Ovine Fetal Thymus Response to Lipopolysaccharide-Induced Chorioamnionitis and Antenatal Corticosteroids

RATIONALE: Chorioamnionitis is associated with preterm delivery and involution of the fetal thymus. Women at risk of preterm delivery receive antenatal corticosteroids which accelerate fetal lung maturation and improve neonatal outcome. However, the effects of antenatal corticosteroids on the fetal thymus in the settings of chorioamnionitis are largely unknown. We hypothesized that intra-amniotic exposure to lipopolysaccharide (LPS) causes involution of the fetal thymus resulting in persistent effects on thymic structure and cell populations. We also hypothesized that antenatal corticosteroids may modulate the effects of LPS on thymic development. METHODS: Time-mated ewes with singleton fetuses received an intra-amniotic injection of LPS 7 or 14 days before preterm delivery at 120 days gestational age (term = 150 days). LPS and corticosteroid treatment groups received intra-amniotic LPS either preceding or following maternal intra-muscular betamethasone. Gestation matched controls received intra-amniotic and maternal intra-muscular saline. The fetal intra-thoracic thymus was evaluated. RESULTS: Intra-amniotic LPS decreased the cortico-medullary (C/M) ratio of the thymus and increased Toll-like receptor (TLR) 4 mRNA and CD3 expression indicating involution and activation of the fetal thymus. Increased TLR4 and CD3 expression persisted for 14 days but Foxp3 expression decreased suggesting a change in regulatory T-cells. Sonic hedgehog and bone morphogenetic protein 4 mRNA, which are negative regulators of T-cell development, decreased in response to intra-amniotic LPS. Betamethasone treatment before LPS exposure attenuated some of the LPS-induced thymic responses but increased cleaved caspase-3 expression and decreased the C/M ratio. Betamethasone treatment after LPS exposure did not prevent the LPS-induced thymic changes. CONCLUSION: Intra-amniotic exposure to LPS activated the fetal thymus which was accompanied by structural changes. Treatment with antenatal corticosteroids before LPS partially attenuated the LPS-induced effects but increased apoptosis in the fetal thymus. Corticosteroid administration after the inflammatory stimulus did not inhibit the LPS effects on the fetal thymus

CTCs-derived xenograft development in a Triple Negative breast cancer case

Triple-negative breast cancer (TNBC) is characterized by high rates of metastasis and no available molecular targets. CTCs derived xenografts (CDX) have demonstrated to be a promising tool for understanding cancer biology. In our study, a CDX from a TNBC patient was developed for the first time. After CDX characterization, WNT signaling was found as the main mechanism related with this tumor biology and potential CTCs markers were identified and subsequently validated in TNBC patients. In this cohort high levels of MELK expression were associated with poorer survival rates. Overall, our study demonstrates that CTCs from TNBC are tumorigenic and CDXs are a useful model to obtain valuable information about the tumor

Abstract P1-14-13: Residual proliferative cancer burden (RPCB) is superior to RCB index as prognostic tool in early breast cancer patients (EBC) treated with neoadjuvant chemotherapy (NAC)

Abstract BACKGROUND: Many different scales have been developed in order to assess response to NAC. Apart from Miller and Payne and RCB systems, recently the addiction of post-NAC pathological Ki 67 (yp Ki67) to RCB, called RPCB system, has been considered as a more accurate prognostic tool. The aim of this study is to assess the prognosis value of RPCB in a routine practice cohort and to compare it to RCB index and ypKi67. METHODS: We performed a retrospective analysis of our database. Patients with stage I-III considered candidate for NAC from July 2008 and August 2011 were included. RPCB and RCB were calculated as previously published. Hormone receptor expression (HR), ypKi 67 and Her2 were assessed following international guidelines. The Harell c-index were used to compare the prognostic value of RPCB, RCB and ypKi 67. Clinical, therapeutic and pathological data were obtained from medical records. A correlation with disease-free survival (DFS) and overall survival (OS) was done using the Kaplan-Meier method and Cox regression model. RESULTS: From our database including 333 EBC patients treated with NAC 184 had data to calculate RPCB, RCB and ypKi 67, of whom 51.6% were HR+Her2- tumours, 21.7% HR+Her2+, 8.2% HR- Her2+ and 18.5% triple negative. Mean tumour size was 37.5 mm (25-45). The majority of the patients had histhological grade II-III tumours (84.2%) and N stage 0-1 (96.7%). 67.4% of the patients received anthracycline and taxane-based NAC, associated to trastuzumab in Her2+ patients (26.1%). Pathological complete response by subtypes were 6.3%, 17.5%, 60% and 26.5%, respectively. With a median follow-up of 49.9 months, DFS and OS at 36 months were 85.2% and 95.1%. In the multivariate analysis all three systems were prognostic for DFS (RPCB p&amp;lt;0.001; RCB p=0.001; ypKi 67 p= 0.002) and OS (RPCB p&amp;lt;0.001; RCB p=0.011; ypKi 67 p= 0.037). Comparison of Harell c-index for DFS between RCPB and RCB showed a trend of RPCB towards a more accurate prognostic power (0.89 vs 0.81, p=0.061) that was significant when comparing RCPB vs ypKi67 and RPCB vs ypKi67 (0.89 vs 0.77, p=0.010). However no statistically differences were found in terms of OS (RPCB vs RCB 0.85 vs 0.82, p=0.357 and RPCB vs ypKi67 0.85 vs 0.72, p= 0.088). CONCLUSION: RPCB, RCB and ypKi67 are prognostic for both DFS and OS in EBC patients treated with NAC. RPCB is a more accurate prognostic tool than ypKi67 and showed a trend towards superiority compared to RCB. Citation Format: Pons V, Pérez-Fidalgo JA, Burgués O, Martín P, Cejalvo JM, Bermejo B, LLuch A. Residual proliferative cancer burden (RPCB) is superior to RCB index as prognostic tool in early breast cancer patients (EBC) treated with neoadjuvant chemotherapy (NAC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-13.</jats:p

