Organoid forming potential as complementary parameter for accurate evaluation of breast cancer neoadjuvant therapeutic efficacy.

BACKGROUND: 13-15% of breast cancer/BC patients diagnosed as pathological complete response/pCR after neoadjuvant systemic therapy/NST suffer from recurrence. This study aims to estimate the rationality of organoid forming potential/OFP for more accurate evaluation of NST efficacy. METHODS: OFPs of post-NST residual disease/RD were checked and compared with clinical approaches to estimate the recurrence risk. The phenotypes of organoids were classified via HE staining and ER, PR, HER2, Ki67 and CD133 immuno-labeling. The active growing organoids were subjected to drug sensitivity tests. RESULTS: Of 62 post-NST BC specimens, 24 were classified as OFP-I with long-term active organoid growth, 19 as OFP-II with stable organoid growth within 3 weeks, and 19 as OFP-III without organoid formation. Residual tumors were overall correlated with OFP grades (P < 0.001), while 3 of the 18 patients (16.67%) pathologically diagnosed as tumor-free (ypT0N0M0) showed tumor derived-organoid formation. The disease-free survival/DFS of OFP-I cases was worse than other two groups (Log-rank P < 0.05). Organoids of OFP-I/-II groups well maintained the biological features of their parental tumors and were resistant to the drugs used in NST. CONCLUSIONS: The OFP would be a complementary parameter to improve the evaluation accuracy of NST efficacy of breast cancers.

The Impact of Baseline 25-Hydroxyvitamin D Level and Gestational Age on Prenatal Vitamin D Supplementation to Prevent Offspring Asthma or Recurrent Wheezing.

BACKGROUND: Prenatal vitamin D deficiency is associated with asthma or recurrent wheezing in offspring. However, evidence from randomized trials on the efficacy of vitamin D supplementation is inconclusive. OBJECTIVES: We aimed to examine the differential efficacy of prenatal vitamin D supplementation based on the maternal baseline vitamin D status and the starting time of supplementation to prevent early life asthma or recurrent wheezing. METHODS: We conducted a secondary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized double-blind trial of prenatal vitamin D supplementation initiated at 10-18 weeks (wks) of gestation (4400 IU of intervention/day compared with 400 IU of placebo/day) to prevent offspring asthma or recurrent wheezing by the age of 6 years. We assessed the effect of modification of supplementation by maternal baseline vitamin D status at enrollment and the timing of initiation of supplementation. RESULTS: An inverse relationship was observed between maternal 25-hydroxyvitamin D (25(OH)D) levels at trial entry and 25(OH)D levels during late pregnancy (32-38 wks of gestation) in both supplementation arms (P < 0.001). Overall, supplementation efficacy was not dependent on the maternal baseline 25(OH)D status. However, a trend toward the reduction of asthma or recurrent wheezing was observed across the baseline groups in the intervention arm (P = 0.01), with the greatest reduction observed in the most severely vitamin D-deficient women (25(OH)D < 12 ng/mL; adjusted odds ratio [aOR] = 0.48; confidence interval [CI]: 0.17, 1.34). Gestational age at trial enrollment modified supplementation efficacy, showing a greater reduction of offspring asthma or recurrent wheezing with earlier intervention during pregnancy (aOR = 0.85; CI = 0.76, 0.95), particularly in women who were 9-12 wk pregnant (aOR = 0.45; CI = 0.24, 0.82). CONCLUSIONS: Pregnant women with severe vitamin D deficiency show the greatest 25(OH)D improvement because of supplementation. In these women, a vitamin D dose of 4400 IU might have a preventive role in the development of early life offspring asthma or recurrent wheezing. Gestational age is suggested to modify the efficacy of prenatal vitamin D supplementation, showing the highest beneficial effect if supplementation is started during the first trimester of pregnancy. This study is an ancillary analysis from the VDAART, which is registered in ClinicalTrials.gov as NCT00902621.

Higher efficacy of resveratrol against advanced breast cancer organoids: A comparison with that of clinically relevant drugs.

The lack of reliable drugs is a therapeutic challenge of advanced breast cancers (ABCs). Resveratrol (Res) exerts inhibitory effects on breast cancer cell lines and animal models, while its efficacy against individual breast cancer cases remains unknown. This study aims to use ABC-derived organoids (ABCOs) as the ex vivo therapeutic platform to clarify the effectiveness of resveratrol against different ABC subtypes. Immunohistochemical staining confirmed that the ABCOs maintained their original tumors' ER, PR, HER2, and Ki67 expression patterns. ABCO proliferation and viability tests showed >50% cell death rates in 79.2% (19/24) of Res-treated, 28.6% (2/7) fulvestrant-treated, 66.7% (4/6) paclitaxel-treated, and 66.7% (6/9) gemcitabine-treated ABCOs. pSTAT3 nuclear translocation was more frequent in Res-sensitive (17/19; 89.47%) than that (1/5; 20%) of Res-insensitive ABCOs, which were suppressed upon Res treatment. Statistical analysis revealed a close correlation of STAT3 activation with the efficacy of Res, but not related to tumor receptor expression patterns (ER, PR, HER2) and pathological classification. We demonstrate for the first time the higher efficacy and broader spectrum of Res against different subtypes of ABCOs in comparison with that of conventional antibreast cancer drugs, providing an alternative approach for better management of ABCs.

The Association of Prenatal Vitamin D Sufficiency With Aeroallergen Sensitization and Allergic Rhinitis in Early Childhood.

