Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia.
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To define prognostic factors in infant acute lymphoblastic leukemia (ALL), the outcome of 106 infants (age /=1,000 blasts/microL) received intensified therapy. Infant ALL was characterized by a high incidence of a white blood cell count greater than 100 x 10(3)/microL (57%), central nervous system leukemia (24%), lack of CD10 expression (59%), 11q23 rearrangement (49%) including the translocation t(4;11) (29%), and a comparatively high proportion of PPR (26%), which were all significantly associated with inferior outcome by univariate analysis. The estimated probability for an event-free survival at 6 years (pEFS) was by far better for PGR compared with PPR, who had a dismal prognosis despite intensified treatment (pEFS, 53% +/- 6% v 15% +/- 7%, P =.0001). Infant PGR, who were less than 6 months of age (n = 40), lacked CD10 expression (n = 43), and/or had an 11q23 rearrangement (n = 17) fared significantly better compared with corresponding PPR, as indicated by a pEFS of 44% +/- 8%, 49% +/- 8%, and 41% +/- 12%, respectively. In multivariate analysis, PPR was the strongest adverse prognostic factor (relative risk, 3.3; 95% confidence interval, 1.9 to 5.8; P <.0001). Infants with PGR, comprising a major subgroup (74%) among infants, might successfully be treated with conventional therapy, whereas PPR require new therapeutic strategies, including early treatment intensification or bone marrow transplantation in first remission. (+info)
Hormonal treatment after cytotoxic therapy stimulates recovery of spermatogenesis.
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Previous studies have shown that treatment of rats with gonadotropin-releasing hormone (GnRH) analogues or steroids either before exposure to procarbazine or radiation or after irradiation enhances subsequent levels of spermatogenesis. We demonstrate here that giving a GnRH agonist after procarbazine injection also enhances spermatogenesis and fertility. We also demonstrate that GnRH agonist stimulated recovery of spermatogenesis and fertility not only when the hormone was administered immediately after irradiation, but also at 20 weeks after irradiation, after the decline in spermatogenesis had occurred. These results suggest that GnRH agonist treatment given to azoospermic men after cytotoxic therapy for cancer may stimulate the recovery of spermatogenesis and fertility. (+info)
Idoxifene antagonizes estradiol-dependent MCF-7 breast cancer xenograft growth through sustained induction of apoptosis.
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Idoxifene is a novel selective estrogen (E2) receptor (ER) modulator that is currently in clinical development for the treatment of breast cancer. Compared to tamoxifen, idoxifene is metabolically more stable, with a higher relative binding affinity for the ER and reduced agonist activity on breast and uterine cells. Idoxifene also inhibits calmodulin, a calcium-binding protein that is involved in cell signal transduction pathways. In this study, the abilities of idoxifene and tamoxifen to antagonize E2-dependent MCF-7 xenograft growth in oophorectomized athymic mice were compared. The basis for idoxifene's antitumor activity was examined by comparing the effectiveness of the clinically used transisomer (referred to here as idoxifene) with its cis-isomer, which has a 50-fold lower relative binding affinity for ER than idoxifene but similar calmodulin-inhibitory activity. Changes in tumor cell proliferation, apoptosis, and ER-dependent protein expression were studied. Both idoxifene and tamoxifen significantly inhibited E2-dependent tumor growth, whereas cis-idoxifene had little effect. Withdrawal of E2 support induced significant tumor regression due to impaired cell proliferation (Ki-67 score, 9 versus 51% compared to E2 controls) and induction of apoptosis (3.6 versus 0.9% compared to E2 controls). Both anti-E2s inhibited cell proliferation and caused a significant 3-fold induction of apoptosis in E2 supported tumors after 1 week, which was maintained for 3 months with idoxifene (3.1 versus 0.48% compared to E2 controls) but decreased back to baseline in tumors treated with tamoxifen (0.69%). In contrast, cis-idoxifene had no effect on either cell proliferation or apoptosis. Both tamoxifen and idoxifene initially induced ER expression, whereas prolonged therapy with tamoxifen significantly reduced progesterone receptor levels. In conclusion, idoxifene resulted in similar inhibition of E2-dependent MCF-7 xenograft growth compared with tamoxifen, an effect that is mediated via ER rather than through calmodulin. Sustained induction of apoptosis may contribute to prolonged antagonism of E2-dependent growth, and it occurred to a greater extent following 3 months of idoxifene, compared to tamoxifen. (+info)
Differential regulation of somatostatin receptor type 2 (sst 2) expression in AR4-2J tumor cells implanted into mice during octreotide treatment.
