The prognostic value of tumour-infiltrating lymphocytes, programmed cell death protein-1 and programmed cell death ligand-1 in Stage I-III triple-negative breast cancer.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) represent a robust biological prognostic biomarker in triple-negative breast cancer (TNBC); however, the contribution of different subsets of immune cells is unclear. We investigated the prognostic value of immune markers, including stromal TILs (sTILs), CD8+T and FOPX3+T cells, PD-1 and PD-L1 in non-metastatic TNBC. METHODS: In total, 259 patients with Stage I-III TNBC were reviewed. The density of sTILs along with the presence of total (t), stromal (s), and intratumoral (i) CD8+T cells and FOPX3+T cells were evaluated by haematoxylin and eosin and immunohistochemical staining. Immunohistochemical staining of PD-1, PD-L1 was also conducted. RESULTS: All immune markers were positively correlated with each other (P < 0.05). In the multivariate analysis, sTILs (P = 0.046), tCD8+T cells (P = 0.024), iCD8+T cells (P = 0.050) and PD-1 (P = 0.039) were identified as independent prognostic factors for disease-free survival (DFS). Further analysis showed that tCD8+T cells (P = 0.026), iCD8+T cells (P = 0.017) and PD-1 (P = 0.037) increased the prognostic value for DFS beyond that of the classic clinicopathological factors and sTILs. CONCLUSIONS: In addition to sTILs, inclusion of tCD8+T, iCD8+T cells, or PD-1 may further refine the prognostic model for non-metastatic TNBC beyond that including classical factors alone.

Restraint stress of female mice during oocyte development facilitates oocyte postovulatory aging.

Studies suggest that psychological stress on women can impair their reproduction and that postovulatory oocyte aging (POA) might increase the risk of early pregnancy loss and affect offspring's reproductive fitness and longevity. However, whether psychological stress during oocyte development would facilitate POA is unknown but worth exploring to understand the mechanisms by which psychological stress and POA damage oocytes. This study observed effects of female restraint stress during oocyte development (FRSOD) on oocyte resistance to POA. Female mice were restrained for 48 h before superovulation, and they were sacrificed at different intervals after ovulation to recover aging oocytes for analyzing their early and late aged characteristics. The effects of FRSOD on aging oocytes included: (1) increasing their susceptibility to activation stimulus with elevated cytoplasmic calcium; (2) impairing their developmental potential with downregulated expression of development-beneficial genes; (3) facilitating degeneration, cytoplasmic fragmentation and apoptosis; (4) worsening the disorganization of cortical granules and spindle/chromosomes; and (5) impairing redox potential with increased oxidative stress. In conclusion, FRSOD impairs oocyte resistance to POA, so that stressed oocytes become aged significantly quicker than unstressed controls. Thus, couples wishing to achieve pregnancy should take steps to avoid not only fertilization of aged oocytes but also pregestational stressful life events.

Timing of postmastectomy radiotherapy following adjuvant chemotherapy for high-risk breast cancer: A post hoc analysis of a randomised controlled clinical trial.

PURPOSE: To investigate the appropriate timing of radiotherapy (RT) after mastectomy and adjuvant chemotherapy for women with high-risk breast cancer. PATIENTS AND METHODS: Post hoc analyses of 584 patients with stage II and III breast cancer from a randomised controlled clinical trial were performed. All patients underwent mastectomy followed by sequential chemotherapy and RT. The optimal cut-off values for the surgery-RT interval (SRI) and the chemotherapy-RT interval (CRI) for overall survival (OS) were determined using the hazard ratio for continuous predictors. The locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and OS rates were estimated using the Kaplan-Meier method. Multivariate analyses were performed using Cox proportional hazards regression. RESULTS: Median follow-up time was 83.5 months. Median SRI and CRI were 168 and 27 days, respectively. An SRI of >210 days was independently associated with higher DM (HR 2.65, 95% CI: 1.49-4.71; HR 2.78, 95% CI 1.51-5.26), lower OS (HR 2.44, 95% CI: 1.28-4.54; HR 2.50, 95% CI: 1.41-4.35), and lower DFS (HR 2.57, 95% CI: 1.45-4.57; HR 2.70, 95% CI: 1.45-5.00) than SRI of <180 or 180-210 days. Furthermore, a CRI of more than 42 days was independently associated with higher DM (HR 1.89, 95% CI: 1.17-3.06; HR 1.96, 95% CI: 1.19-3.22), lower OS (HR 2.44, 95% CI: 1.41-4.35; HR 1.92, 95% CI: 1.10-3.33), and lower DFS (HR 1.84, 95% CI: 1.14-2.96; HR 1.82, 95% CI: 1.12-2.94) than a CRI of <28 or 28-42 days. However, SRI and CRI had no significant effect on LRR. CONCLUSIONS: Based on the present findings, the timing of the initiation of RT both after mastectomy and after the completion of adjuvant chemotherapy is crucial for patients with high-risk breast cancer.

