Investigating the causal associations between five anthropometric indicators and nonalcoholic fatty liver disease: Mendelian randomization study.

BACKGROUND: Although the etiology of nonalcoholic fatty liver disease (NAFLD) has not been thoroughly understood, the emerging roles of anthropometric indicators in assessing and predicting the risk of NAFLD have been highlighted by accumulating evidence. AIM: To evaluate the causal relationships between five anthropometric indicators and NAFLD employing Mendelian randomization (MR) design. METHODS: The Anthropometric Consortium provided genetic exposure data for five anthropometric indicators, including hip circumference (HC), waist circumference (WC), waist-to-hip ratio (WHR), body mass index (BMI), and body fat percentage (BF). Genetic outcome data for NAFLD were obtained from the United Kingdom Biobank and FinnGen Consortium. Genome-wide significant single nucleotide polymorphisms were chosen as instrumental variables. Univariable MR (UVMR) and multivariable MR (MVMR) designs with analytical approaches, including inverse variance weighted (IVW), MR-Egger, weighted median (WM), and weighted mode methods, were used to assess the causal relationships between anthropometric indicators and NAFLD. RESULTS: Causal relationships were revealed by UVMR, indicating that a higher risk of NAFLD was associated with a per-unit increase in WC [IVW: odds ratio (OR) = 2.67, 95%CI: 1.42-5.02, P = 2.25 × 10-3], and BF was causally associated with an increased risk of NAFLD (WM: OR = 2.23, 95%CI: 1.07-4.66, P = 0.033). The presence of causal effects of WC on the decreased risk of NAFLD was supported by MVMR after adjusting for BMI and smoking. However, no causal association between BF and NAFLD was observed. In addition, other causal relationships of HC, WHR (BMI adjusted), and BMI with the risk of NAFLD were not retained after FDR correction. CONCLUSION: This study establishes a causal relationship, indicating that an increase in WC is associated with a higher risk of NAFLD. This demonstrates that a suitable decrease in WC is advantageous for preventing NAFLD.

Real-world data on neoadjuvant chemotherapy with dual-anti HER2 therapy in HER2 positive breast cancer.

BACKGROUND: Neoadjuvant chemotherapy with dual-targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)-positive breast cancer. Although the dual-targeted therapy has significantly improved the pathological complete response (pCR) rate, further investigation is needed to identify biomarkers that predict the response to neoadjuvant therapy. METHODS: This retrospective study analyzed 353 patients with HER2-positive breast invasive ductal carcinoma. The correlation between clinicopathological factors and pCR rate was evaluated. A nomogram was constructed based on the results of the multivariate logistic regression analysis to predict the probability of pCR. RESULTS: The breast pCR (b-pCR) rate was 56.1% (198/353) and the total pCR (t-pCR) rate was 52.7% (186/353). Multivariate analysis identified ER status, PR status, HER2 status, Ki-67 index, and neoadjuvant chemotherapy regimens as independent indicators for both b-pCR and t-pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.73 (95% CI: 0.68-0.78). According to the nomogram, the t- pCR rate was highest in the ER-PR- HER2-positive patients (131/208) and lowest in the ER + PR + HER2-positive patients (19/73). The subgroup analyses showed that there was no significant difference in pCR rate among the neoadjuvant chemotherapy regimens in ER positive, PR positive, HER2 IHC 2 + , Ki67 index < 30% population. However, for ER-PR-HER2-positive patients, the neoadjuvant chemotherapy regimen has a great influence on the pCR rates. CONCLUSIONS: Patients with ER-negative, PR-negative, HER2 3 + and high KI-67 index were more likely to achieve pCR. THP may be used as an alternative to AC-THP or TCbHP in selected HER2-positive patients.

The regrouping of Luminal B (HER2 negative), a better discriminator of outcome and recurrence score.