BACKGROUND: The role of prenatal vitamin D sufficiency and supplementation in the development of childhood aeroallergen sensitization and allergic rhinitis remains uncertain. OBJECTIVE: To describe the association of prenatal vitamin D sufficiency with childhood allergic outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial, a randomized controlled trial of prenatal vitamin D supplementation. METHODS: We included 414 mother-offspring pairs with offspring aeroallergen sensitization data available at age 6 years in this analysis. We examined the association between prenatal vitamin D sufficiency status, based on vitamin D levels measured in the first and third trimesters, or vitamin D supplementation treatment assignment with the outcomes of aeroallergen sensitization, parent-reported clinical allergic rhinitis, parent-reported clinical allergic rhinitis with aeroallergen sensitization, food sensitization, any sensitization, eczema, and total IgE at ages 3 and 6 years. RESULTS: Compared with early and late insufficiency, early prenatal vitamin D insufficiency with late sufficiency was associated with reduced development of clinical allergic rhinitis with aeroallergen sensitization at 3 years (adjusted odds ratio [aOR] = 0.34; 95% confidence interval [CI], 0.13-0.82; P = .02) and 6 years (aOR = 0.54; 95% CI, 0.29-0.98; P = .05). At 6 years, clinical allergic rhinitis with sensitization was significantly decreased in offspring whose mothers received high-dose vitamin D (aOR = 0.54; 95% CI, 0.32-0.91; P = .02) compared with offspring whose mothers who received low-dose vitamin D. Associations of prenatal vitamin D with aeroallergen sensitization were strengthened among children who also developed asthma or who had a maternal history of atopy. CONCLUSIONS: Among mothers with first-trimester vitamin D insufficiency, we detected a protective effect of third-trimester prenatal vitamin D sufficiency on the development of clinical allergic rhinitis with aeroallergen sensitization at ages 3 and 6 years.

Effect of early and late prenatal vitamin D and maternal asthma status on offspring asthma or recurrent wheeze.

BACKGROUND: Childhood asthma developmental programming is complex. Maternal asthma is a strong risk factor for childhood asthma, whereas vitamin D (VD) has emerged as a modifiable prenatal exposure. OBJECTIVE: Our aim was to examine the combined effect of early and late prenatal VD status in during pregnancies in women with and without asthma on childhood asthma or recurrent wheeze development. METHODS: We conducted a cohort study using prospectively collected data from the Vitamin D Antenatal Asthma Reduction Trial, a randomized, double-blinded, placebo-controlled VD supplementation trial in pregnant women at high risk of offspring asthma (N = 806 mother-offspring pairs). 25-Hydroxyvitamin-D (25(OH)D) level was measured in early and late pregnancy. Our main exposure was an ordered variable representing early and late prenatal VD sufficiency (25(OH)D level ≥ 30 ng/mL) status during pregnancy in women with and without asthma. The primary outcome was offspring with asthma or recurrent wheeze by age 3 years. We also examined the effect of prenatal VD level on early life asthma or recurrent wheeze progression to active asthma at age 6 years. RESULTS: Among mothers with asthma versus among mothers with early and late prenatal VD insufficiency, those with early or late VD sufficiency (adjusted odds ratio = 0.56; 95% CI = 0.31-1.00) or early and late VD sufficiency (adjusted odds ratio = 0.36; 95% CI = 0.15-0.81) had a lower risk of offspring with asthma or recurrent wheeze by age 3 years (Pfor trend = .008). This protective trend was reiterated in asthma or recurrent wheeze progression to active asthma from age 3 to 6 years (Pfor trend = .04). CONCLUSION: This study implies a protective role for VD sufficiency throughout pregnancy, particularly in attenuating the risk conferred by maternal asthma on childhood asthma or recurrent wheeze development.

Determinants and Measurement of Neonatal Vitamin D: Overestimation of 25(OH)D in Cord Blood Using CLIA Assay Technology.

CONTEXT: Vitamin D (VD) deficiency in pregnancy and the neonatal period has impacts on childhood outcomes. Maternal VD sufficiency is crucial for sufficiency in the neonate, though the effect of early versus late pregnancy 25-hydroxy-vitamin D (25(OH)D) levels on neonatal levels is unknown. Furthermore, chemiluminescence immunoassays (CLIAs) are widely used, though their validity in measuring 25(OH)D specifically in cord blood specimens has not been established. OBJECTIVE: To assess the validity of a CLIA in the measurement of cord blood 25(OH)D and to evaluate maternal determinants of neonatal 25(OH)D, including early versus late pregnancy 25(OH)D levels. DESIGN: This is an ancillary analysis from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized, double-blinded, placebo-controlled study. PARTICIPANTS AND INTERVENTION: A total of 881 pregnant women at high risk of having offspring asthma were randomized to receive VD supplementation or placebo. Serum samples were collected from mothers in early and late pregnancy and from offspring cord blood at birth. 25(OH)D levels were assayed by CLIA in all maternal and offspring samples and by LC-MS/MS in all offspring samples and a subset of 200 maternal third trimester samples. RESULTS: Cord blood 25(OH)D levels were higher as measured by CLIA (mean 37.13 ng/mL [SD 18.30]) than by LC-MS/MS (mean 23.54 ng/mL [SD 11.99]), with a mean positive bias of 13.54 ng/mL (SD 12.92) by Bland-Altman analysis. This positive bias in measurement by CLIA was not observed in maternal samples. Third trimester 25(OH)D was a positive determinant of neonatal 25(OH)D levels. CONCLUSION: Chemiluminescence immunoassays overestimate 25(OH)D levels in human cord blood samples, an effect not observed in maternal blood samples. The quantification of 25(OH)D by CLIA should therefore not be considered valid when assayed in cord blood samples. Third trimester, but not first trimester, maternal 25(OH)D is one of several determinants of neonatal 25(OH)D status.