Exploration of anatomical distribution of brain metastasis from breast cancer at first diagnosis assisted by artificial intelligence.

Objectives: This study aimed to explore the spatial distribution of brain metastases (BMs) from breast cancer (BC) and to identify the high-risk sub-structures in BMs that are involved at first diagnosis. Methods: Magnetic resonance imaging (MRI) scans were retrospectively reviewed at our centre. The brain was divided into eight regions according to its anatomy and function, and the volume of each region was calculated. The identification and volume calculation of metastatic brain lesions were accomplished using an automatically segmented 3D BUC-Net model. The observed and expected rates of BMs were compared using 2-tailed proportional hypothesis testing. Results: A total of 250 patients with BC who presented with 1694 BMs were retrospectively identified. The overall observed incidences of the substructures were as follows: cerebellum, 42.1 %; frontal lobe, 20.1 %; occipital lobe, 9.7 %; temporal lobe, 8.0 %; parietal lobe, 13.1 %; thalamus, 4.7 %; brainstem, 0.9 %; and hippocampus, 1.3 %. Compared with the expected rate based on the volume of different brain regions, the cerebellum, occipital lobe, and thalamus were identified as higher risk regions for BMs (P value ≤ 5.6*10-3). Sub-group analysis according to the type of BC indicated that patients with triple-negative BC had a high risk of involvement of the hippocampus and brainstem. Conclusions: Among patients with BC, the cerebellum, occipital lobe and thalamus were identified as higher-risk regions than expected for BMs. The brainstem and hippocampus were high-risk areas of the BMs in triple negative breast cancer. However, further validation of this conclusion requires a larger sample size.

A machine learning approach using 18F-FDG PET and enhanced CT scan-based radiomics combined with clinical model to predict pathological complete response in ESCC patients after neoadjuvant chemoradiotherapy and anti-PD-1 inhibitors.

Background: We aim to evaluate the value of an integrated multimodal radiomics with machine learning model to predict the pathological complete response (pCR) of primary tumor in a prospective cohort of esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT) and anti-PD-1 inhibitors. Materials and methods: Clinical information of 126 ESCC patients were included for analysis. Radiomics features were extracted from 18F-FDG PET and enhanced plan CT images. Four machine learning algorithms, including SVM (Support Vector Machine), Random Forest (RF), and eXtreme Gradient Boosting (XGB) and logistic regression (LR), were applied using k-fold cross-validation to predict pCR after nCRT. The predictive ability of the models was assessed using receiver operating characteristics (ROC) curve analysis. Results: A total of 842 features were extracted. Among the four machine learning algorithms, SVM achieved the most promising performance on the test set for PET(AUC:0.775), CT (AUC:0.710) and clinical model (AUC:0.722). For all combinations of various modalities-based models, the combination model of 18 F-FDG PET, CT and clinical features with SVM machine learning had the highest AUC of 0.852 in the test set when compared to single-modality models in various algorithms. The other combined models had AUC ranged 0.716 to 0.775. Conclusion: Machine learning models utilizing radiomics features from 18F-FDG PET and enhanced plan CT exhibit promising performance in predicting pCR in ESCC after nCRT and anti-PD-1 inhibitors. The fusion of features from multiple modalities radiomics and clinical features enhances the better predictive performance compared to using a single modality alone.

Evaluation of complexity and deliverability of IMRT treatment plans for breast cancer.

This study aimed to predict the outcome of patient specific quality assurance (PSQA) in IMRT for breast cancer using complexity metrics, such as MU factor, MAD, CAS, MCS. Several breast cancer plans were considered, including LBCS, RBCS, LBCM, RBCM, left breast, right breast and the whole breast for both Edge and TrueBeam LINACS. Dose verification was completed by Portal Dosimetry (PD). The receiver operating characteristic (ROC) curve was employed to determine whether the treatment plans pass or failed. The area under the curve (AUC) was used to assess the classification performance. The correlation of PSQA and complexity metrics was examined using Spearman's rank correlation coefficient (Rs). For LINACS, the most suitable complexity metric was found to be the MU factor (Edge Rs = - 0.608, p < 0.01; TrueBeam Rs = - 0.739, p < 0.01). Regarding the specific breast cancer categories, the optimal complexity metrics were as follows: MAD (AUC = 0.917) for LBCS, MCS (AUC = 0.681) for RBCS, MU factor (AUC = 0.854) for LBCM and MAD (AUC = 0.731) for RBCM. On the Edge LINAC, the preferable method for breast cancers was MCS (left breast, AUC = 0.938; right breast, AUC = 0.813), while on the TrueBeam LINAC, it became MU factor (left breast, AUC = 0.950) and MCS (right breast, AUC = 0.806), respectively. Overall, there was no universally suitable complexity metric for all types of breast cancers. The choice of complexity metric depended on different cancer types, locations and treatment LINACs. Therefore, when utilizing complexity metrics to predict PSQA outcomes in IMRT for breast cancer, it was essential to select the appropriate metric based on the specific circumstances and characteristics of the treatment.

