We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international ...standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.
FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1–3, pN0–1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio HR of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.
Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were −0·3% (−1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and −0·7% (−1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1–5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy.
26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.
National Institute for Health Research Health Technology Assessment Programme.
Prenatal detection (PND) has benefits for infants with hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), but associations between sociodemographic and geographic ...factors with PND have not been sufficiently explored. This study evaluated whether socioeconomic quartile (SEQ), public insurance, race and ethnicity, rural residence, and distance of residence (distance and driving time from a cardiac surgical center) are associated with the PND or timing of PND, with a secondary aim to analyze differences between the United States and Canada.
In this retrospective cohort study, fetuses and infants <2 months of age with HLHS or TGA admitted between 2012 and 2016 to participating Fetal Heart Society Research Collaborative institutions in the United States and Canada were included. SEQ, rural residence, and distance of residence were derived using maternal census tract from the maternal address at first visit. Subjects were assigned a SEQ
score using the neighborhood summary score or Canadian Chan index and separated into quartiles. Insurance type and self-reported race and ethnicity were obtained from medical charts. We evaluated associations among SEQ, insurance type, race and ethnicity, rural residence, and distance of residence with PND of HLHS and TGA (aggregate and individually) using bivariate analysis with adjusted associations for confounding variables and cluster analysis for centers.
Data on 1862 subjects (HLHS: n=1171, 92% PND; TGA: n=691, 58% PND) were submitted by 21 centers (19 in the United States). In the United States, lower SEQ was associated with lower PND in HLHS and TGA, with the strongest association in the lower SEQ of pregnancies with fetal TGA (quartile 1, 0.78 95% CI, 0.64-0.85, quartile 2, 0.77 95% CI, 0.64-0.93, quartile 3, 0.83 95% CI, 0.69-1.00, quartile 4, reference). Hispanic ethnicity (relative risk, 0.85 95% CI, 0.72-0.99) and rural residence (relative risk, 0.78 95% CI, 0.64-0.95) were also associated with lower PND in TGA. Lower SEQ was associated with later PND overall; in the United States, rural residence and public insurance were also associated with later PND.
We demonstrate that lower SEQ, Hispanic ethnicity, and rural residence are associated with decreased PND for TGA, with lower SEQ also being associated with decreased PND for HLHS. Future work to increase PND should be considered in these specific populations.
Background
Tetralogy of Fallot with absent pulmonary valve is associated with high mortality, but it remains difficult to predict outcomes prenatally. We aimed to identify risk factors for mortality ...in a large multicenter cohort.
Methods and Results
Fetal echocardiograms and clinical data from 19 centers over a 10‐year period were collected. Primary outcome measures included fetal demise and overall mortality. Of 100 fetuses, pregnancy termination/postnatal nonintervention was elected in 22. Of 78 with intention to treat, 7 (9%) died in utero and 21 (27%) died postnatally. With median follow‐up of 32.9 months, no deaths occurred after 13 months. Of 80 fetuses with genetic testing, 46% had chromosomal abnormalities, with 22q11.2 deletion in 35%. On last fetal echocardiogram, at a median of 34.6 weeks, left ventricular dysfunction independently predicted fetal demise (odds ratio OR, 7.4; 95% CI 1.3, 43.0;
P
=0.026). Right ventricular dysfunction independently predicted overall mortality in multivariate analysis (OR, 7.9; 95% CI 2.1–30.0;
P
=0.002). Earlier gestational age at delivery, mediastinal shift, left ventricular/right ventricular dilation, left ventricular dysfunction, tricuspid regurgitation, and Doppler abnormalities were associated with fetal and postnatal mortality, although few tended to progress throughout gestation on serial evaluation. Pulmonary artery diameters did not correlate with outcomes.
Conclusions
Perinatal mortality in tetralogy of Fallot with absent pulmonary valve remains high, with overall survival of 64% in fetuses with intention to treat. Right ventricular dysfunction independently predicts overall mortality. Left ventricular dysfunction predicts fetal mortality and may influence prenatal management and delivery planning. Mediastinal shift may reflect secondary effects of airway obstruction and abnormal lung development and is associated with increased mortality.
The establishment and maintenance of spermatogenesis in mammals requires specialized networks of gene expression programs in the testis. The gonad-specific TAF4b component of TFIID (formerly ...TAF(II)105) is a transcriptional regulator enriched in the mouse testis. Herein we show that TAF4b is required for maintenance of spermatogenesis in the mouse. While young Taf4b-null males are initially fertile, Taf4b-null males become infertile by 3 mo of age and eventually exhibit seminiferous tubules devoid of germ cells. At birth, testes of Taf4b-null males appear histologically normal; however, at post-natal day 3 gonocyte proliferation is impaired and expression of spermatogonial stem cell markers c-Ret, Plzf, and Stra8 is reduced. Together, these data indicate that TAF4b is required for the precise expression of gene products essential for germ cell proliferation and suggest that TAF4b may be required for the regulation of spermatogonial stem cell specification and proliferation that is obligatory for normal spermatogenic maintenance in the adult.