Risk factors to identify the indication for regional nodal irradiation in T1-2N1M0 breast cancer: A joint analysis of 4,243 real-world cases from two institutions.

Purpose: The aim of this study is to evaluate the role of regional nodal irradiation (RNI) in patients with T1-2N1M0 breast cancer and to identify the subgroup that could benefit from RNI. Methods and materials: A total of 4,243 women with pT1-2N1M0 breast cancer treated at two institutions in China were retrospectively reviewed. Survival rates were calculated by the Kaplan-Meier method and compared by the log-rank test. The association of risk factors with survival outcomes was evaluated using multivariable proportional hazards regression. Results: A total of 932 patients (22.0%) received RNI. At a median follow-up of 5.9 years, the 5-year locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) rates were 4.0% and 7.2% (P = 0.001), 13.2% and 10.6% (P = 0.465), 85.0% and 84.7% (P = 0.131), and 93.9% and 92.8% (P = 0.004) in the RNI and non-RNI groups, respectively. Multivariate analysis revealed that RNI was an independent prognostic factor for lower LRR (P = 0.001) and longer DFS (P = 0.013). Patients were stratified into low-, intermediate-, and high-risk groups based on the eight non-therapeutic risk factors. RNI significantly decreased the 5-year LRR (2.2% vs. 7.0%, P = 0.001) and improved the 5-year DFS (88.8% vs. 84.9%, P = 0.015) and OS (95.8% vs. 93.9%, P = 0.010) in the intermediate-risk group. However, neither the low-risk group nor the high-risk group had survival benefit from RNI. Conclusion: T1-2N1M0 breast cancer is a heterogeneous disease. We found that RNI only improved survival in the intermediate-risk group. It might be omitted in low-risk patients, and the role of RNI in high-risk patients needs further study.

Effect of postmastectomy radiotherapy on pT1-2N1 breast cancer patients with different molecular subtypes.

OBJECTIVE: To clarify the effect of postmastectomy radiotherapy (PMRT) on pT1-2N1 breast cancer patients with different molecular subtypes. METHODS: We retrospectively analyzed the data of 5442 patients with pT1-2N1 breast cancer treated using modified radical mastectomy in 11 hospitals in China. Univariate, multivariate, and propensity score matching (PSM) analyses were used to evaluate the effect of PMRT on locoregional recurrence (LRR). RESULTS: With a median follow-up duration of 63.8 months, the 5-year LRR rates were 4.0% and 7.7% among patients treated with and without PMRT, respectively (p < 0.001). PMRT was independently associated with reduced LRR after adjustments for confounders (p < 0.001). After grouping the patients according to the molecular subtype of cancer and conducting PSM, we found that the 5-year LRR rates among patients treated with and without PMRT (in that order) were as follows: luminal HER2-negative cancer, 1.9% and 6.5% (p < 0.001); luminal HER2-positive cancer, 3.8% and 13.7% (p = 0.041); HER2-overexpressing cancer, 10.2% and 15.5% (p = 0.236); and triple-negative cancer, 4.6% and 15.9% (p = 0.002). Among patients with HER2-overexpressing and triple-negative cancers, the LRR hazard rate displayed a dominant early peak, and was extremely low after 5 years. However, patients with luminal cancer continued to have a long-lasting high annual LRR hazard rate during follow-up. CONCLUSION: PMRT significantly reduced the LRR risk in patients with pT1-2N1 luminal and triple-negative breast cancers, but had no effect on the LRR risk in patients with HER2-overexpressing cancer. Patients with different molecular subtypes displayed different annual LRR patterns, and the late recurrence of the luminal subtype suggests the necessity of long-term follow-up to evaluate the efficacy of PMRT.