Impact of multidisciplinary team on the pattern of care for brain metastasis from breast cancer.

Purpose: The aim of this study was to explore how a multidisciplinary team (MDT) affects patterns of local or systematic treatment. Methods: We retrospectively reviewed the data of consecutive patients in the breast cancer with brain metastases (BCBM) database at our institution from January 2011 to April 2021. The patients were divided into an MDT group and a non-MDT group. Results: A total of 208 patients were analyzed, including 104 each in the MDT and non-MDT groups. After MDT, 56 patients (53.8%) were found to have intracranial "diagnosis upgrade". In the matched population, patients in the MDT group recorded a higher proportion of meningeal metastases (14.4% vs. 4.8%, p = 0.02), symptomatic tumor progression (11.5% vs. 5.8%, p = 0.04), and an increased number of occurrences of brain metastases (BM) progression (p < 0.05). Attending MDT was an independent factor associated with ≥2 courses of intracranial radiotherapy (RT) [odds ratio (OR) 5.4, 95% confidence interval (CI): 2.7-10.9, p < 0.001], novel RT technique use (7.0, 95% CI 3.5-14.0, p < 0.001), and prospective clinical research (OR 5.7, 95% CI 2.4-13.4, p < 0.001). Conclusion: Patients with complex conditions are often referred for MDT discussions. An MDT may improve the qualities of intracranial RT and systemic therapy, resulting in benefits of overall survival for BC patients after BM. This encourages the idea that treatment recommendations for patients with BMBC should be discussed within an MDT.

Nodal response to primary systemic therapy predicts prognosis of cN3c breast cancer patients receiving multimodality therapy.

AIM: To investigate the survival outcomes, patterns and risks of recurrence in cN3c breast cancer patients after multimodality therapy, as well as the predictors of candidates for ipsilateral supraclavicular (SCV) area boosting. METHOD: Consecutive cN3c breast cancer patients from January 2009 to December 2020 were retrospectively reviewed. Based on nodal response to primary systemic therapy (PST), patients were categorized into three groups: clinical complete response (cCR) not achieved in SCV lymph nodal (SCLN, Group A), SCLN cCR but axillary node (ALN) did not achieve pathological complete response (pCR, Group B), cCR in SCLN and pCR in ALN (Group C). RESULTS: The median follow-up time was 32.7 months. The 5-year overall survival (OS) and recurrence-free survival (RFS) were 64.6% and 43.7% respectively. Multivariate analysis showed cumulative SCV dose and ypT stage, ALN response and SCV response to PST were significantly associated with OS and RFS respectively. Compared with Group A or B, Group C showed significantly improved 3 y-RFS (53.8% vs 73.6% vs 100%, p = 0.003), and the lowest rate of DM as first failure (37.9% vs 23.5% vs 0%, p = 0.010). In Group A, the 3 y-OS for patients receiving the cumulative SCV dose of ≥60 Gy versus <60 Gy was 78.0% versus 57.3% (p = 0.029). CONCLUSION: Nodal response to PST is an independent prognostic factor for survival and pattern of failure. A cumulative SCV dose of ≥60 Gy is positively associated with improved OS, especially in Group A. Our data supports the perspective of optimizing radiotherapeutic strategy based on nodal response.

Identification of patients with locally advanced rectal cancer eligible for neoadjuvant chemotherapy alone: Results of a retrospective study.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy (nCT) appears in a few clinical studies as an alternative to neoadjuvant chemoradiation (nCRT) in selected patients with locally advanced rectal cancer (LARC). We aimed to compare the clinical outcomes of nCT with or without nCRT in patients with LARC and to identify patients who may be suitable for nCT alone. MATERIALS AND METHODS: A total of 155 patients with LARC who received neoadjuvant treatment (NT) were retrospectively analysed from January 2016 to June 2021. The patients were divided into two groups: nCRT (n = 101) and nCT (n = 54). More patients with locally advanced disease (cT4, cN+ and magnetic resonance imaging-detected mesorectal fascia [mrMRF] positive [+]) were found in the nCRT group. Patients in the nCRT group received a dose of 50 Gy/25 Fx irradiation with concurrent capecitabine, and the median number of nCT cycles was two. In the nCT group, the median number of cycles was four. RESULTS: The median follow-up duration was 30 months. The pathologic complete response (pCR) rate in the nCRT group was significantly higher than that in the nCT group (17.5% vs. 5.6%, p = 0.047). A significant difference was observed in the locoregional recurrence rate (LRR); 6.9% in the nCRT group and 16.7% in the nCT group (p = 0.011). Among patients with initial mrMRF (+) status, the LRR in the nCRT group was significantly lower than that in the nCT group (6.1% vs. 20%, p = 0.007), but not in patients with initial mrMRF negative (-) (10.5% in each group, p = 0.647). Compared with the nCT group, a lower LRR was observed in patients in the nCRT group with initial mrMRF (+) converted to mrMRF (-) after NT (5.3% vs. 23%, p = 0.009). No significant difference was observed between the two groups regarding acute toxicity and overall and progression-free survivals. Multivariate analysis showed that nCRT and ypN stage were independent prognostic factors for the development of LRR. CONCLUSION: Patients with initial mrMRF (-) may be suitable for nCT alone. However, patients with initial mrMRF (+) converted to mrMRF (-) after nCT are still at high risk of LRR, and radiotherapy is recommended. Prospective studies are required to confirm these findings.

