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CLINICAL ONCOLOGY survival rates of 79% in the control group and 85% in patients treated with zoledronic acid (adjusted HR 0.74; 95% CI 0.55–0.98, P = 0.04). The data from both ABCSG-12 and AZURE 6,9 trials suggest that the beneficial effects of adjuvant zoledronic acid treatment are dependent on an environment with low reproductive hormone levels. The mechanisms underlying this observation are under investigation. Prostate cancer has the propensity to metastasize almost exclusively to the bone and, therefore, provides the ideal clinical setting for the evaluation of bone-targeting treatments to modify the disease course. In a study by Smith and colleagues, 10 1,432 men with non-metastatic castration-resistant prostate cancer at high risk for bone metastasis (determined by either a PSA level ≥8.0 ng/ml and/or PSA doub ling time of ≤10 months) were randomly assigned to receive a monthly treatment of denosumab (120 mg) or placebo. Bone metastasis-free survival was significantly increased with denosumab by a median of 4.2 months (HR 0.85; 95%CI 0.73–0.98, P = 0.028), and the onset of first symptomatic bone metastases was delayed. This effect, however, did not translate into any improvement in overall survival, and as the cumulative incidence of Don’t miss out! Sign up to free e-ALERTS and be notified when new articles are published in Nature Reviews Clinical Oncology. Research Highlights, News & Views, Reviews, and Perspectives—you won’t miss a thing! http://www.nature.com/register ONJ was high (4% after 3 years), whether the efficacy of denosumab to reduce bone meta stasis is sufficient to change clinical practice is unclear. Overall, 2011 saw important developments in the prevention and management of bone metastasis. Integrating the current bone-targeting treatments in routine clinical practice and achieving a better understanding of the cellular processes involved in bone metastasis are the challenges for the future. Sheffield Cancer Research Center, Academic Unit of Clinical Oncology, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK. r.e.coleman@sheffield.ac.uk Competing interests The author declares associations with the following companies: Amgen and Novartis. See the article online for full details of the relationships. 1. Stopeck, A. T. et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J. Clin. Oncol. 28, 5132–5139 (2010). 2. Fizazi, K. et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011). 3. Henry, D. H. et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J. Clin. Oncol. 29, 1125–1132 (2011). 4. Saad, F. et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded activecontrolled phase III trials in cancer patients with bone metastases. Ann. Oncol. http:// dx.doi.org/10.1093/annonc/mdr435. 5. Parker, C. et al. Overall survival benefit of radium-223 chloride (alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a phase III randomised trial (ALSYMPCA) [abstract]. Eur. J. Cancer 47 (Suppl. 2), a3 (2011). 6. Gnant, M. et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N. Engl. J. Med. 360, 679–691 (2009). 7. Gnant, M. et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 12, 631–641 (2011). 8. Gnant, M. et al. Overall survival with adjuvant zoledronic acid in patients with premenopausal breast cancer with complete endocrine blockade: Long-term results from ABCSG-12 [abstract]. J. Clin. Oncol. 29 (Suppl. 15), a520 (2011). 9. Coleman, R. E. et al. Breast-cancer adjuvant therapy with and without zoledronic acid. N. Engl. J. Med. 365, 1396–1405 (2011). 10. Smith, M. R. et al. Denosumab and bone metastasis-free survival in men with castrationresistant prostate cancer: results of a global phase 3, randomised, placebo-controlled trial. Lancet http://dx.doi.org/10.1016/ S0140-6736(11)61226-9. S20 | JANUARY 2012 www.nature.com/reviews