Quality of Life After Partial or Whole-Breast Irradiation in Breast-Conserving Therapy for Low-Risk Breast Cancer: 1-Year Results of a Phase 2 Randomized Controlled Trial.

PURPOSE: To report patients' quality of life (QoL) at 1 year in a phase 2 randomized trial comparing partial breast irradiation (PBI) with whole-breast irradiation (WBI) after breast-conserving surgery (BCS) for breast cancer. METHODS: Women aged ≥ 45 years with low-risk breast cancer after BCS were randomly assigned (1:1) to receive PBI (40 Gy in 10 fractions over 2 weeks) or WBI (43.5 Gy in 15 fractions over 3 weeks). The primary endpoint-the incidence of toxicities of grade 2 or higher-will be reported when participants complete 5 years of follow-up. QoL was assessed at baseline (T0), at the end of radiotherapy (RT) (T1), 6 months (T2) and 1 year (T3) after RT by using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. We calculated the scores for all QOL subscales and differences in mean scores were compared. This study was registered at ClinicalTrials.gov (NCT03583619). RESULTS: Between June 2017 and January 2019, 140 women were randomly assigned to receive PBI or WBI (n = 70 per group). Fifty-nine and 56 patients treated with PBI and WBI, respectively, were eligible for the QoL analysis. There were no significant differences in any subscale scores at T0, T1, T2, or T3 between the PBI and WBI arms. The scores for most QoL subscales that were influenced by RT recovered to a similar or better level relative to T0 scores within 1 year after RT, except for the scores of the dyspnea subscale. Longitudinal analysis showed that time since RT had a significant impact on physical functioning, role functioning, social functioning, fatigue, pain, dyspnea, financial difficulties, body image, and breast and arm symptoms. CONCLUSION: PBI using the intensity-modulated RT affords QoL comparable to that provided by WBI. Most QoL subscale scores that were influenced by RT recovered to a similar or better level relative to baseline scores within 1 year after RT.

Radiotherapy plays an important role in improving the survival outcome in patients with T1-2N1M0 breast cancer - a joint analysis of 4262 real world cases from two institutions.

BACKGROUND: To compare the survival outcomes between breast-conserving surgery (BCS) and modified radical mastectomy (MRM), and to investigate the role of radiotherapy (RT) in patients with pT1-2N1M0 breast cancer. METHODS: A total of 4262 women with T1-2N1M0 breast cancer treated at two institutions were retrospectively reviewed. A total of 3858 patients underwent MRM, and 832 (21.6%) of them received postoperative RT (MRM + RT). A total of 404 patients received BCS plus postoperative RT (BCS + RT). All patients received axillary lymph node dissection, while 3.8% of them had upfront sentinel node biopsy. The association of survival outcomes with different surgical modalities (BCS vs. MRM) and the role of RT were evaluated using multivariable proportional hazards regression and confirmed by the propensity score-matching (PSM) method. RESULTS: At a median follow-up of 71 months (range of 6-230 months), the 5-year overall survival (OS) rates of the BCS and MRM groups were 96.5 and 92.7%, respectively (P = .001), and the corresponding 5-year disease-free-survival (DFS) and locoregional recurrence (LRR) rates were 92.9 and 84.0%, and 2.0 and 7.0% (P = .001), respectively (P < .001). Multivariate analysis revealed that RT was an independent prognostic factor for improved OS (P = .001) and DFS (P = .009), and decreased LRR (P < .001). However, surgery procedure was not independently associated with either OS (P = .495), DFS (P = .204), or LRR (P = .996), which was confirmed by PSM analysis. CONCLUSION: Postoperative radiotherapy rather than the surgery procedures was associated with superior survival outcomes in patients with T1-2N1M0 breast cancer.

Timing of Chemotherapy and Radiotherapy Following Breast-Conserving Surgery for Early-Stage Breast Cancer: A Retrospective Analysis.

