Novel nomograms for predicting survival for immediate breast reconstruction patients diagnosed with invasive breast cancer-a single-center 15-year experience.

Background: Immediate breast reconstruction is widely accepted following oncologic mastectomy. This study aimed to build a novel nomogram predicting the survival outcome for Chinese patients undergoing immediate reconstruction following mastectomy for invasive breast cancer. Methods: A retrospective review of all patients undergoing immediate reconstruction following treatment for invasive breast cancer was performed from May 2001 to March 2016. Eligible patients were assigned to a training set or a validation set. Univariate and multivariate Cox proportional hazard regression models were used to select associate variables. Two nomograms were developed based on the training cohort for breast cancer-specific survival (BCSS) and disease-free survival (DFS). Internal and external validations were performed, and the C-index and calibration plots were generated to evaluate the performance (discrimination and accuracy) of the models. Results: The 10-year estimated BCSS and DFS were 90.80% (95% CI: 87.30%-94.40%) and 78.40% (95% CI: 72.50%-84.70%), respectively, in the training cohort. In the validation cohort, they were and 85.60% (95% CI, 75.90%-96.50%) and 84.10% (95% CI, 77.80%-90.90%), respectively. Ten independent factors were used to build a nomogram for prediction of 1-, 5- and 10-year BCSS, while nine were used for DFS. The C-index was 0.841 for BCSS and 0.737 for DFS in internal validation, and the C-index was 0.782 for BCSS and 0.700 for DFS in external validation. The calibration curve for both BCSS and DFS demonstrated acceptable agreement between the predicted and actual observation in the training and the validation cohorts. Conclusion: The nomograms provided valuable visualization of factors predicting BCSS and DFS in invasive breast cancer patients with immediate breast reconstruction. The nomograms may have tremendous potential in guiding individualized decision-making for physicians and patients in choosing the optimized treatment methods.

Enhancer reprogramming promotes the activation of cancer-associated fibroblasts and breast cancer metastasis.

Rationale: Cancer associated fibroblasts (CAFs) are a subpopulation of cells within the tumor microenvironment that usually promote cancer progression and metastasis. Hence it is critical to find out the driving factors and mechanisms for the development of CAFs from normal fibroblasts (NFs) in response to sustained stimulation of cancer cells. Here we perform transcriptomic and epigenomic analyses in paired NFs and CAFs associated with breast cancer metastasis to investigate the molecular mechanisms for stromal fibroblasts reprogramming. Methods: We conducted transcriptomic analyses in paired NFs and CAFs isolated from clinical specimens of breast cancer patients with metastasis. Meanwhile, genome-wide mapping of histone marks H3K4me1 and H3K27ac was also performed to characterize CAF-specific enhancer landscape. The function and mechanisms of activated JUN in stromal fibroblasts were studied using in vitro and in vivo models. Results: We have identified CAF-specific signature genes and activated enhancers, which are significantly associated with pro-metastatic programs. Among the CAF activated enhancers, FOS and JUN family of transcription factors are enriched. In line with this, we find that JUN protein is highly activated in the stroma of metastatic breast cancers. And through gain and loss-of-function studies, we demonstrate that activated JUN is necessary and sufficient to remodel enhancers and maintain the activation of CAF-specific enhancers, and thereby promotes breast cancer invasiveness in a non-cell-autonomous manner. Conclusions: Our study gets an insight into the transcriptomic features of invasive breast stroma and transcription regulatory mechanisms for stroma cell transformation, providing a proof-of-concept of stroma-targeting strategy in cancer treatment.

A Single-Center Retrospective Analysis of Local and Distant Relapse of Breast Cancer Following Immediate Breast Reconstruction According to Molecular Subtypes.

Purpose: Concerns have been raised about the oncologic safety of immediate breast reconstruction (IBR) following mastectomy for breast cancer. This study aimed to evaluate locoregional recurrence (LRR) and distant metastasis (DM) of breast cancer according to its molecular subtype in patients who underwent mastectomy alone or IBR after mastectomy. Methods: In this retrospective cohort study, consecutive breast cancer patients treated by the single senior surgeon (XZ) between February 2010 and December 2014 were eligible. In total, 389 consecutive patients were included; 295 patients underwent mastectomy alone and 94 patients underwent mastectomy with IBR. Data were retrospectively collected and analyzed for LRR and DM stratified by molecular subtypes. Results: With a median follow-up of 73 and 87.5 months, 1.69% of patients in the mastectomy alone group developed LRR compared to 0% in the reconstruction group (p = 0.342) and the total incidence of DMs was 11.52% in patients who received mastectomy alone and 7.44% in patients who received postmastectomy IBR (p = 0.262), respectively. The cumulative incidence of LRR was 2.1% vs. 0% for luminal A, 0% vs. 0% for luminal B, 0% vs. 0% for human epidermal growth factor receptor 2 (HER2)-enriched, and 4.5% vs. 0% for triple-negative in the mastectomy alone group compared to the postmastectomy IBR group. The cumulative incidence of DM was 15.5% vs. 5.7% for luminal A, 10% vs. 8.7% for luminal B, 17.3% vs. 0% for HER2-enriched, and 6.8% vs. 7.1% for triple-negative in the mastectomy alone group compared to the postmastectomy IBR group. On multivariable Cox regression analysis, lymph node metastasis was associated with an increased risk of DM in the mastectomy alone group (p = 0.03) and neoadjuvant chemotherapy was associated with an increased risk of DM in the postmastectomy IBR group (p = 0.021). Conclusion: This study suggests that IBR does not have a negative impact on the LRR and DM of breast cancer according to molecular subtypes.