ENDOCRINOLOGY THYROID DISEASE IN PREGNANCY IN 2011 Thyroid function—effects on mother and baby unraveled Anthony P. Weetman The complex relationship between pregnancy and thyroid function, and its clinical effect on mother and baby, continued to stimulate research in 2011. Key advances were made on three important issues: how long maternal thyroid function affects fetal thyroid hormone levels; whether thyroid autoimmunity affects pregnancy outcome; and the prevalence of permanent hypothyroidism after postpartum thyroiditis. Weetman, A. P. Nat. Rev. Endocrinol. 8, 69–70 (2012); published online 6 December 2011; doi:10.1038/nrendo.2011.217 The fetal thyroid gland starts to develop at 12 weeks of gestation, and for the first half of pregnancy, transplacental passage of maternal thyroid hormone is essential for normal fetal development. Failure to deliver sufficient thyroid hormone to the fetus causes impaired neurological development, although whether other elements of fetal development are also affected remains unclear. The essentially normal outcome in neonates with congenital hypothyroidism promptly treated with levothyroxine after birth suggests that maternal thyroid hormones also have a fetal role in the second half of pregnancy. In a prospective survey of 886 pregnant Dutch women published in 2011, neonates born to mothers who had high-normal TSH levels (above the 97.5 th percentile) one or more times during pregnancy had lower total T 4 levels when routine screening was performed for congenital hypothyroidism than neonates born to mothers whose TSH levels had remained below the 97.5 th percentile. 1 This result contrasts with that of a previous study that showed no relationship between maternal and neonatal thyroid function, 2 a difference possibly related to the use of pregnancy-specific refer ence ranges for TSH measurement in the 2011 study. Although the women with high-normal TSH levels had normal free T 4 levels, the TSH levels might reflect a resetting of the pituitary–thyroid axis, which resulted in less T 4 being available to cross the placenta. Alternatively, an unsuspected increase in placental deiodinase activity might have been responsible for low T 4 availability to the fetus. Low gestational age was associated with low neonatal thyroxine levels in this and previous studies, which raises the possibility that maternal thyroid function throughout pregnancy, rather than just the first trimester, is an important determinant of gestational outcome. Detailed sampling of maternal thyroid function is required to investigate this hypo thesis further. In a related study from 2011, maternal thyroid function variables measured at 28 weeks gestation were compared with those measured in the umbilical cord at birth in 616 preg nancies in the UK. 3 Maternal free T 4 and cord free T 4 values showed a positive correlation, and maternal TSH levels were inversely corre lated with cord free T 4 levels. This evidence by Shields and co-investigators is consistent with that of the Dutch study 1 and sug gests that maternal thyroid function has a measurable effect on fetal thyroid hormone levels throughout pregnancy. Shields et al. also examined the effect of thyroid hormone levels on various parameters of fetal growth. Cord free T 4 levels were associated with birth weight, length and skin-fold thickness. These results imply that fetal thyroid hormone levels have an important role in regulating fetal growth, especially when taken in conjunction with the results of animal experiments. 4 An unexplained finding was that birth weight was negatively associated with maternal free T 4 levels, given that maternal and cord free T 4 levels were positively associated. Together, these two studies highlight the intricacy of the maternal–fetal relationship with regard to thyroid function and its clinically important effects on fetal growth and ges tational age. Studies with detailed assessment of maternal thyroid function throughout the third trimester that incorpo rate assess ment of placental deiodinase activity are needed. Variable iodine intake is also a con founding factor that needs addressing, given the surprising discovery in 2011 of inade quate dietary supplies in the UK and in other countries. 5 Multiple studies have shown that euthyroid pregnant woman with positive thyroid peroxidase (TPO) antibodies have an increased risk of spontaneous mis carriage and possibly preterm delivery. Two mechanisms might be responsible. Firstly, even though ‘euthyroid’, these women may have subtle impairment of thyroid function, and the effects of maternal thyroid function on the fetus, as discussed above, are responsible. Secondly, thyroid auto immunity dis torts the immunological balance required to maintain tolerance to the fetal semi-allograft. 6 In 2011, a study of 245 TPO-antibodypositive women with TSH levels
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UROLOGY PROSTATE CANCER IN 2011 Red
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BLADDER CANCER IN 2011 The dawn of
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