Preconception care: it’s never too early

The preconception window has been recognized as one of the earliest sensitive windows of human development, and interventions that focus on this period have the potential to affect not only pregnancy but long term outcomes as well. The journal Reproductive Health has published a supplement entitled ‘Preconception Interventions’ which includes a series of systematic reviews regarding the impact of public health interventions during the preconception period on maternal and child health. These articles describe the role that poor preconception health plays in creating health disparities across the globe. The reviews highlight our current understanding (or lack thereof) regarding how both maternal and paternal preconception health and knowledge shapes the long-term health of not only children, but of families, communities, and nations. Researchers and healthcare workers should take particular note of these interventions, as the preconception time period may be as important as the pregnancy and post-pregnancy periods, and is critical in terms of bridging the gap in the continuum of care, particularly for adolescents.Fil: Mumford, Sunni L.. National Institutes of Health; Estados UnidosFil: Michels, Kara A.. National Institutes of Health; Estados UnidosFil: Salaria, Natasha. BioMed Central; Reino UnidoFil: Valanzasca, Pilar. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Belizan, Jose. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Heat Suppresses Activation of an Auxin-Responsive Promoter in Cultured Guard Cell Protoplasts of Tree Tobacco1[OA]

Cultured guard cell protoplasts (GCP) of tree tobacco (Nicotiana glauca) comprise a novel system for investigating the cell signaling mechanisms that lead to acquired thermotolerance and thermoinhibition. At 32°C in a medium containing an auxin (1-naphthaleneacetic acid [NAA]) and a cytokinin (6-benzylaminopurine), GCP expand, regenerate cell walls, dedifferentiate, and divide. At 38°C, GCP acquire thermotolerance within 24 h, but their expansion is limited and they neither regenerate walls nor reenter the cell cycle. These putative indicators of auxin insensitivity led us to hypothesize that heat suppresses induction of auxin-regulated genes in GCP. Protoplasts were transformed with BA-mgfp5-ER, in which the BA auxin-responsive promoter regulates transcription of mgfp5-ER encoding thermostable green fluorescent protein (GFP) or with a similar 35S-cauliflower mosaic virus constitutive promoter construct. Heat suppressed NAA-mediated activation of BA. After 21 h at 32°C in media with NAA, 49.0% ± 3.9% of BA-mgfp5-ER transformants strongly expressed GFP; expression percentages were similar to those of 35S-mgfp5-ER transformants at 32°C or 38°C. After 21 h at 38°C in media with NAA, 7.9% ± 1.6% of BA-mgfp5-ER transformants weakly expressed GFP, similar to GCP cultured at 32°C in media lacking NAA. Expression at 38°C was not increased by incubating for 48 h or increasing NAA concentrations 20-fold. After 9 to 12 h at 38°C, BA was no longer activated when cells were transferred to 32°C. Heat-stressed cells accumulate reactive oxygen species, and hydrogen peroxide (H2O2) suppresses auxin-responsive promoter activation in Arabidopsis (Arabidopsis thaliana) mesophyll protoplasts. H2O2 did not suppress BA activation at 32°C, nor did superoxide and H2O2 scavengers prevent BA suppression at 38°C

Circulating androgens and postmenopausal ovarian cancer risk in the Women's Health Initiative Observational Study

Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC-MS/MS assays, we evaluated associations between pre-diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency-matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI-OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n = 102 serous/67 non-serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone-glucuronide (ADT-G) and total 5-α reduced glucuronide metabolites (markers of tissue-level androgenic activity) were at increased risk of developing non-serous ovarian cancer: ADT-G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68-11.32), p-heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47-8.95), 0.002. Risk of developing serous tumors was unrelated to these markers. ADT-G and total glucuronide metabolites, better markers of tissue-level androgenic activity in women than testosterone, were associated with an increased risk of developing non-serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non-serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer

Circulating androgens and postmenopausal ovarian cancer risk in the Women's Health Initiative Observational Study

Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC-MS/MS assays, we evaluated associations between pre-diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency-matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI-OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n = 102 serous/67 non-serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone-glucuronide (ADT-G) and total 5-α reduced glucuronide metabolites (markers of tissue-level androgenic activity) were at increased risk of developing non-serous ovarian cancer: ADT-G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68-11.32), p-heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47-8.95), 0.002. Risk of developing serous tumors was unrelated to these markers. ADT-G and total glucuronide metabolites, better markers of tissue-level androgenic activity in women than testosterone, were associated with an increased risk of developing non-serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non-serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer

Endogenous Progestogens and Colorectal Cancer Risk among Postmenopausal Women.

BackgroundThe role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women.MethodsThe markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992-1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)].ResultsHigh concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40-1.25; progesterone HR, 1.25; 95% CI, 0.71-2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75-1.44; P trend, 0.06).ConclusionsWe used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women.ImpactOur findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women