RESUMEN
INTRODUCTION: Breast conserving surgery (BCS) aims to remove a breast cancer completely and obtain clear margins. Complete excision is essential to reduce the risk of local recurrence. The ClearEdge™ (CE) imaging device examines margins of excised breast tissue intra-operatively. The aim of this study was to investigate the potential of the device in detecting margin involvement in patients having BCS. METHODS: In Phase-1 58 patients underwent BCS and had 334 margins assessed by the device. In Phase-2 the device was used in 63 patients having BCS and 335 margins were assessed. Patients with margins considered close or involved by the CE device were re-excised. RESULTS: The margin assessment accuracies in Phase-1 and Phase-2 compared to permanent section pathology were very similar: sensitivity (84.3% and 87.3%), specificity (81.9% and 75.6%), positive predictive value (67.2% and 63.6%), and negative predictive value (92.2% and 92.4%). The false positive rate (18.1% and 24.4%) and false negative rate (15.7% and 12.7%) were low in both phases. In Phase-2 re-excision rate was 37%, but in the 54 where the CE device was used appropriately the re-excision rate was 17%. Had all surgeons interpreted all images appropriately and re-excised margins detected as abnormal by the device in Phase-2 then the re-excision rate would have been 7%. CONCLUSION: This study shows that the CE device has potential to reduce re-excision after BCS and further randomized studies of its value are warranted.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Carcinoma Ductal de Mama/diagnóstico por imagen , Carcinoma Intraductal no Infiltrante/diagnóstico por imagen , Carcinoma Lobular/diagnóstico por imagen , Espectroscopía Dieléctrica/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/complicaciones , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/complicaciones , Carcinoma Intraductal no Infiltrante/cirugía , Carcinoma Lobular/cirugía , Espectroscopía Dieléctrica/instrumentación , Femenino , Humanos , Periodo Intraoperatorio , Masculino , Márgenes de Escisión , Mastectomía Segmentaria , Persona de Mediana Edad , Neoplasia Residual , Valor Predictivo de las PruebasRESUMEN
The phosphatidylinositol-3-kinase pathway plays an important role in proliferation, migration and survival in breast cancer and may play a role in resistance to endocrine therapy. Pathway activation occurs as a result of mutations in PIK3CA or loss of functional PTEN. Matched primary and recurrent samples from 120 breast cancer patients treated with endocrine therapy were profiled with a qPCR-based mutation assay covering eight mutational hotspots in PIK3CA. PTEN was assayed by immunohistochemistry. Samples were well characterized with respect to anatomic location of recurrence (metastatic nodal or local recurrence as opposed to contralateral or ipsilateral new primary cancers). In total, 43 % of patients had at least one PIK3CA mutation at diagnosis, and 41 % had a mutation at the time of recurrence. Only 8 % of patients with local recurrence, metastatic disease or progression on primary endocrine treatment changed their PIK3CA mutation status (four gains, two losses, total 76). The most common changes in PIK3CA mutation status were seen in patients who developed a new cancer either in the treated or contralateral breast (64 %, three gains, four losses, total 11). PIK3CA mutation status does not change in the majority of patients with breast cancer and the acquisition of mutations in PIK3CA is not responsible for the development of endocrine resistance. PTEN loss at diagnosis is associated with a significantly shorter time to progression compared with tumours in which PTEN was retained. These are the most comprehensive data currently available correlating PIK3CA status, site of recurrence and endocrine resistance.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Neoplasias Hormono-Dependientes/genética , Fosfatidilinositol 3-Quinasas/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/mortalidad , Carcinoma Intraductal no Infiltrante/secundario , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/mortalidad , Carcinoma Lobular/secundario , Fosfatidilinositol 3-Quinasa Clase I , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/mortalidad , Neoplasias Hormono-Dependientes/secundario , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/secundario , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasa/genética , Pronóstico , Tasa de SupervivenciaRESUMEN