PURPOSE: To investigate the effect of chemotherapy and radiotherapy timing after breast conserving surgery (BCS) on recurrence and survival of women with early-stage breast cancer. PATIENTS AND METHODS: We retrospectively analyzed 900 patients who underwent BCS followed by both adjuvant chemotherapy and radiotherapy. Of these, 488 women received chemotherapy first (CT-first group) while the other 412 received radiotherapy first (RT-first group). Locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) rates were calculated using the Kaplan-Meier method and further confirmed with propensity-score matching (PSM) and the Cox proportional hazards model. The optimal cut-off value of interval time from surgery to the start of chemotherapy was calculated by Maxstat. RESULTS: The median follow-up was 7.1 years. In pre-match analysis, the CT-first group had a significantly higher 8-year DFS than the RT-first group (90.4% vs. 83.1%, P = 0.005). PSM analysis of 528 patients indicated that the 8-year DFS (91.0% vs. 83.3%, P = 0.005) and DM (8.6% vs. 14.6%, P = 0.017) were significantly better in the CT-first group, but that the OS (P = 0.096) and LRR (P = 0.434) were similar. We found the optimal cut-off value of interval from surgery to chemotherapy was 12 weeks. Patients starting chemotherapy later than 12 weeks after surgery had significantly inferior survival outcomes. CONCLUSION: For women with breast cancer who require both chemotherapy and radiotherapy after BCS, adjuvant chemotherapy should be started within 12 weeks. Delaying the initiation of radiotherapy, for administration of long-course chemotherapy, does not compromise outcomes.

Hypofractionated Versus Conventional Fractionated Radiotherapy After Breast-Conserving Surgery in the Modern Treatment Era: A Multicenter, Randomized Controlled Trial From China.

PURPOSE: No randomized trials have compared hypofractionated radiotherapy (HFRT) with conventional fractionated radiotherapy (CFRT) after breast-conserving surgery in the Asian population. This study aimed to determine whether a 3.5-week schedule of HFRT is noninferior to a standard 6-week schedule of CFRT in China. PATIENTS AND METHODS: Patients from 4 Chinese institutions who had undergone breast-conserving surgery and had T1-2N0-3 invasive breast cancers participated this study. Patients were randomly assigned (1:1) using a computer-generated central randomization schedule, without stratification, to receive whole-breast irradiation with or without nodal irradiation, followed by tumor-bed boost, either at a dose of 50 Gy in 25 fractions over 5 weeks with a boost of 10 Gy in five fractions over 1 week (CFRT) or 43.5 Gy in 15 fractions over 3 weeks with a boost of 8.7 Gy in three daily fractions (HFRT). The primary endpoint was 5-year local recurrence (LR), and a 5% margin of 5-year LR was used to establish noninferiority. RESULTS: Between August 2010 and November 2015, 734 patients were assigned to the HFRT (n = 368) or CFRT (n = 366) group. At a median follow-up of 73.5 months (interquartile range, 60.5-91.4 months), the 5-year cumulative incidence of LR was 1.2% in the HFRT group and 2.0% in the CFRT group (hazard ratio, 0.62; 95% CI, 0.20 to 1.88; P = .017 for noninferiority). There were no significant differences in acute and late toxicities, except that the HFRT group had less grade 2-3 acute skin toxicity than the CFRT group (P = .019). CONCLUSION: CFRT and HFRT with a tumor-bed boost may have similar low LR and toxicity.

Glucocorticoids impair oocyte competence and trigger apoptosis of ovarian cells via activating the TNF-α system.

Mechanisms by which female stress and particularly glucocorticoids impair oocyte competence are largely unclear. Although one study demonstrated that glucocorticoids triggered apoptosis in ovarian cells and oocytes by activating the FasL/Fas system, other studies suggested that they might induce apoptosis through activating other signaling pathways as well. In this study, both in vivo and in vitro experiments were conducted to test the hypothesis that glucocorticoids might trigger apoptosis in oocytes and ovarian cells through activating the TNF-α system. The results showed that cortisol injection of female mice (1.) impaired oocyte developmental potential and mitochondrial membrane potential with increased oxidative stress; (2.) induced apoptosis in mural granulosa cells (MGCs) with increased oxidative stress in the ovary; and (3.) activated the TNF-α system in both ovaries and oocytes. Culture with corticosterone induced apoptosis and activated the TNF-α system in MGCs. Knockdown or knockout of TNF-α significantly ameliorated the pro-apoptotic effects of glucocorticoids on oocytes and MGCs. However, culture with corticosterone downregulated TNF-α expression significantly in oviductal epithelial cells. Together, the results demonstrated that glucocorticoids impaired oocyte competence and triggered apoptosis in ovarian cells through activating the TNF-α system and that the effect of glucocorticoids on TNF-α expression might vary between cell types.