Circulating miR-30b-5p levels in plasma as a novel potential biomarker for early detection of breast cancer

Background: Recently, microRNAs have been demonstrated to be potential non-invasive biomarkers for diagnosis, prognosis assessment or prediction of response to treatment in cancer. In this study, we evaluate the potential of miR-30b-5p as a biomarker for early diagnosis of breast cancer (BC) in tissue and plasma. Methods: Expression of miR-30b-5p was determined in a series of 112 BC and 40 normal breast tissues. Circulating miR- 30b-5p levels in plasma samples were determined in a discovery cohort of 38 BC patients and 40 healthy donors and in a validation cohort of 83 BC patients and 83 healthy volunteers. miR-30b-5p expression was measured by quantitative real-time PCR and receiver operating characteristics curve analysis was carried out. Results: The miR-30b-5p expression was significantly lower in BC tissue than in healthy breast samples. In contrast, circulating miR-30b-5p levels were significantly higher in BC patients compared with healthy donors. Furthermore, circulating miR-30b-5p levels were significantly higher in patients with positive axillary lymph node and de novo metastatic patients. Receiver operating characteristics curve analysis demonstrated a good diagnostic potential of miR-30b-5p to detect BC even at an early stage of the disease. Conclusion: Thus, we highlight the potential of miR-30b-5p as a non-invasive, fast, reproducible and cost-effective diagnostic biomarker of BC

Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine

Purpose: Predictive biomarkers for capecitabine benefit in triple-negative breast cancer (TNBC) have been recently proposed using samples from phase III clinical trials, including non-basal phenotype and biomarkers related to angiogenesis, stroma, and capecitabine activation genes. We aimed to validate these findings on the larger phase III GEICAM/CIBOMA clinical trial. Experimental Design: Tumor tissues from patients with TNBC randomized to standard (neo)adjuvant chemotherapy followed by capecitabine versus observation were analyzed using a 164-gene NanoString custom nCounter codeset measuring mRNA expression. A prespecified statistical plan sought to verify the predictive capacity of PAM50 non-basal molecular subtype and tested the hypotheses that breast tumors with increased expression of (meta) genes for cytotoxic cells, mast cells, endothelial cells, PDL2, and 38 individual genes benefit from adjuvant capecitabine for distant recurrence-free survival (DRFS; primary endpoint) and overall survival. Results: Of the 876 women enrolled in the GEICAM/CIBOMA trial, 658 (75%) were evaluable for analysis (337 with capecitabine and 321 without). Of these cases, 553 (84%) were profiled as PAM50 basal-like whereas 105 (16%) were PAM50 non-basal. Non-basal subtype was the most significant predictor for capecitabine benefit [HRcapecitabine, 0.19; 95% confidence interval (CI), 0.07–0.54; P < 0.001] when compared with PAM50 basal-like (HRcapecitabine, 0.9; 95% CI, 0.63–1.28; P = 0.55; Pinteraction<0.001, adjusted P value = 0.01). Analysis of biological processes related to PAM50 non-basal subtype revealed its enrichment for mast cells, extracellular matrix, angiogenesis, and features of mesenchymal stem-like TNBC subtype. Conclusions: In this prespecified correlative analysis of the GEICAM/CIBOMA trial, PAM50 non-basal status identified patients with early-stage TNBC most likely to benefit from capecitabine. © 2022 The Authors