PURPOSE Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer. METHODS This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up). RESULTS This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial’s stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar. CONCLUSION For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.

BackgroundBreast 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-β (TGF-β) pathway plays critical roles during breast cancer epithelial–mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-β signaling, promotes breast cancer metastasis through induction of EMT.MethodsThe 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.ResultsmiR-190 down-regulation is required for TGF-β-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.ConclusionsOur data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-β network in breast cancer metastasis.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0818-9) contains supplementary material, which is available to authorized users.

Introduction: Late cardiotoxicity related to radiotherapy (RT) in breast cancer and Hodgkin's lymphoma has been wellreported. However, the relatively higher cardiac dose exposure for esophageal cancer (EC) may result in the earlier onset of cardiac diseases. In this report, we examined the incidence, onset, and long-term survival outcomes of high-grade cardiac events after RT in a large cohort of patients with EC.Methods: Between March 2005 and August 2017, a total of 479 patients with EC from a prospectively maintained institutional database at The University of Texas MD Anderson Cancer Center were analyzed. All patients were treated with either intensity-modulated RT or proton beam therapy, either preoperatively or definitively. We focused on any grade 3 or higher (G3þ) cardiac events according to the Common Terminology Criteria for Adverse Events, version 5.0.Results: G3þ cardiac events occurred in 18% of patients at a median of 7 months with a median follow-up time of 76 months. Preexisting cardiac disease (p ¼ 0.001) and radiation modality (intensity-modulated RT versus proton beam therapy) (p ¼ 0.027) were significantly associated with G3þ cardiac events. Under multivariable analysis, the mean heart dose, particularly of less than 15 Gy, was associated with reduced G3þ events. Furthermore, G3þ cardiac events were associated with worse overall survival (p ¼ 0.041).Conclusions: Severe cardiac events were relatively common in patients with early onset EC after RT, especially those with preexisting cardiac disease and higher radiation doses to the heart. Optimal treatment approaches should be taken to reduce cumulative doses to the heart, especially for patients with preexisting cardiac disease.

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Primary squamous cell carcinoma of the breast (PSCCB) is a rare type of breast carcinoma, the clinical behavior of which has not been accurately characterized. The aim of this study was to evaluate its prevalence, characteristics, prognosis, and effective treatment modalities in patients attending our institution. The records of the Cancer Institute and Hospital of Tianjin Medical University from 1985 to 2013 were searched and 29 patients with PSCCB (0.086 % of all patients with breast cancer) identified. Their clinicopathological features, treatment methods used, and outcomes were analyzed. The median tumor size was 4.50 cm. Axillary lymph nodes metastases were present in 41.4 % of patients. The median overall survival was 39 months (range 7-144 months), with 34.5 % surviving at 5 years. The median relapse-free survival was 32 months (range 4-144 months), with 27.6 % relapse-free surviving at 5 years. According to univariate analysis, the time interval between onset of the first symptom and first presentation to a health professional (TI) (P = 0.017), use of adjuvant chemotherapy (P = 0.044), and T stage (P = 0.048, T1 vs. T2, T3, T4) were significant prognostic factors for overall survival. PSCCB is an extremely aggressive disease associated with large tumor size, rapid progression, frequent relapse, and a high death rate. Imaging findings are nonspecific and easily misinterpreted as benign. Cisplatin-based chemotherapy may be effective. Early diagnosis and treatment of this rare entity are critical to patient prognosis.

Glycogen-rich clear cell carcinoma (GRCC) of the breast is a rare type of breast carcinoma. Knowledge about the characteristics of this type is fragmentary, and the prognosis is on debate. In this study, we aimed to summarize the clinical, pathologic, and biologic characteristics of GRCC of the breast and analyze the survival. We reviewed the cases of breast cancer in our hospital between January 1999 and December 2009 and identified 28 patients as GRCC of the breast. The routine hematoxylin-eosin staining, periodic acid-Schiff (PAS) staining, and diastase PAS staining were performed on the tumor tissues. The expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), Ki67 and P53 were evaluated by immunohistochemistry. Tumors with a HER-2 score of 2+ were confirmed by fluorescent in situ hybridization test. Each GRCC case, who had complete follow-up data, was compared with four cases of usual invasive ductal carcinomas as controls in the same database and matched with age, year of diagnosis, tumor size, nodal status, and immunophenotype. The chi-squared test and the Fisher's exact test were used to compare the characteristics of GRCC cases and controls. The univariate analysis was used to study the prognosis, and Kaplan-Meier method was used to compare the survival of two groups. The clinicopathologic and imaging features were analyzed in the GRCC cases. Tumor sizes ranged from 0.8 to 7.5 cm (mean, 3.2 cm). Thirteen cases (46.4%) had positive lymph nodes. The positivity of ER and PR was 61.5% (16 of 26). HER-2 was positive for three cases (12%). The positivity of Ki67 and P53 were 87.5% and 45.8%, respectively. Twenty-four cases were followed up from 19 to 158 months. The prognosis of GRCC of the breast was significantly related with the number of positive lymph nodes (p < 0.001), and patients with more than 10 positive lymph nodes were at high risk of recurrence or metastasis. There was no significant difference in overall survival (p = 0.547), and disease-free survival (p = 0.900) between GRCC of the breast and the usual invasive ductal carcinomas. GRCC of the breast may not have a worse survival.

Lan Mu and Nannan Zhu have contributed equally to this work. AbstractBackground The aim of our study was to investigate whether pre-existing type 2 diabetes and insulin therapy have an impact on the prognosis of breast cancer patients.

miR-410-3p acts as an oncogene or tumor-suppressor gene in various types of cancer. However, its role in breast cancer remains unknown. In the present study, expression of miR-410-3p in 30 breast cancer and paired adjacent normal tissues was detected by RT-qPCR. The expression of miR-410-3p was downregulated in 76.7% of the breast cancer samples. To further validate the expression of miR-410-3p in breast cancer, we analyzed miR-410-3p expression profiling data set from The Cancer Genome Atlas (TCGA) including 683 breast cancer and 87 normal breast tissues. We observed that the expression of miR-410-3p was downregulated in breast cancer tissues. Next, we investigated the influence of miR-410-3p on cell proliferation by transiently transfecting the miR-410-3p mimic or inhibitor, as well as their corresponding controls in the MDA-MB-231 and MCF7 cell lines. miR-410-3p overexpression reduced cell growth, colony formation and the number of EdU-positive cells in the MDA-MB-231 cells. In contrast, inhibition of miR-410-3p in the MCF7 cells resulted in a higher proliferation rate as assessed by MTT assay, plate colony formation and EdU assays. Furthermore, miR-410-3p inhibited epithelial-mesenchymal transition. In addition, Snail was found to be a direct target of miR-410-3p based on a luciferase assay. Overexpression of Snail was able to rescue the effect of miR-410-3p in breast cancer cells. Moreover, miR‑410-3p was inversely expressed with Snail in breast cancer samples. Our data provide new knowledge regarding the role of miR-410-3p in breast cancer progression.