examined using currently-available administrative data (such as Medicare claims): institution of new anticancer therapies or continuation of ongoing treatments very near death; a high number of emergency room visits, inpatient hospital admissions, or intensive care unit days near the end of life; and a high proportion of patients never enrolled in hospice, only admitted in the last few days of life, or dying in an acute-care setting. Concepts such as access to psychosocial and other multidisciplinary services and pain and symptom control are important and may eventually be feasible, but they cannot currently be applied in most data systems. Indicators based on limiting the use of treatments with low probability of benefit or indicators based on economic efficiency were not acceptable to patients, family members, or physicians. CONCLUSION: Several promising claims-based quality indicators were identified that, if found to be valid and reliable within data systems, could be useful in identifying health-care systems in need of improving end-of-life services.     

Septal-lateral annnular cinching perturbs basal left ventricular transmural strains.

OBJECTIVE: Septal-lateral annular cinching ('SLAC') corrects both acute and chronic ischemic mitral regurgitation in animal experiments, which has led to the development of therapeutic surgical and interventional strategies incorporating this concept (e.g., Edwards GeoForm ring, Myocor Coapsys, Ample Medical PS3). Changes in left ventricular (LV) transmural cardiac and fiber-sheet strains after SLAC, however, remain unknown. METHODS: Eight normal sheep hearts had two triads of transmural radiopaque bead columns inserted adjacent to (anterobasal) and remote from (midlateral equatorial) the mitral annulus. Under acute, open chest conditions, 4D bead coordinates were obtained using videofluoroscopy before and after SLAC. Transmural systolic strains were calculated from bead displacements relative to local circumferential, longitudinal, and radial cardiac axes. Transmural cardiac strains were transformed into fiber-sheet coordinates (X(f), X(s), X(n)) oriented along the fiber (f), sheet (s), and sheet-normal (n) axes using fiber (alpha) and sheet (beta) angle measurements. Results: SLAC markedly reduced (approximately 60%) septal-lateral annular diameter at both end-diastole (ED) (2.5+/-0.3 to 1.0+/-0.3 cm, p=0.001) and end-systole (ES) (2.4+/-0.4 to 1.0+/-0.3 cm, p=0.001). In the LV wall remote from the mitral annulus, transmural systolic strains did not change. In the anterobasal region adjacent to the mitral annulus, ED wall thickness increased (p=0.01) and systolic wall thickening was less in the epicardial (0.28+/-0.12 vs 0.20+/-0.06, p=0.05) and midwall (0.36+/-0.24 vs 0.19+/-0.11, p=0.04) LV layers. This impaired wall thickening was due to decreased systolic sheet thickening (0.20+/-0.8 to 0.12+/-0.07, p=0.01) and sheet shear (-0.15+/-0.07 to -0.11+/-0.04, p=0.02) in the epicardium and sheet extension (0.21+/-0.11 to 0.10+/-0.04, p=0.03) in the midwall. Transmural systolic and remodeling strains in the lateral midwall (remote from the annulus) were unaffected. CONCLUSIONS: Although SLAC is an alluring concept to correct ischemic mitral regurgitation, these data suggest that extreme SLAC adversely effects systolic wall thickening adjacent to the mitral annulus by inhibiting systolic sheet thickening, sheet shear, and sheet extension. Such alterations in LV strains could result in unanticipated deleterious remodeling and warrant further investigation.     

Physician assistants in academic radiology: the harborview experience

We describe a model of how physician assistants can be used in an academic medical center to expand radiologist productivity, and to enhance the departmental academic and educational missions. At Harborview Medical Center, following a training program and graduated responsibility under supervision, physician assistants provide initial interpretation of radiology studies, consultation to referring physicians, and perform less complicated interventional procedures. Acceptance of physician assistants by the radiologists, radiology residents, and referring physicians has been high. Although the impact of physician assistants on departmental clinical productivity is difficult to measure, our data suggest that radiologists are more efficient when physician assistants are assigned to service, both in terms of numbers of studies interpreted, and timeliness of reporting and billing. As a result of the success of our program, we believe that physician assistants can have an important role in radiology practice.     

Management of the metabolic syndrome-nicotinic acid.

Nicotinic acid effectively treats each of the common lipid abnormalities found in the metabolic syndrome, and much progress has recently been made in understanding its mechanisms of action.Early concern that nicotinic acid can precipitate or worsen diabetes has been eased with recent trials, which demonstrated its safety and effectiveness in insulin-resistant states. Furthermore, nicotinic acid prevents cardiovascular disease and death in persons with a high prevalence of risk factors for the metabolic syndrome. When used by an experienced physician and taken by a motivated patient, nicotinic acid can be safe and effective in treating the dyslipidemia of the metabolic syndrome.