Elevated serum levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) are found in patients with phosphate wasting diseases and chronic kidney disease-mineral and bone disorder (CKD-MBD). These diseases are associated with rickets and renal osteodystrophy, respectively. FGF23 is secreted from osteoblastic cells and signals through FGFRs, membrane coreceptor alpha-Klotho (Klotho), and, possibly, a circulating form of Klotho. Despite the absence of detectable Klotho on osteoblastic cells, studies have suggested that forced FGF23 expression in osteoblasts inhibited mineralization. Thus, we examined the effects of exogenously applied FGF23 on osteoblastic MC3T3.E1 cell proliferation and differentiation, with and without soluble Klotho. MC3T3.E1 cells were cultured in osteoblast differentiation medium, supplemented with FGF23 (0.1-1,000 ng/mL), Klotho (50 ng/mL), the combination FGF23 + Klotho, and FGF2 (100 ng/mL) as a control. Neither FGF23 nor Klotho exposure affected proliferation of day 4 growth phase cells or mineralization of day 14 cultures. In contrast, FGF23 + Klotho resulted in inhibition of mineralization and osteoblast activity markers at day 14, and a slight, reproducible induction of proliferation. Inhibition of FGFR1, but not FGFR2 or FGFR3, completely restored FGF23 + Klotho-induced inhibition of alkaline phosphatase (ALP) activity at day 7. ALP activity was partially restored by the MAPK inhibitor U0126 but not inhibitors p38 and P13K. Thus, soluble Klotho enables FGF23 signaling in MC3T3.E1 cells, likely through FGFR 1(IIIc). Elevated FGF23 actions, in part, appear to parallel FGF2 with lower potency. In addition to affecting bone via indirect phosphate wasting pathways, supraphysiological FGF23 and soluble Klotho may directly impact bone in diseases with elevated FGF23 levels.
Asunto(s)
Calcificación Fisiológica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/farmacología , Glucuronidasa/farmacología , Osteoblastos/efectos de los fármacos , Animales , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Proteínas Klotho , Ratones , Osteoblastos/metabolismo , Osteoblastos/fisiología , Receptores de Factores de Crecimiento de Fibroblastos/genética , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Estudios de Validación como AsuntoRESUMEN
mTOR plays a key role in tumor cell cycle control, proliferation, and survival. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and thus downstream signaling pathways. 31 post-menopausal women with early breast cancer were given 5 mg RAD001 once daily for 14 days prior to surgery. Biopsies were taken at diagnosis and at surgery (post 14 days of treatment) and assessed for immunohistochemical changes in proliferation (Ki67), apoptosis (active caspase-3), p-AKT (s473), p-S6 (s235/236 and s240/244), p-mTOR (s2448), ER, and PR. Five patients did not complete the 2-week treatment period due to adverse events. All adverse events were grade 1 or 2 (NCIC-CTC scale). RAD001 treatment significantly decreased proliferation (geometric mean reduction 74% from baseline (p = 0.019)), particularly in HER-2 positive tumors. High Ki67 pre-treatment correlated with reduction in Ki67, an increase in apoptosis, a reduction in p-AKT (cytoplasmic) and reduction in p-mTOR following treatment. Nuclear expression of p-AKT was significantly reduced with treatment. Tumors that had a reduction in Ki67 with treatment exhibited a significant reduction in cytoplasmic p-AKT. p-S6 staining was significantly reduced independently of Ki67 (p < 0.001 for two sites of phosphorylation). RAD001 5 mg/daily is safe and tolerable in postmenopausal early breast cancer patients and inhibits the mTOR pathway and its downstream effectors, significantly reducing tumor cell proliferation. Tumors with high Ki67, high p-AKT, and HER-2 positivity may be more responsive to mTOR inhibition with RAD001. This is the first study to report results of RAD001 5 mg as a single agent in early breast cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Everolimus , Femenino , Humanos , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Sirolimus/efectos adversos , Sirolimus/uso terapéuticoRESUMEN