BACKGROUND: Breast cancer (BC) remains the leading cause of cancer-related deaths worldwide. High recurrence risk Luminal BC receives adjuvant chemotherapy in addition to standard hormone therapy. Considering the heterogeneity of Luminal B BC, a more accurate classification model is urgently needed. METHODS: In this study, we retrospectively reviewed the data of 1603 patients who were diagnosed with HER2-negative breast invasive ductal carcinoma. According to the expression level of PR and Ki-67 index, the Luminal B (HER2-negative) BCs were divided into three groups: ER+PR-Ki67low (ER-positive, PR-negative, and Ki-67 index <20%), ER+PR+Ki67high (ER-positive, PR-positive, and Ki-67 index ≥20%), and ER+PR-Ki67high (ER-positive, PR-negative, and Ki-67 index ≥20%). The cox proportional hazards regression model was used to evaluate the correlation between each variable and outcomes. Besides, discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve and log-rank χ2 value. RESULTS: The analysis results showed that there was a significant correlation between subtypes using this newly defined classification and overall survival (p < 0.001) and disease-free survival (DFS) (p < 0.001). Interestingly, patients in the ER+PR-Ki67high subgroup have the worst survival outcome in Luminal B (HER2-negative) subtype, similar to Triple-negative patients. Besides, the ER+PR+Ki67high has worse 5-year DFS compared with Luminal A group. There was a significant relationship between the regrouping subtype and the recurrence score index (RI) (p < 0.001). Moreover, the results showed that patients in ER+PR-Ki67high subtype were more likely to have high RI for distance recurrence (RI-DR) and local recurrence (RI-LRR). Our newly defined classification has a better discrimination ability to predict survival outcome and recurrence score of Luminal B (HER2-negative) BC patients, which may help in clinical decision-making for individual treatment.

The role of surgery on locoregional treatment of patients with breast cancer newly diagnosed with ipsilateral supraclavicular lymph node metastasis.

Background: Radiotherapy is a practical locoregional treatment approach for women with breast cancer who show ipsilateral supraclavicular lymph node metastasis (ISLNM) on diagnosis. However, there is controversy around the role of supraclavicular lymph node dissection. Therefore, we aimed to study the significance of supraclavicular surgery based on radiotherapy. Patients and Methods: We retrospectively reviewed the data of 142 patients with breast cancer who presented with isolated ISLNM and received radiotherapy between the years 2000 and 2016. We also defined the effect of surgery on locoregional treatment of these patients by analyzing the prognostic factors for recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: We observed that, of the 142 patients, 104 who received radiotherapy underwent supraclavicular lymph node dissection. Also, among the study group, the progesterone receptor (PR) status (P = 0.044) and the number of axillary lymph nodes (ALNs) involved (P = 0.002) were significant independent predictors of RFS. Also, tumor size (P = 0.007), PR (P < 0.001), and number of ALNs (P < 0.001) were independent predictors of DMFS and were statistically significant. Also, PR was an independent prognostic factor of OS (P = 0.033), whereas the supraclavicular surgery was not an independent prognostic factor for RFS, DMFS, and OS. Furthermore, our study focused on 92 patients with negative estrogen receptors (ERs). The result showed that supraclavicular surgery was statistically significant for RFS (P = 0.023); no significant differences in DMFS and OS were found between patients who received supraclavicular surgery and those who did not. Conclusion: Radiotherapy may be the primary locoregional treatment approach for patients with breast cancer who present with newly diagnosed ISLNM. Additionally, supraclavicular surgery may be more appropriate for patients with negative ER who received radiotherapy.

A mathematical prediction model incorporating molecular subtype for risk of non-sentinel lymph node metastasis in sentinel lymph node-positive breast cancer patients: a retrospective analysis and nomogram development.