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Octreotide is a somatostatin analogue that is widely used for cancer therapy and tumor imaging. Its efficacy in tumors depends mainly on the expression of the somatostatin receptor type 2 (sst 2). Desensitization and down-regulation of sst 2 after agonist exposure can have important consequences for patients under ongoing octreotide therapy because it may induce temporary tumor unresponsiveness and impair sst 2-based tumor scintigraphy. Therefore, we have investigated the effect of octreotide on sst 2 expression in vitro, as well as in a tumor mouse model. In vitro, short exposure to octreotide induced rapid dose-dependent down-regulation of sst 2 in the rat pancreatic AR4-2J cell line. Within 0.5 h, 80% of sst 2 had disappeared from the cell surface. A total recovery required 24 h and was shown to depend on protein synthesis, but not on new sst 2 mRNA transcription, indicating that sst 2 was probably degraded during the down-regulation process. Similar results were obtained in vivo. On the other hand, long-term continuous release of octreotide for 7 days, as achieved with octreotide-containing osmotic minipumps, caused sst 2 up-regulation in vivo, but not in vitro. Furthermore, this up-regulation of sst 2 in tumor-bearing scid mice was shown to depend on constant exposure of the animals to octreotide, as it was not observed when octreotide was given discontinuously in two s.c. daily injections. These results demonstrate that the continuous release of a small amount of octreotide, which in cancer therapy may be achieved with long-acting release formulations of the peptide, can induce sst 2 up-regulation on cancer cells. This may improve the efficacy of both tumor imaging and long-term octreotide therapy. (+info)
Breast cancer treatment and chemoprevention.
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OBJECTIVE: To outline modern principles of surgery, radiation therapy, and systemic treatment of breast cancer, and to review preliminary data on breast cancer prevention. QUALITY OF EVIDENCE: A MEDLINE search was conducted from 1966 to the beginning of 1999; most of the studies reviewed are randomized clinical trials. MAIN MESSAGE: Breast conservation surgery should be offered to all women with early breast cancer because studies demonstrate survival rates equivalent to those with mastectomy. If mastectomy is chosen, breast reconstruction should be offered. Most women with breast cancer are treated systemically with either chemotherapy or tamoxifen, or both, and mortality is substantially reduced. Data indicating that tamoxifen prevents breast cancer are promising; more studies with both tamoxifen and raloxifene are under way. All women should be strongly encouraged to enter clinical trials. CONCLUSIONS: Because many issues face women recently diagnosed with breast cancer, they often seek out family physicians as advisors to help negotiate a complex treatment path. The possibility of preventing breast cancer will undoubtedly raise questions among family members of women with breast cancer that should appropriately be answered and referred, if necessary, by family physicians. (+info)
Is adjuvant tamoxifen used optimally in the treatment of breast cancer? Results of an Italian survey.