The characteristics of oncological clinical trials investigating the synergistic effect of radiotherapy and immune checkpoint inhibitors: a cross-sectional study.

Background: The combined use of radiotherapy (RT) and immune checkpoint inhibitors (ICIs) is a promising strategy in the treatment of cancer patients. We sought to comprehensively summarize the characteristics of oncological trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov. Methods: In this cross-sectional study, oncological trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov from database inception to November 30, 2021 were retrieved. The characteristics of the included trials were assessed. Results: Overall, 403 registered trials were identified for analysis. Of these trials, 393 (97.5%) were interventional trials and 10 (2.5%) were observational trials. The top 3 most-studied conditions were gastrointestinal cancer (25.8%), head and neck cancer (18.6%), and non-small cell lung cancer (NSCLC) (17.9%). Approximately, 60.0% of the trials comprised ≤50 participants and 22.6% of the trials comprised >100 participants. More than half of the registered trials were prospective phase 2 trials (54.3%). In relation to trial location, 39.7% of the trials were conducted in the United States, which was the most common registered area, followed by China (33.7%) and Europe (19.4%). In relation to the radiation fractionation, the conventional fractionation size of 1.8-2.0 Gy was comparable to the ultra-hypofractionation size of ≥5 Gy (46.4% vs. 32.8%), and the most commonly used ultra-hypofractionation regimen was 24 Gy/3 Fx (24%), followed by 25 Gy/5 Fx (11%) and 30 Gy/5 Fx (11%). Additionally, the most commonly used ICI in the registered trials was pembrolizumab (20.1%), followed by durvalumab (11.4%) and nivolumab (9.2%). Among all the registered trials, only 4% of the trials had been completed, but 61.5% of the completed trials had reported their results on ClinicalTrials.gov. The conventional fractionation trials were more likely to be phase 3 trials, located in China, and performed in patients with head and neck cancer or gynecological cancer (all P values <0.05), while the ultra-hypofractionation trials were more likely to be phase 1 trials, stopped early, located in the United States, and performed in patients with lung cancer (all P values <0.05). Conclusions: The number of prospective trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov has increased significantly over the past decade. The ultra-hypofractionation size of the registered trials varies, but the 24 Gy/3 Fx regimen is commonly used. The clinical results of registered trials examining the synergistic effect of RT in combination with ICIs, specifically in terms of ultra-hypofractionation, remain limited.

Pretreatment absolute lymphocyte count is an independent predictor for survival outcomes for esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiotherapy and pembrolizumab: An analysis from a prospective cohort.

BACKGROUND: The aim of the study was to analyze the relationship between pretreatment inflammatory biomarkers (IBs) and survival outcomes for patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (neo-CRT) and pembrolizumab. METHODS: Clinical variables and IBs (absolute monocyte count [AMC], absolute lymphocyte count [ALC], platelet count [PLT], neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], pan-immune inflammation value [PIV], systemic immunoinflammatory index [SII], systemic immunoreactivity index [SIRI] and prognostic nutritional index [PNI]) were collected. Univariate and multivariate analysis were performed to identify the independent factors for outcomes of ESCC. RESULTS: A total of 51 patients were included. Of these, 35 patients achieved pathological complete response (pCR) after neo-CRT and pembrolizumab (pCR: 68.6%). With a median follow-up of 20 months, the two-year PFS and OS of the cohort was 64% and 91%, respectively. Multivariate logistic regression analysis indicated that ALC (overall response [OR] 4.4, p = 0.051) and PLT (OR 6.7, p = 0.023) were two independent predictors for achieving pCR among ESCC treated with neo-CRT and pembrolizumab. Multivariate Cox regression analysis showed that ALC (HR 0.27, p = 0.028) and SIRI (HR 3.13, p = 0.048) were two independent predictors associated with PFS. Kaplan Meier analysis demonstrated that the PFS of ESCC with high baseline ALC was significantly better than those with low ALC (2-year PFS: 77% vs. 47%, p = 0.027), but not for overall survival (2-year OS: 96% vs. 87%, p = 0.46). CONCLUSIONS: This retrospective analysis based on a prospective cohort for the first time demonstrates that pretreatment ALC is an independent predictor for achieving pCR and favorable outcomes of ESCC treated with neo-CRT and pembrolizumab.