Comparison of outcomes between immediate implantbased and autologous reconstruction: 15-year, single-center experience in a propensity score-matched Chinese cohort.

OBJECTIVE: The number of immediate breast reconstruction (IBR) procedures has been increasing in China. This study aimed to investigate the oncological safety of IBR, and to compare the survival and surgical outcomes between implant-based and autologous reconstruction. METHODS: Data from patients diagnosed with invasive breast cancer who underwent immediate total breast reconstruction between 2001 and 2016 were retrospectively reviewed. Long-term breast cancer-specific survival (BCSS), disease-free survival (DFS), and locoregional recurrence-free survival (LRFS) were evaluated. Patient satisfaction with the breast was compared between the implant-based and autologous groups. BCSS, DFS, and LRFS were compared between groups after propensity score matching (PSM). RESULTS: A total of 784 IBR procedures were identified, of which 584 were performed on patients with invasive breast cancer (implant-based, n = 288; autologous, n = 296). With a median follow-up of 71.3 months, the 10-year estimates of BCSS, DFS, and LRFS were 88.9% [95% confidence interval (CI) (85.1%-93.0%)], 79.6% [95% CI (74.7%-84.8%)], and 94.0% [95% CI (90.3%-97.8%)], respectively. A total of 124 patients completed the Breast-Q questionnaire, and no statistically significant differences were noted between groups (P = 0.823). After PSM with 27 variables, no statistically significant differences in BCSS, DFS, and LRFS were found between the implant-based (n = 177) and autologous (n = 177) groups. Further stratification according to staging, histological grade, lymph node status, and lymph-venous invasion status revealed no significant survival differences between groups. CONCLUSIONS: Both immediate implant-based and autologous reconstruction were reasonable choices with similar long-term oncological outcomes and patient-reported satisfaction among patients with invasive breast cancer in China.

LncRNA FAM83H-AS1 promotes triple-negative breast cancer progression by regulating the miR-136-5p/metadherin axis.

In this study, we evaluated the function and regulation of the long non-coding RNA (lncRNA) FAM83H-AS1 in triple-negative breast cancer (TNBC). Our data show that the FAM83H-AS1 levels are increased in human TNBC cells and tissues. Proliferation, migration, and invasion of TNBC cells are decreased by FAM83H-AS1 suppression, but increased by FAM83H-AS1 overexpression. Bioinformatics analysis revealed that miR-136-5p is a potential target of FAM83H-AS1. MiR-136-5p expression is decreased in TNBC tissues, and its overexpression suppresses TNBC cell proliferation, migration, and invasion. MiR-136-5p suppression reverses the FAM83H-AS1 silencing-mediated inhibition of TNBC cell proliferation, migration, and invasion, suggesting that FAM83H-AS1 exerts its oncogenic effect by inhibiting miR-136-5p. Our data identify metadherin (MTDH) as the target gene of miR-136-5p, and demonstrate that the MTDH expression is increased in human TNBC tissues, which induces proliferation, migration, and invasion of TNBC cells. Importantly, our in vivo data show that FAM83H-AS1 also promotes tumor growth in TNBC mouse xenografts. Together, our results demonstrate that FAM83H-AS1 functions as an oncogenic lncRNA that regulates miR-136-5p and MTDH expression during TNBC progression, and suggest that targeting the FAM83H-AS1/miR-136-5p/MTDH axis may serve as a novel therapeutic target in TNBC.

Effects of Tianqijiangtang capsule on survival, self-renewal and differentiation of hippocampal neural stem cells of embryonic rats cultured in high glucose medium.