BACKGROUND: Molecular subtype of breast cancer is associated with sentinel lymph node status. We sought to establish a mathematical prediction model that included breast cancer molecular subtype for risk of positive non-sentinel lymph nodes in breast cancer patients with sentinel lymph node metastasis and further validate the model in a separate validation cohort. METHODS: We reviewed the clinicopathologic data of breast cancer patients with sentinel lymph node metastasis who underwent axillary lymph node dissection between June 16, 2014 and November 16, 2017 at our hospital. Sentinel lymph node biopsy was performed and patients with pathologically proven sentinel lymph node metastasis underwent axillary lymph node dissection. Independent risks for non-sentinel lymph node metastasis were assessed in a training cohort by multivariate analysis and incorporated into a mathematical prediction model. The model was further validated in a separate validation cohort, and a nomogram was developed and evaluated for diagnostic performance in predicting the risk of non-sentinel lymph node metastasis. Moreover, we assessed the performance of five different models in predicting non-sentinel lymph node metastasis in training cohort. RESULTS: Totally, 495 cases were eligible for the study, including 291 patients in the training cohort and 204 in the validation cohort. Non-sentinel lymph node metastasis was observed in 33.3% (97/291) patients in the training cohort. The AUC of MSKCC, Tenon, MDA, Ljubljana, and Louisville models in training cohort were 0.7613, 0.7142, 0.7076, 0.7483, and 0.671, respectively. Multivariate regression analysis indicated that tumor size (OR = 1.439; 95% CI 1.025-2.021; P = 0.036), sentinel lymph node macro-metastasis versus micro-metastasis (OR = 5.063; 95% CI 1.111-23.074; P = 0.036), the number of positive sentinel lymph nodes (OR = 2.583, 95% CI 1.714-3.892; P < 0.001), and the number of negative sentinel lymph nodes (OR = 0.686, 95% CI 0.575-0.817; P < 0.001) were independent statistically significant predictors of non-sentinel lymph node metastasis. Furthermore, luminal B (OR = 3.311, 95% CI 1.593-6.884; P = 0.001) and HER2 overexpression (OR = 4.308, 95% CI 1.097-16.912; P = 0.036) were independent and statistically significant predictor of non-sentinel lymph node metastasis versus luminal A. A regression model based on the results of multivariate analysis was established to predict the risk of non-sentinel lymph node metastasis, which had an AUC of 0.8188. The model was validated in the validation cohort and showed excellent diagnostic performance. CONCLUSIONS: The mathematical prediction model that incorporates five variables including breast cancer molecular subtype demonstrates excellent diagnostic performance in assessing the risk of non-sentinel lymph node metastasis in sentinel lymph node-positive patients. The prediction model could be of help surgeons in evaluating the risk of non-sentinel lymph node involvement for breast cancer patients; however, the model requires further validation in prospective studies.

miR-190 suppresses breast cancer metastasis by regulation of TGF-ß-induced epithelial-mesenchymal transition.

BACKGROUND: Breast cancer is the most common cancer among women worldwide and metastasis is the leading cause of death among patients with breast cancer. The transforming growth factor-ß (TGF-ß) pathway plays critical roles during breast cancer epithelial-mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-ß signaling, promotes breast cancer metastasis through induction of EMT. METHODS: The expression of miR-190 and SMAD2 in breast cancer tissues, adjacent normal breast tissues and cell lines were determined by RT-qPCR. The protein expression levels and localization were analyzed by western blotting and immunofluorescence. ChIP and dual-luciferase report assays were used to validate the regulation of ZEB1-miR-190-SMAD2 axis. The effect of miR-190 on breast cancer progression was investigated both in vitro and in vivo. RESULTS: miR-190 down-regulation is required for TGF-ß-induced EMT. miR-190 suppresses breast cancer metastasis both in vitro and in vivo by targeting SMAD2. miR-190 expression is down-regulated and inversely correlates with SMAD2 in breast cancer samples, and its expression level was associated with outcome in patients with breast cancer. Furthermore, miR-190 is transcriptionally regulated by ZEB1. CONCLUSIONS: Our data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-ß network in breast cancer metastasis.