Estrogen stimulates breast development during puberty and mammary tumors in adulthood through estrogen receptor-α (ERα). These effects are proposed to occur via ERα+ luminal cells and not the mammary ...stem cells (MaSCs) that are ERαneg. Since ERα+ luminal cells express stem cell antigen-1 (SCA-1), we sought to determine if SCA-1 could define an ERα+ subset of EpCAM+/CD24+/CD49fhi MaSCs. We show that the MaSC population has a distinct SCA-1+ population that is abundant in pre-pubertal mammary glands. The SCA-1+ MaSCs have less stem cell markers and less in vivo repopulating activity than their SCA-1neg counterparts. However, they express ERα and specifically enter the cell cycle at puberty. Using estrogen-deficient aromatase knockouts (ArKO), we showed that the SCA-1+ MaSC could be directly modulated by estrogen supplementation. Thus, SCA-1 enriches for an ERα+, estrogen-sensitive subpopulation within the CD24+/CD49fhi MaSC population that may be responsible for the hormonal sensitivity of the developing mammary gland.
•SCA-1+ delineates ER-positive cells in the CD24+ CD49fhi mammary stem population•SCA-1+ cells have lower repopulation activity•SCA-1+ cells are estrogen responsive
Mouse mammary stem cells are thought to be estrogen-receptor negative and receive hormonal influence via estrogen-receptor-positive luminal neighbors. In this article, Britt and colleagues describe a population within the mammary stem cell-enriched compartment that is estrogen-receptor positive and directly responsive to estrogens. This has implications for understanding how aberrant hormone exposure affects breast cancer risk.
Estrogen stimulates breast development during puberty and mammary tumors in adulthood through estrogen receptor-α (ERα). These effects are proposed to occur via ERα
luminal cells and not the mammary ...stem cells (MaSCs) that are ERα
. Since ERα
luminal cells express stem cell antigen-1 (SCA-1), we sought to determine if SCA-1 could define an ERα
subset of EpCAM
/CD24
/CD49f
MaSCs. We show that the MaSC population has a distinct SCA-1
population that is abundant in pre-pubertal mammary glands. The SCA-1
MaSCs have less stem cell markers and less in vivo repopulating activity than their SCA-1
counterparts. However, they express ERα and specifically enter the cell cycle at puberty. Using estrogen-deficient aromatase knockouts (ArKO), we showed that the SCA-1
MaSC could be directly modulated by estrogen supplementation. Thus, SCA-1 enriches for an ERα
, estrogen-sensitive subpopulation within the CD24
/CD49f
MaSC population that may be responsible for the hormonal sensitivity of the developing mammary gland.
The prostaglandin endoperoxide synthase-2 (PGS-2) gene encodes an isoform of prostaglandin synthase that is transiently induced by protein kinase A (luteinizing hormone/cAMP) and protein kinase C ...(gonadotropin-releasing hormone) agonists in granulosa cells of ovulating follicles. The promoter of the rat PGS-2 gene contains a CAAT enhancer-binding protein consensus site (CAAT box) which can confer hormone inducibility to a PGS-2·CAT reporter gene, as well as a putative E-box region. To determine if the E-box region was involved in hormone induced trans-activation of the rat PGS-2 gene, constructs with the CAAT box and E-box regions (−192 PGS-2·CAT), only the putative E-box (−110 PGS-2·CAT), or neither region (−52 PGS-2·CAT) were transiently transfected into rat granulosa cell cultures. CAT activity was induced in both the −192 and −110 PGS-2·CAT vectors by luteinizing hormone (10-fold) and gonadotropin-releasing hormone (6-fold), whereas CAT activity of the −52 PGS-2·CAT construct did not differ from the promoterless vector (pCAT-Basic). Deletion of 1 base pair from the E-box within the −110 PGS-2·CAT construct, as well as point mutations within the CAAT box, E-box, or both regions of the −192 PGS-2·CAT construct, demonstrated that the E-box is critical for basal transcription, and that regions, in addition to the CAAT box, are involved in hormone induction of the PGS-2 gene. An oligonucleotide spanning the rat PGS-2 E-box bound two specific protein complexes which were supershifted in the presence of antibody specific for the upstream stimulatory factor. Thus, in rat granulosa cells, the PGS-2 E-box region appears to interact with upstream cis-acting elements other than the CAAT box to confer hormonal regulation of the gene. The E-box region of the rat PGS-2 promoter does not contain ATF/CRE activity found in the human and mouse PGS-2 promoters, but is critical for basal transcription of the PGS-2 gene in rat granulosa cells and binds the upstream stimulatory factor (as do E-box regions of other genes regulated in the ovary).
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