Role of AMP-activated protein kinase during postovulatory aging of mouse oocytes†.

Studies suggested that postovulatory oocyte aging might be prevented by maintaining a high maturation-promoting factor (MPF) activity. Whether AMP-activated protein kinase (AMPK) plays any role in postovulatory oocyte aging is unknown. Furthermore, while activation of AMPK stimulates meiotic resumption in mouse oocytes, it inhibits meiotic resumption in pig and bovine oocytes. Thus, the species difference in AMPK regulation of oocyte MPF activities is worth in-depth studies. This study showed that AMPK activation with metformin or 5-aminoimidazole- 4-carboxamide- 1-beta-d- ribofuranoside and inactivation with compound C significantly increased and decreased, respectively, the activation susceptibility (AS) and other aging parameters in aging mouse oocytes. While AMPK activity increased, MPF activity and cyclic adenosine monophosphate (cAMP) decreased significantly with time post ovulation. In vitro activation and inactivation of AMPK significantly decreased and increased the MPF activity, respectively. MPF upregulation with MG132 or downregulation with roscovitine completely abolished the effects of AMPK activation or inactivation on AS of aging oocytes, respectively. AMPK facilitated oocyte aging with increased reactive oxygen species (ROS) and cytoplasmic calcium. Furthermore, treatment with Ca2+/calmodulin-dependent protein kinase (CaMK) inhibitors significantly decreased AS and AMPK activation. Taken together, the results suggested that AMPK facilitated oocyte aging through inhibiting MPF activities, and postovulatory oocyte aging activated AMPK with decreased cAMP by activating CaMKs via increasing ROS and cytoplasmic calcium.

Radiation-Induced Lymphopenia Predicts Poorer Prognosis in Patients With Breast Cancer: A Post Hoc Analysis of a Randomized Controlled Trial of Postmastectomy Hypofractionated Radiation Therapy.

PURPOSE: The aim of this study was to determine whether radiation-induced lymphopenia affects the survival of patients with breast cancer. METHODS AND MATERIALS: Post hoc analysis was conducted on data from 598 patients with breast cancer from a randomized controlled trial comparing postmastectomy hypofractionated radiation therapy (HFRT; 43.5 Gy in 15 fractions over 3 weeks) with conventional fractionated radiation therapy (CFRT; 50 Gy in 25 fractions over 5 weeks). Mean peripheral lymphocyte count (PLC) at different time points in the 2 groups was compared by the t test. Disease-free survival and overall survival were analyzed by the Kaplan-Meier method and compared between groups by the log-rank test. RESULTS: Baseline PLC (pre-PLC) was comparable between HFRT and CFRT patients (1.60 ± 0.57 × 109/L vs 1.56 ± 0.52 × 109/L; P = .33). In both groups, the PLC declined steadily during the course of radiation therapy but started to recover at 1 month after radiation therapy. Incidence of lymphopenia was significantly lower in HFRT patients (45.4% vs 55.7%; P = .01). Nadir-PLC was significantly higher in HFRT patients (1.08 ± 0.37 × 109/L vs 0.97 ± 0.31× 109/L; P < .001), as was the nadir-PLC/pre-PLC ratio (0.72 ± 0.28 vs 0.67 ± 0.28; P = .02). Median follow-up was 57.6 months (interquartile range, 38.5-81.4). The 5-year disease-free survival was significantly lower in patients with a nadir-PLC/pre-PLC ratio <0.8 than in those with a ratio ≥0.8 (71.8% vs 82.6%; P = .01); however, overall survival was comparable between the groups (85.8% vs 90.6%; P = .24). CONCLUSIONS: The risk of radiation-induced lymphopenia in patients with breast cancer is lower with HFRT than with CFRT. A low nadir-PLC/pre-PLC ratio may predict poor prognosis.

Trastuzumab Provides a Comparable Prognosis in Patients With HER2-Positive Breast Cancer to Those With HER2-Negative Breast Cancer: Post Hoc Analyses of a Randomized Controlled Trial of Post-Mastectomy Hypofractionated Radiotherapy.