The combined pN stage and breast cancer subtypes in breast cancer: a better discriminator of outcome can be used to refine the 8th AJCC staging manual.

BACKGROUND: pN stage and breast cancer subtypes (BCS) are both well-recognized prognostic indicators. Our previous work has highlighted that patients even with the same pN stage exhibited a significant survival difference in different BCS. Given this achievement, we hypothesized that a statistical interaction might exist between pN stage and BCS. The aim of this retrospective cohort study was to compare the prognostic value of the combined pN stage and BCS (pNnew stage) with either pN stage or BCS alone, and to determine if this combined new stage could serve as an alternative discriminator of outcome. METHODS: We combined pN stage and BCS to create a new variable named pNnew stage and then divided it into four groups: pN0new, pN1new, pN2new, and pN3new. Survival analysis was performed with the use of the Kaplan-Meier method and the log-rank test was used for univariate analysis. For multivariate analysis, cox proportional hazard models were applied, allowing for the estimation of disease-free survival (DFS). To assess discriminatory accuracy of the models, we compared the area under the receiver-operating characteristic curve (AUROC), the Akaike information criterion (AIC), and the Bayesian information criterion (BIC) values. Then, we used this pNnew stage to generate a TNnewM staging system according to the 7th AJCC staging system. RESULTS: A statistical interaction between pN stage and BCS was found. In multivariate survival analysis, the pNnew stage has been confirmed as an independent prognostic variable of 5-year DFS. The pNnew stage, with a smaller AIC or BIC value and larger AUROC, was a more powerful predictor of DFS than either pN stage or BCS alone. Results were validated in a separate cohort of patients. The TNnewM stage proposed in our present study was found comparable to the new 8th AJCC edition which includes anatomic T, N, and M plus tumor grade and the status of the biomarkers Her-2, ER, and PR with respect to prognostic value for breast cancer patients. CONCLUSIONS: The pNnew stage (combined pN stage and BCS) appears to be a more powerful predictor and discriminator for the outcome of breast cancer, as compared to pN stage or BCS alone, and the TNnewM stage may serve as a simple, easy-to-use alternative to the 8th AJCC edition staging manual.

Endoscopic sentinel lymph node biopsy and endoscopic axillary lymphadenectomy without liposuction in patients with early stage breast cancer.

BACKGROUND: Our purpose was to present a new method of endoscopic sentinel lymph node biopsy (ESLNB) and endoscopic axillary lymphadenectomy (EALND) without liposuction for treating early-stage breast cancer, and compare results with traditional open dissection. METHODS: The medical records of patients with early-stage breast cancer who underwent EALND/ESLNB without liposuction or traditional open dissection between March 2015 and September 2016 were retrospectively reviewed. Outcomes between the 2 groups were compared. RESULTS: A total 65 patients with a mean age of 41.2 ± 9.3 years (range, 23-60 years) were included. Thirty-three patients underwent traditional open lymph node dissection and 32 patients underwent endoscopic treatment. The 2 groups were similar with respect to age, body mass index (BMI), menopausal status, tumor location, and tumor disease stage (all, p > 0.05). The mean operating time was significantly higher in the endoscopic group (91.2 vs. 75.2 min, p = 0.022), while the mean blood loss was significantly lower (28.7 vs. 37.0 ml, p = 0.034). The mean number of SLNs harvested in the open (2.4 ± 1.6) and the endoscopic (2.3 ± 1.4) groups were not different (p = 0.829), with a sentinel lymph node retrieval rate of 80%. The mean number of axillary lymph nodes harvested in the open (13.8 ± 3.3) and the endoscopic (13.3 ± 3.1) groups were not different (p = 0.457). Scars were minimal in the endoscopic group. CONCLUSION: ESLNB and EALND without liposuction for early-stage breast cancer is feasible, has a low complication rate, a lymph node harvest rate similar to that of open dissection, and has good cosmetic results. Future studies, however, are required to evaluate oncological outcomes.