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BACKGROUND: Institutional and physician-related factors can influence the way in which physicians interpret research results. The aim of this study was to determine what physicians know about, and their opinions of, hormone treatment in breast cancer patients, and the factors comprising their medical decision-making. MATERIALS AND METHODS: A questionnaire was mailed to a random sample of physicians inquiring as to their preferences with respect to adjuvant tamoxifen, and the usual duration of the treatment applied in various clinical scenarios (according to a woman's menopausal status, the oestrogen receptor status and the stage of disease). RESULTS: Of 500 physicians identified, 38% returned the questionnaire. Of the non-responders, a random sample of 60 physicians was interviewed by phone. The total number of available questionnaires was 250 (50%). About 3/4 of the doctors would prescribe tamoxifen in older ER+ women and 30%-40% in post-menopausal ER-patients, but only 2/5 would do so in younger ER+ women. The vast majority of physicians considered five years as standard for ER+ patients. Nevertheless, about 1/4 of the doctors chose a shorter treatment duration for node-negative, pre-menopausal patients. A minority of physicians used tamoxifen for longer than five years. Older clinicians were less likely to prescribe tamoxifen, particularly for low-risk patients. CONCLUSIONS: According to the data of the recent EBCTG overview, an additional 20,000 lives could be saved worldwide each year if tamoxifen were given to all early breast cancer patients with hormone-sensitive disease, irrespective of age and disease stage, and for a minimum of five years. Our study, involving a representative sample of physicians practicing in Italy, shows that tamoxifen is not used optimally, with a substantial under-use in younger women and women with node-negative disease. (+info)
A collection method and high-sensitivity enzyme immunoassay for sweat pyridinoline and deoxypyridinoline cross-links.
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BACKGROUND: Collagen cross-link molecules such as pyridinoline (PYD), deoxypyridinoline (DPD), and N-terminal cross-linked peptides (NTX) have been measured in urine as indices of bone resorption. However, very little is known regarding the excretion of pyridinolines into other biological fluids. We report a collection device, normalizing analyte, and high-sensitivity immunoassay for quantitative analysis of free pyridinoline cross-links in sweat. METHODS: Flame atomic emission and ion-selective electrode techniques were used to measure potassium as a sweat volume marker. The Pyrilinks immunoassay for urine free pyridinolines was optimized to increase sensitivity for measurements in sweat. The precision, accuracy, and detection limit of this assay were characterized. To assess values and variability of sweat pyridinolines in human subjects, a nonocclusive skin patch was used to collect sweat samples from a reference group and from a mixed group experiencing accelerated bone resorption, postmenopausal women and men receiving gonadotropin-releasing hormone for prostate cancer. RESULTS: The immunoassay intra- and interassay variations were +info)
Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer.
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Cyclin D1 is a key cell cycle regulatory protein with demonstrated oncogenic activity in a variety of malignancies. Cyclin D1 mRNA and protein are overexpressed in approximately 50% of primary breast carcinomas; however, the pathophysiological consequences of increased expression remain unclear. To investigate the functional sequelae of cyclin D1 mRNA overexpression, we analyzed clinical outcome in relation to the cyclin D1 mRNA level in 253 primary breast cancer patients (median follow-up, 75 months) with particular reference to estrogen receptor (ER) status and endocrine response. Overall, with the exception of the relationship between cyclin D1 mRNA expression and the ER, cyclin D1 mRNA was not associated with other clinicopathological features such as age, menopausal status, axillary lymph node status, vascular invasion, tumor size, type, and grade. However, in patients with ER-positive tumors (n = 182), high levels of cyclin D1 mRNA were associated with increased risk of relapse (P = 0.0016), local recurrence (P = 0.025), metastasis (P = 0.019), and death (P = 0.025). In contrast, there were no clinical correlations with cyclin D1 expression in ER-negative disease (n = 71). In 33 patients who received endocrine therapy for their primary or recurrent breast cancers, there was an apparent association between a high cyclin D1 mRNA level and a shorter response duration within the ER-positive subgroup (P = 0.04). Our findings indicate that overexpression of cyclin D1 mRNA correlates with a worse prognosis within the ER-positive breast cancer phenotype and may be a contributing factor to the development of endocrine resistance in ER-positive disease. (+info)