BACKGROUND AND PURPOSE: We investigated the locoregional effect of trastuzumab, and determined whether patients with human epidermal growth factor receptor (HER)2-positive breast cancer (BC) treated with trastuzumab could achieve comparable efficacy to that of patients with HER2-negative BC. MATERIALS AND METHODS: This was post hoc analyses of data of 793 BC patients from a randomized controlled trial comparing post-mastectomy hypofractionated radiotherapy with conventional fractionated radiotherapy. Survival rates were analyzed by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Patients were classified into three groups: HER2-negative (HER2-; n = 547), HER2-positve with trastuzumab (HER2+ + T; n = 136), and HER2-positive without trastuzumab (HER2+ - T; n = 110). The HER2+ + T group had significantly lower locoregional recurrence (LRR, 6.0% vs. 13.9%), distant metastasis (DM, 17.4% vs. 33.8%) and higher disease-free survival (DFS, 81.2% vs. 61.9%) at 5 years than that of the HER2+ - T group (P <.05). The HER2- group had significantly lower LRR (6.8% vs. 13.9%), DM (22.4% vs. 33.8%) and higher DFS (76.1% vs. 61.9%) at 5 years than that of the HER2+ - T group (P <.05). The difference in LRR, DM and DFS at 5 years was not significant between the HER2+ + T group and HER2- group (P >.05). Different annual LRR patterns was found among groups according to HR status. CONCLUSION: Trastuzumab reduces LRR in patients with locally advanced HER2-positive BC who have received post-mastectomy radiotherapy. It provides comparable DFS to that with patients with HER2-negative BC.

Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.

BACKGROUND: To our knowledge, no randomised study has compared postmastectomy hypofractionated radiotherapy with conventional fractionated radiotherapy in patients with breast cancer. This study aimed to determine whether a 3-week schedule of postmastectomy hypofractionated radiotherapy is as efficacious and safe as a 5-week schedule of conventional fractionated radiotherapy. METHODS: This randomised, non-inferiority, open-label, phase 3 study was done in a single academic hospital in China. Patients aged 18-75 years who had undergone mastectomy and had at least four positive axillary lymph nodes or primary tumour stage T3-4 disease were eligible to participate. Patients were randomly assigned (1:1) according to a computer-generated central randomisation schedule, without stratification, to receive chest wall and nodal irradiation at a dose of 50 Gy in 25 fractions over 5 weeks (conventional fractionated radiotherapy) or 43·5 Gy in 15 fractions over 3 weeks (hypofractionated radiotherapy). The modified intention-to-treat population (including all eligible patients who underwent randomisation but excluding those who were considered ineligible or withdrew consent after randomisation) was used in primary and safety analyses. The primary endpoint was 5-year locoregional recurrence, and a 5% margin was used to establish non-inferiority (equivalent to a hazard ratio <1·883). This trial is registered at ClinicalTrials.gov, number NCT00793962. FINDINGS: Between June 12, 2008, and June 16, 2016, 820 patients were enrolled and randomly assigned to the conventional fractionated radiotherapy group (n=414) or hypofractionated radiotherapy group (n=406). 409 participants in the conventional fractionated radiotherapy group and 401 participants in the hypofractionated radiotherapy group were included in the modified intention-to-treat analyses. At a median follow-up of 58·5 months (IQR 39·2-81·8), 60 (7%) patients had developed locoregional recurrence (31 patients in the hypofractionated radiotherapy group and 29 in the conventional fractionated radiotherapy group); the 5-year cumulative incidence of locoregional recurrence was 8·3% (90% CI 5·8-10·7) in the hypofractionated radiotherapy group and 8·1% (90% CI 5·4-10·6) in the conventional fractionated radiotherapy group (absolute difference 0·2%, 90% CI -3·0 to 2·6; hazard ratio 1·10, 90% CI 0·72 to 1·69; p<0·0001 for non-inferiority). There were no significant differences between the groups in acute and late toxicities, except that fewer patients in the hypofractionated radiotherapy group had grade 3 acute skin toxicity than in the conventional fractionated radiotherapy group (14 [3%] of 401 patients vs 32 [8%] of 409 patients; p<0·0001). INTERPRETATION: Postmastectomy hypofractionated radiotherapy was non-inferior to and had similar toxicities to conventional fractionated radiotherapy in patients with high-risk breast cancer. Hypofractionated radiotherapy could provide more convenient treatment and allow providers to treat more patients. FUNDING: National Key Projects of Research and Development of China; the Chinese Academy of Medical Science Innovation Fund for Medical Sciences; and Beijing Marathon of Hope, Cancer Foundation of China.