Downregulation of delta-aminolevulinate dehydratase is associated with poor prognosis in patients with breast cancer.

Delta-aminolevulinate dehydratase (ALAD) catalyzes the second step in the biosynthesis of heme and is also an endogenous inhibitor of the 26S proteasome. The role of ALAD in breast cancer progression is still unclear. In this study, we found that the expression of ALAD was downregulated in breast cancer tissues compared with adjacent normal breast tissues. Enhanced ALAD expression was associated with a favorable outcome in patients with breast cancer. Overexpression of ALAD suppresses breast cancer cell proliferation and invasion and inhibits the epithelial-mesenchymal transition phenotype. Furthermore, we found that ALAD regulates transforming growth factor-ß-mediated breast cancer progression. This finding suggests that ALAD might be a potential biomarker for breast cancer that suppresses breast cancer progression by regulating transforming growth factor-ß-mediated epithelial-mesenchymal transition.

The prognostic value of node status in different breast cancer subtypes.

Nodal metastases and breast cancer subtypes (BCS) are both well-recognized prognostic indicators. However, the association between nodal metastases and BCS, and the prognostic value of nodal metastases in different BCS are still remains unclear. Our aim was to investigate the association between nodal metastases and BCS, and the prognostic value of nodal metastases in the different BCS.We found that the breast cancer subtype was closely associated with the pN stage. pN stage and breast cancer subtype were significantly associated with disease-free survival. The subgroup analysis showed that the patients in higher pN stage had a poor outcome than patients in lower pN stage in each breast cancer subtype. Furthermore, when the analysis was stratified by breast cancer subtype, we found that even in the same pN stage (pN0-pN2), there was significant survival difference among patients in different BCS, and Luminal A breast cancer patients had the best survival outcome. However, there were no significant survival difference between Luminal A patients and other breast cancer subtype when patients in pN3 stage. Thus, our study suggested that both lymph node status and molecular subtype played important roles in the outcome of breast cancer patients and they cannot replace each other.

Number of negative lymph nodes as a prognostic factor for ypN0-N1 breast cancer patients undergoing neoadjuvant chemotherapy.

Some of node-positive patients could have a pathologically complete response in terms of lymph nodes. For these patients, the number of negative lymph nodes (NLNs) may be higher than that in the same-stage patients who initially received mastectomy. After neoadjuvant chemotherapy (NAC), the following treatment especially the postmastectomy radiotherapy (PMRT) is controversial for ypN1 (with one to three positive lymph nodes after NAC) patients. A total of 289 patients who received NAC from 2006 to 2009 were included in the investigation. The prognostic value of the number of NLNs on these patients was analyzed. Besides, we analyzed if the number of NLNs would give some indications on PMRT in ypN1 patients. The follow-up of all the patients began the first chemotherapy on 15 March 2015. The 5-year disease-free survival (DFS) and overall survival (OS) rates were determined as 67.2 and 81.1 %, respectively. The number of NLNs was associated with primary stage (p < 0.001), pathological tumor size (p < 0.05), pathological nodal stage (p < 0.001), and pathological stage after NAC (p < 0.001). The univariate and multivariate analyses revealed that the number of NLNs is an independent prognostic factor in both DFS and OS. In ypN0-N1 stage, patients with >13 NLNs had better DFS (p < 0.001) and OS (p < 0.001) than the patients with ≤13 NLNs. Although the fact patients in ypN2-N3 stage with >13 NLNs had better DFS and OS than the others, there were no significant statistical difference. In the subgroup analysis, PMRT improved the OS (p < 0.05) and DFS (p < 0.05) of ypN1 patients with ≤13 NLNs. The number of NLNs is a prognostic indicator in ypN0-N1 patients. Patients in ypN1 stage with less number of NLNs will benefit from PMRT.