OBJECTIVE: This study aims to investigate the effects of Tianqijiangtang capsule on the survival, self-renewal and differentiation of hippocampal neural stem cells (NSCs) of embryonic rats cultured in high glucose medium. MATERIALS AND METHODS: A cell model of diabetic encephalopathy was established. Cell viability was assessed to screen the optimal concentration of glucose for the cell model of diabetic encephalopathy. Then, the effects of Tianqijiangtang capsule on the proliferation and differentiation of NSCs, and the expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in the culture medium and cells were detected. RESULTS: High glucose significantly reduced the ability of survival, proliferation and differentiation of NSCs, which was statistically significant, when compared to the control group (P < 0.05 or 0.01). Tianqijiangtang capsule significantly enhanced the survival, proliferation and differentiation of NSCs cultured in high glucose medium, which was statistically significant, when compared with the high glucose group (P < 0.05 or 0.01). The high glucose culture resulted in a significant decrease in VEGF and BDNF levels in culture medium and cells of NSCs. Tianqijiangtang capsule significantly increased the level of VEGF nuclear BDNF in cells and the culture medium, which was significantly higher, when compared to that in the high glucose group (P < 0.05 or 0.01). CONCLUSION: Tianqijiangtang capsule enhances the level of neurotrophic factor synthesized and secreted by hippocampal NSCs cultured with high glucose through the autocrine and paracrine pathway, promotes the NSC survival, replication and differentiation of new neurons and astrocytes, and reduces the degeneration and necrosis of nerve cells.

CCAT1 promotes triple-negative breast cancer progression by suppressing miR-218/ZFX signaling.

Long non-coding RNAs (lncRNAs) regulate cancer development and progression. Here, we investigated the role of the lncRNA CCAT1 in triple-negative breast cancer (TNBC). CCAT1 expression was higher in TNBC cells than normal breast epithelial cells. Additionally, CCAT1 expression was higher in TNBC patient tumor tissue than adjacent normal breast tissue. Silencing CCAT1 inhibited TNBC cell proliferation, migration, and invasion in vitro, and tumor growth and progression in vivo. Bioinformatics analysis revealed that microRNA-218 (miR-218) is a potential target of CCAT1. Silencing CCAT1 resulted in an increase in miR-218 expression and inhibited TNBC cell proliferation, migration, and invasion. Silencing miR-218 reversed the effects of CCAT1 knockdown on cell proliferation, migration, and invasion, suggesting that CCAT1 promotes TNBC progression by downregulating miR-218 expression. We identified the zinc finger protein ZFX as a putative downstream target of miR-218 through bioinformatics analysis. ZFX expression was higher in TNBC than normal breast cell lines and higher in TNBC tumor tissue than adjacent normal breast tissue. Overexpression of ZFX reversed the tumor-suppressive effects of miR-218 on TNBC cell proliferation, migration, and invasion. Our data indicate that CCAT1 promotes TNBC progression by targeting the miR-218/ZFX axis.

Association of sociodemographic and oncological features with decision on implant-based versus autologous immediate postmastectomy breast reconstruction in Chinese patients.

BACKGROUND AND OBJECTIVES: Immediate postmastectomy breast reconstruction (IPBR) has gained wide popularity in China. We sought to clarify the prevalence and predictors of implant-based vs autologous IPBR among Chinese patients. METHODS: A retrospective cohort study was performed using a prospectively maintained database. Women who underwent IPBR during 2001-2017 were included. The modality-specific trends were deciphered by curve fitting analysis. The association of sociodemographic and oncological features with the decision for implant-based vs autologous IPBR was investigated using multivariate logistic regression and structural equation modeling. RESULTS: Among 905 patients included in the study, 479 underwent implant-based IPBR and 426 underwent autologous procedures. The implant/autologous ratio has increased exponentially over time. Multivariate analysis demonstrated that unmarried patients with BMI ≤ 24 kg/m2 , earlier clinical tumor stage, and preoperative pathological diagnosis of noninvasive lesion are more likely to choose implant-based IPBR compared to autologous procedures. The indirect effects of age, mastectomy type, and neoadjuvant chemotherapy were further demonstrated by the structural equations. CONCLUSIONS: The sociodemographic and oncological features are directly or indirectly associated with the decision on type of IPBR. The findings may facilitate both patients and physicians to make a high-quality decision by holistic evaluation of the sociodemographic and oncological features.

Single-Surgeon Experience for Maximizing Outcomes in Implant-Based Breast Reconstruction in Chinese Patients.