Cumulus cell-released tumor necrosis factor (TNF)-α promotes post-ovulatory aging of mouse oocytes.

Although previous studies indicated that cumulus cells (CCs) accelerate oocyte aging by releasing soluble factors, the factors have yet to be characterized. While demonstrating that CCs promoted oocyte aging by releasing soluble Fas ligand (sFasL), our recent study suggested that CCs might secrete other factors to mediate oocyte aging as well. This study tested whether CCs accelerate oocyte aging by secreting tumor necrosis factor (TNF)-α. The results showed that mouse CCs undergoing apoptosis released soluble TNF-α (sTNF-α) during in vitro aging. While ethanol activation rates were higher, the maturation-promoting factor (MPF) activity was lower significantly after culture of cumulus-denuded oocytes (DOs) in medium conditioned with CCs for 36 h than in medium conditioned for 24 h. Aging mouse oocytes expressed TNF-receptor 1. The CCs released equal amounts of sTNF-α and sFasL during aging in vitro, and the TNF-α-knockdown CCs secreted less sFasL than the control CCs did. Treatment of DOs in vitro with sTNF-α significantly accelerated their aging. The aging-promoting effect of sTNF-α was significantly reduced in TNF-α-knocked-down CCs and in CCs from the TNF-α-knockout mice. It is concluded that mouse CCs accelerate oocyte aging by secreting sTNF-α as well as sFasL.

Mechanisms for the species difference between mouse and pig oocytes in their sensitivity to glucorticoids.

Although in vitro exposure to physiological concentrations of glucorticoids did not affect maturation of mouse oocytes, it significantly inhibited nuclear maturation of pig oocytes. Studies on this species difference in oocyte sensitivity to glucocorticoids will contribute to our understanding of how stress/glucocorticoids affect oocytes. We showed that glucorticoid receptors (NR3C1) were expressed in both oocytes and cumulus cells (CCs) of both pigs and mice; however, while cortisol inhibition of oocyte maturation was overcome by NR3C1 inhibitor RU486 in pigs, it could not be relieved by RU486 in mice. The mRNA level of 11ß-hydroxysteroid dehydrogenase 1 (HSD11B1) was significantly higher than that of HSD11B2 in pig cumulus-oocyte complexes (COCs), whereas HSD11B2 was exclusively expressed in mouse COCs. Pig and mouse cumulus-denuded oocytes (DOs) expressed HSD11B2 predominantly and exclusively, respectively. In the presence of cortisol, although inhibiting HSD11B2 decreased maturation rates of COCs in both species, inhibiting HSD11B1 improved maturation of pig COCs while having no effect on mouse COCs. Cortisol-cortisone interconversion observation confirmed high HSD11B1 activities in pig oocytes but none in mouse oocytes, a higher HSD11B2 activity in mouse than in pig oocytes, and a rapid cortisol-cortisone interconversion in pig COCs catalyzed by HSD11B1 from CCs and HSD11B2 from DOs. In conclusion, the species difference in glucocorticoid sensitivity between pig and mouse oocytes is caused by their different contents/ratios of HSD11B1 and HSD11B2, which maintain different concentrations of active glucocorticoids. While cortisol inhibited pig oocytes by interacting with NR3C1, glucocorticoid suppression of mouse oocytes was apparently not mediated by NR3C1.

[Distribution characteristic and bioaccessibility of lead in kindergarten dust of Wuhan City].

The characteristics of lead pollution and the associated health risk of children for the dust samples from 69 representative kindergartens in different type districts of Wuhan were investigated. Total lead concentration and bioaccessibility according to physiologically based extraction test (PBET) were determined. Results showed that the levels of lead concentration in dust ranged from 36.3 to 1 523 mg x kg(-1) with an average value of 169 mg x kg(-1), lower than published data from other areas. The great spatial variation of Pb in dust indicated that specific sites have been seriously contaminated by Pb. The bioaccessibilities of Pb in dusts were 35% +/- 15% at gastric phases and 7.6% +/- 5.8% at intestinal phases. According to the predicted model with the Integration Exposure Uptake Biokinetic Model (IEUBK), the geometric mean blood lead of children (0-6 years) was 2.73 microg x dL(-1), of which over 10 microg x dL(-1) was less than 0.001% and exceeded 5 microg x dL(-1) was 3.32%.