INTRODUCTION: Changes in proliferation as measured by Ki67 occur within 14 days of starting treatment with an aromatase inhibitor and these changes have been shown to be predictors of long term outcome. This study aimed to compare changes in proliferation following 14 days of treatment with anastrozole and letrozole. METHODS: Two hundred and six women with 209 estrogen receptor (ER) positive operable breast cancers (three bilateral) were randomly allocated to receive either 14 days treatment with 2.5 mg of letrozole or 1 mg of anastrozole prior to surgery. Changes in expression of estrogen (ER) and progesterone receptors (PgR) as assessed by ALLRED scores and proliferation as assessed by Ki67 were analysed. The HER2 status of each tumour was also assessed using a combination of the Hercept test and FISH. RESULTS: Both letrozole and anastrozole reduced ER expression (ALLRED score) by a mean of 0.32 (0.20-0.44), P<0.001 and PgR fell by a mean of 2.54 (2.20-2.89) P<0.0001. Letrozole reduced proliferation from a geometric mean of 6.37% to 0.81%, P<0.0001 and anastrozole reduced proliferation from 5.81% to 0.77%, P<0.0001. There was no differences between drugs in the fall in ER, PgR or proliferation. Both letrozole and anastrozole produced significant falls in proliferation in both HER2 positive and HER2 negative cancers, all P<0.001. DISCUSSION: 14 days of both letrozole and anastrozole reduces proliferation, ER and PgR expression. No significant difference between these two drugs was identified.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/biosíntesis , Nitrilos/uso terapéutico , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anastrozol , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Antígeno Ki-67/biosíntesis , Letrozol , Persona de Mediana Edad , Posmenopausia , Receptores de Progesterona/biosíntesis , Resultado del TratamientoRESUMEN
Early clinical trials of anticancer agents may be enriched by robust biomarkers of activity. Surrogate measures used in trials of cytotoxic agents, such as tumor size regression, may not be informative when investigating targeted agents that act principally to inhibit invasion or proliferation. This study aimed to determine the validity of invasion-related biomarkers of activity for AZD0530, a potent Src inhibitor currently in clinical development. Focal adhesion kinase (FAK) and paxillin are downstream phosphorylation substrates of Src and mediate tumor cell adhesion and invasiveness. These were therefore selected as biologically relevant markers of Src inhibition. Early breast cancer was chosen as a model as multiple samples can be collected during standard treatment and there is an intervening period in which experimental intervention can be applied. Tumor tissue was collected from diagnostic core biopsies and subsequent surgical tumor excision samples in 29 women with early breast cancer attending a single center. Protein levels were assessed quantitatively by Luminex and qualitatively by immunohistochemistry. AZD0530 inhibited tumor growth in a manner independent of dose and inhibited phosphorylation of FAK and paxillin in a dose-dependent manner in a Calu-6 xenograft model. In the clinical study, agreement of within-visit and also of between-visit measurements was high and the estimated number of patients required to detect a drug effect would be low enough to allow use of these markers as endpoints in future dose selection studies.
Asunto(s)
Benzodioxoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 1 de Adhesión Focal/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Paxillin/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteína Tirosina Quinasa CSK , Estudios de Factibilidad , Femenino , Humanos , Técnicas para Inmunoenzimas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Fosforilación/efectos de los fármacos , Ratas , Ratas Desnudas , Células Tumorales Cultivadas , Familia-src QuinasasRESUMEN
Fulvestrant (Faslodex) is a pure anti-oestrogen that reduces markers of hormone sensitivity and proliferation in postmenopausal women with oestrogen-receptor (ER)-positive breast cancer. This randomised trial compared the effects on the tumours of a single dose of 750mg fulvestrant to those of daily tamoxifen (20mg) taken 14-16 days prior to surgery in 60 premenopausal women with ER-positive primary breast cancer. There were statistically significant falls in the expression of ER and Ki67 levels compared to the baseline with both drugs. Both drugs caused a decrease in PgR expression from baseline but this was only statistically significant with fulvestrant. No statistically significant differences were seen between the two treatment groups. Fulvestrant caused an increase in circulating levels of oestradiol, irrespective of the stage of the menstrual cycle at which patients commenced treatment. No major changes were seen in LH, FSH and progesterone levels with either drug. The most common adverse events with fulvestrant were headaches, hot flushes, nausea and disturbance of menses. Contrary to previous studies with fulvestrant 250mg, these findings suggest that at a dose of 750mg fulvestrant is effective at reducing the effects of oestrogen on ER-positive breast cancer in premenopausal women.
Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Estradiol/análogos & derivados , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Receptores de Estrógenos/metabolismo , Tamoxifeno/administración & dosificación , Adulto , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/sangre , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Estradiol/administración & dosificación , Estradiol/efectos adversos , Estradiol/sangre , Femenino , Fulvestrant , Humanos , Inyecciones Intramusculares , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Neoplasias Hormono-Dependientes/metabolismo , Premenopausia/efectos de los fármacos , Premenopausia/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/efectos adversos , Tamoxifeno/sangre , Resultado del TratamientoRESUMEN
Sixty-three postmenopausal women with large primary breast cancers were treated with neoadjuvant letrozole (2.5 mg daily) for 3 months. Tumour samples were taken at diagnosis and after 10-14 days and 3 months treatment. Immunohistochemical staining for Ki67, oestrogen receptor (ER) and progesterone receptor (PgR) was performed and related to clinical (ClinR) and pathological responses (PathR) after 3 months treatment. ClinR was observed in 48 of 63 cases (76.2%) and PathR in 47 of 62 (75.8%). Pretreatment Ki67 scores were similar in responders (R) and non-responders (NR). Highly significant Ki67 decreases occurred in all tumour subgroups at 10-14 days (P<0.005). A significant difference in Ki67 scores at 10-14 days (P<0.007) was found between PathR and PathNR but not between ClinR and ClinNR. At 3 months, decreases from pretreatment Ki67 scores were highly significant in all tumour subgroups irrespective of response status. However, whereas Ki67 scores were significantly different between pathological R and NR (P = 0.009), the corresponding comparison of ClinR status was not. Significant decreases between 10-14 days and 3 months were found only in ClinR and PathR (P = 0.02 and 0.045, respectively). Treatment significantly reduced PgR expression at 14 days and 3 months (both P<0.0001), but the level of changes was not different between response status groups. In summary, letrozole produces rapid and profound decreases in expression of Ki67 and PgR but changes do not always correlate with clinical and pathological responses.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Nitrilos/farmacología , Nitrilos/uso terapéutico , Triazoles/farmacología , Triazoles/uso terapéutico , Anciano , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Antígeno Ki-67/análisis , Letrozol , Persona de Mediana Edad , Terapia Neoadyuvante , Posmenopausia , Receptores de Estrógenos/análisis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/análisis , Receptores de Progesterona/biosíntesis , Resultado del TratamientoRESUMEN
Overexpression of erbB2 in breast tumours can predict resistance to tamoxifen therapy. We conducted a small trial to determine if erbB2 status correlates with tumour response and biochemical changes in postmenopausal women receiving neoadjuvant therapy with the aromatase inhibitor, anastrozole. Twenty-four postmenopausal women with oestrogen receptor (ER)-rich, large, operable breast tumours received three months of neoadjuvant anastrozole, 1 or 10 mg daily, then surgery, followed by another five years of anastrozole 1 mg daily. Response to the treatment was based on changes in clinical and ultrasound measurements of tumour volume and changes in tumour proliferation and progesterone receptor (PgR) status. After follow-up for a median duration of four years therapy, there was no apparent difference between erbB2 0/1+ and erbB2 3+ tumours in clinical response or changes in proliferation and PgR expression. In conclusion, anastrozole appears to be an effective endocrine option in this patient population, irrespective of the erbB2 status.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Nitrilos/uso terapéutico , Triazoles/uso terapéutico , Anciano , Anastrozol , Neoplasias de la Mama/genética , Proliferación Celular , Método Doble Ciego , Femenino , Genes erbB-2 , Humanos , Metástasis Linfática , Posmenopausia , Receptor ErbB-2 , Receptores de Progesterona/metabolismoRESUMEN