INTRODUCTION: Breast reconstruction for Chinese patients is vastly different given cultural differences, patient preferences, access to resources, and insurance coverage in China. Given these unique factors, a different approach for optimizing outcomes should be considered. METHODS: Retrospective review of all patients undergoing implant-based breast reconstruction from January 2013 to May 2016 was performed. Esthetic evaluations were made both by the patients and 1 nonoperative surgeon at least 6 months postoperative, and patient satisfaction was assessed using the Breast-Q. RESULTS: Overall, 135 patients undergoing 141 implant-based breast reconstructions were reviewed. The majority of implants (n = 134) were placed in a subpectoral position, whereas 7 were placed prepectorally, and no acellular dermal matrix was used. Given the limitations in acellular dermal matrix usage, soft-tissue coverage was augmented with local regional flaps. Ninety-four reconstructions (66.7%) used latissimus dorsi, 39 (27.7%) used serratus anterior, and 7 (5.0%) used mastectomy skin flaps only for implant coverage. Four patients (2.8%) underwent revision surgery to the reconstructed breasts. Grade III and grade IV capsular contracture was observed in 10 (7.1%) and 2 (1.4%) reconstructions, respectively. Both the patient's and the surgeon's satisfaction were higher than 80% in breast symmetry. CONCLUSIONS: Our implant selection method fit the Chinese population characteristics and could be extended to different types of implant-based breast reconstruction. It produced good esthetic outcomes and was reproducible, predictable, and simple to master in the clinical setting.

Considering the Optimal Timing of Breast Reconstruction With Abdominal Flaps With Adjuvant Irradiation in 370 Consecutive Pedicled Transverse Rectus Abdominis Myocutaneous Flap and Free Deep Inferior Epigastric Perforator Flap Performed in a Chinese Oncology Center: Is There a Significant Difference Between Immediate and Delayed?

PURPOSE: There is an ongoing debate on the optimal sequence of radiation and breast reconstruction. The purpose of this article was to (a) assess the impact of radiation on autologous breast reconstruction and (b) analyze the best timing for autologous breast reconstruction in the setting of radiation in a Chinese population. METHODS: A retrospective review of patients undergoing breast reconstruction with autologous lower abdominal flaps between 2001 and 2014 in the Tianjin Medical University and Cancer Hospital was performed. Patients were grouped by their irradiation status (irradiated vs nonirradiated). The irradiated group was further stratified into 2 groups by the timing of irradiation (immediate breast reconstruction followed by radiation vs prior radiation and delayed breast reconstruction). The primary outcomes were early and late breast complications, secondary and revision surgeries to the reconstructed breast, whereas the secondary outcomes were aesthetic and psychological evaluations of the patients. Logistic regression was used to assess the potential association between irradiation, patient and treatment variables, and surgical outcomes. RESULTS: Three hundred sixty patients with 370 reconstructed breasts were included in the study. Two hundred seventy-eight cases were nonirradiated, of which 158 were immediate and 120 were delayed. Ninety-two cases were irradiated, of which 61 were immediate, and 31 were delayed. Three hundred thirty-two cases underwent pedicled transverse rectus abdominis myocutaneous flap, 38 had deep inferior epigastric perforator flap. The irradiated group had a significant increase in secondary surgery due to fat necrosis (P < 0.001) and in late complications (P = 0.011). A significant increase in flap contracture (P = 0.043) and an increasing trend in the severity of fat necrosis were observed when radiation was performed after breast reconstruction. However, radiation and its timing did not have an adverse impact on patients' aesthetic and psychological evaluations by the Breast-Q survey. CONCLUSIONS: Radiation administered to the reconstructed breast mound increased the rate of late complications and the need for secondary surgery with increased abdominal flap shrinkage and contracture and the severity of flap fat necrosis. Irradiation on the reconstructed breast did not lead to worse aesthetic outcomes due to the generally different expectation in the Chinese female patients in that they were more focused on the breast shape when clothed. Immediate breast reconstruction followed by irradiated was a generally successful treatment sequence in the Chinese module.

Acute inflammation stimulates a regenerative response in the neonatal mouse heart.

Cardiac injury in neonatal 1-day-old mice stimulates a regenerative response characterized by reactive cardiomyocyte proliferation, which is distinguished from the fibrotic repair process in adults. Acute inflammation occurs immediately after heart injury and has generally been believed to exert a negative effect on heart regeneration by promoting scar formation in adults; however, little is known about the role of acute inflammation in the cardiac regenerative response in neonatal mice. Here, we show that acute inflammation induced cardiomyocyte proliferation after apical intramyocardial microinjection of immunogenic zymosan A particles into the neonatal mouse heart. We also found that cardiac injury-induced regenerative response was suspended after immunosuppression in neonatal mice, and that cardiomyocytes could not be reactivated to proliferate after neonatal heart injury in the absence of interleukin-6 (IL-6). Furthermore, cardiomyocyte-specific deletion of signal transducer and activator of transcription 3 (STAT3), the major downstream effector of IL-6 signaling, decreased reactive cardiomyocyte proliferation after apical resection. Our results indicate that acute inflammation stimulates the regenerative response in neonatal mouse heart, and suggest that modulation of inflammatory signals might have important implications in cardiac regenerative medicine.