Neoadjuvant hormonal therapy for oestrogen receptor (ER) and/or progesterone receptor (PgR) positive large operable or locally advanced breast cancer is effective and a safe alternative to chemotherapy in postmenopausal women. A randomised trial has demonstrated that the response rate and the incidence and degree of downstaging with the aromatase inhibitor letrozole is significantly greater than with tamoxifen [J. Clin. Oncol. 19 (2001) 3808]. Tumours at all levels of ER appear to respond better to letrozole than tamoxifen but at low levels of ER responses are seen only with letrozole and not with tamoxifen. Patients most likely to benefit from neoadjuvant therapy and those who achieve the greatest reduction in tumour volume are those patients with tumours that express very high levels of ER (ALLRED category score 8). Both letrozole and anastrozole appear effective in both erbB2 positive and negative breast cancers. Three months of treatment is adequate to determine if a tumour will respond. Following breast-conserving surgery and radiotherapy, local recurrence rates appear satisfactory.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Tamoxifeno/uso terapéutico , Anastrozol , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Antígeno Ki-67/metabolismo , Letrozol , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/estadística & datos numéricos , Nitrilos/farmacología , Nitrilos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/efectos de los fármacos , Receptores de Progesterona/metabolismo , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
Anastrozole, an orally active, nonsteroidal aromatase inhibitor, was evaluated in a randomized, double-blind, single-center study to determine its efficacy as neoadjuvant therapy in postmenopausal women with newly diagnosed, estrogen receptor-rich, locally advanced or large (>3 cm), operable breast cancers. Twenty-four eligible patients were recruited into the study and received either 1 mg (n = 12) or 10 mg (n = 12) of anastrozole daily over a 3-month period. Tumor volumes were estimated clinically, by using caliper measurements and ultrasound (at baseline and after 1, 2, and 3 months' treatment) and by mammography (at baseline and after 3 months). Tumor volume was also measured in surgical specimens. Twenty-one patients were classified as T2, two patients as T3, and one patient as T4B at baseline. Three patients had clinical evidence of lymph node involvement. When considering the difference between the volume as measured by each assessment and the actual pathological volume, the interquartile range and the difference between the maximum and minimum values were smaller for ultrasound when compared with those measured with calipers and mammography. Therefore, of the three clinical assessments of tumor volume used in this study, the data suggest that ultrasound may be the most accurate. The median reductions in tumor volumes as measured by ultrasound for those patients with a measurable 12-week assessment were 80.5 and 69.6% for anastrozole (1 and 10 mg, respectively) after 12 weeks of treatment and 75.5% when both doses were grouped together. Moreover, of these patients, 11 of 12 given 1 mg and 7 of 11 given 10 mg of anastrozole were found on ultrasound to have a >50% reduction in tumor volume after 12 weeks of treatment. Of the 17 patients who would have required a mastectomy at initiation of treatment, 15 were suitable for breast conservation after anastrozole treatment. These results suggest that anastrozole is highly effective as neoadjuvant therapy in postmenopausal women with estrogen receptor-rich, large, operable breast cancer. Future studies comparing anastrozole with tamoxifen as a neoadjuvant treatment should be considered.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante , Nitrilos/farmacología , Posmenopausia , Triazoles/farmacología , Anciano , Anastrozol , Neoplasias de la Mama/diagnóstico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Metástasis Linfática , Mamografía , Persona de Mediana Edad , Receptores de Estrógenos/biosíntesis , Resultado del Tratamiento , UltrasonografíaRESUMEN
Postmenopausal patients with oestrogen receptor-positive locally advanced T4b, N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients), 1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There was no apparent difference in response rate between 2.5 and 10 mg letrozole. Only 17 patients with anastrozole have so far completed the 3-month treatment period. Median clinical, mammographic and ultrasound reductions in tumour volumes for patients treated with letrozole were 81% (95% confidence interval (CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI 52-76) respectively. This compares with a median reduction in tumour volume for tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48). There were seven complete clinical responses (CR), sixteen patients who achieved 50% or greater reduction in tumour volume (PR) and one no change (NC) for letrozole and four CRs, twelve PRs and one progressive disease for anastrozole. Best radiological responses were one CR, twenty PRs and three NCs for letrozole and one CR, fifteen PRs and one NC for anastrozole. This study has shown that the new aromatase inhibitors, letrozole and anastrozole, are highly effective agents in the neoadjuvant setting and they should now be compared with tamoxifen as first-line treatment in a randomised study.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de la Aromatasa , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Antagonistas de Estrógenos/uso terapéutico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Nitrilos/uso terapéutico , Tamoxifeno/uso terapéutico , Triazoles/uso terapéutico , Anciano , Anastrozol , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/cirugía , Ensayos Clínicos como Asunto , Terapia Combinada , Femenino , Humanos , Letrozol , Persona de Mediana Edad , Neoplasias Hormono-Dependientes/metabolismo , Neoplasias Hormono-Dependientes/cirugía , Posmenopausia , Receptores de Estrógenos/metabolismoRESUMEN
Little is known about how information diffuses to clinicians and influences their purchase and use of new technology. This is especially true about the role of the scientific literature. As a case study, we examined the literature for magnetic resonance imaging (MRI) during the years preceding and the first five years following its clinical introduction. Using a computerized retrieval system, we identified approximately 1,700 citations in which MRI was the major topic. The clinical literature on MRI was heavily concentrated in radiology journals. Less than 28% of articles compared MRI with alternative diagnostic technologies. During the first five years of clinical availability, the diffusion patterns of scientific articles and operational units mirrored the example set by computerized tomography (CT), in that a substantial number of units were purchased in both research and nonresearch settings before studies were available comparing them to alternative diagnostic technologies. These patterns of diffusion, combined with other studies of the MRI literature's content and methodology, suggest that less comprehensive and objective sources of information were important in early purchasing decisions. This study also suggests that the present readership and publication patterns of professional journals may not facilitate effective, rapid information dissemination about innovations to a broad spectrum of clinicians.
Asunto(s)
Difusión de Innovaciones , Servicios de Información , Imagen por Resonancia Magnética , Edición , MEDLINE , Pautas de la Práctica en MedicinaRESUMEN
Chronic immune thrombocytopenic purpura (ITP) is due to platelet destruction by circulating antiplatelet antibody. Although autoantibodies against the platelet glycoprotein IIb/IIIa (GPIIb/IIIa) complex and GPIb have been demonstrated using various methods, practical assays for detection of platelet-associated or plasma autoantibodies have not been available. We studied 59 patients with chronic immune thrombocytopenic purpura in whom platelet-associated and plasma autoantibodies against the GPIIb/IIIa complex and GPIb were measured using a newly developed immunobead assay and a previously reported microtiter-well assay. Platelet-associated autoantibody was detected using the immunobead assay in 21 of 28 patients (75.0%; 13 with anti-GPIIb/IIIa, 8 with anti-GPIb). Plasma autoantibodies were noted in 34 of 59 patients (57.6%; 21 with anti-GPIIb/IIIa, 11 with anti-GPIb, and 2 with both). Positive results were noted in 30 of 59 patients using the immunobead assay and in only 14 of 59 using the microtiter-well assay, suggesting that solubilization of the platelets prior to antibody addition, as in the microtiter-well assay, alters epitope stability. Of the 31 thrombocytopenic control patients studied, all gave negative results using both assays. We conclude that these clinically adaptable assays allow detection of autoantibodies in most patients with chronic ITP, confirming the presence of an autoimmune process.
Asunto(s)
Autoanticuerpos/análisis , Plaquetas/inmunología , Glicoproteínas/inmunología , Enfermedades del Sistema Inmune/inmunología , Plasma/inmunología , Púrpura Trombocitopénica/inmunología , Enfermedad Crónica , Humanos , Enfermedades del Sistema Inmune/sangre , Púrpura Trombocitopénica/sangre , Esplenectomía , Trombocitopenia/inmunologíaRESUMEN
Four patients with acute leukemia received transplants from HLA-mismatched, related donors. Marrow cells that had been depleted of T lymphocytes using a monoclonal anti-T-lymphocyte antibody and rabbit complement were used. In vitro studies showed that 80-97% of the mature T lymphocytes were removed using this procedure. Infusion of the treated marrow was accomplished without complications, and engraftment occurred in each case. Graft-versus-host disease occurred in 3 of the 4 patients. These results show that additional manipulations of the marrow will be required to allow complete T lymphocyte removal from the marrow before the feasibility of this approach in HLA-mismatched patients can be determined.