The influence of axillary surgery and radiotherapeutic strategy on the risk of lymphedema and upper extremity dysfunction in early breast cancer patients.

PURPOSE: To explore the risk factors for breast cancer-related lymphedema (BCRL) and upper extremity dysfunction (UED) in patients with early breast cancer after modern comprehensive treatment and to compare the toxicity of different treatment strategies. METHODS: From 2017 to 2020, a total of 1369 female patients with pT1-3N0-1M0 breast cancer who underwent adjuvant radiotherapy in our centre were retrospectively reviewed. BCRL and UED were identified by the Norman and QuickDASH questionnaires. The incidence, severity and risk factors for BCRL and UED were evaluated. RESULTS: After a median follow-up of 25 months, a total of 249 patients developed BCRL; axillary lymph node dissection (ALND), increased number of dissected nodes, right-sided and hypofractionated radiotherapy containing RNI were found to be significant risk factors (all p values < 0.05). The sentinel lymph node biopsy (SLNB)+ regional nodal irradiation (RNI) group had a significantly lower BCRL risk than the ALND + RNI group (10.8% vs. 32.5%, HR = 0.426, p = 0.020), while there was no significant difference between ALND vs. ALND + RNI or SLNB vs. SLNB + RNI. A total of 193 patients developed UED, and ALND (p = 0.02) was the only significant risk factor. The SLNB + RNI group had a significantly decreased risk of UED compared with the ALND + RNI group (7.5% vs. 23.9%, HR = 0.260, p = 0.001), and there was no significant difference between SLNB vs. SLNB + RNI or ALND vs. ALND + RNI. CONCLUSION: Aggressive ALND remains the primary risk factor for BCRL and UED while RNI does not. Thus, replacing ALND with tailored radiotherapy would be an effective preventive strategy in early breast cancer patients.

The optimal regional irradiation volume for breast cancer patients: A comprehensive systematic review and network meta-analysis of published studies.

Background: Currently, the optimal adjuvant regional nodal irradiation (RNI) volume for breast cancer (BC) remained controversial. We aimed to define the optimal RNI treatment volume for BC by using a comprehensive network meta-analysis (NMA) of published studies. Materials and methods: PubMed, Embase, Medline, and Cochrane Central Register of Controlled Trials were searched from database inception to 30 May 2022. Studies assessing different adjuvant RNI volumes for BC were eligible for inclusion. The primary outcome was overall survival (OS), and secondary outcome was disease-free survival (DFS) and distant-metastasis-free survival (DMFS). Results: A total of 29,640 BC patients from twenty studies were included. The pooled hazard ratio demonstrated that internal mammary node irradiation (IMNI) in BC patients significantly improved OS giving HR (hazard ratio) of 0.87 (95%CI: 0.83-0.91, p<0.001), DFS with HR of 0.78 (95%CI: 0.68-0.90, p<0.01), and DMFS with HR of 0.87 (95%CI: 0.79-0.97, p<0.01) when compared to controls. Sub-group analysis indicated that RNI with IMNI significantly improved OS (HR 0.87, 95%CI: 0.81-0.93, p<0.01), DFS (HR 0.65, 95%CI: 0.56-0.77, p<0.01), and DMFS (HR 0.90, 95%CI: 0.82-0.98, p=0.02) when compared to RNI without IMNI. NMA showed that CW/WB (chest wall/whole breast) + RNI with IMNI significantly improved DFS (HR 0.93, 95%CI: 0.86-1.00) and DMFS (HR 0.90, 95%CI: 0.81-0.99), but not for OS (HR 0.93, 95%CI: 0.84-1.03) when compared to CW/WB alone. Based on the analysis of the treatment ranking, CW/WB+RNI with IMNI appeared as the best treatment approach for BC patients. Conclusions: Our pooled results demonstrated that RNI with IMNI yielded a significant survival advantage for BC patients. NMA showed that CW/WB+RNI with IMNI was the optimal radiation volume for BC patients.

Hypofractionated versus conventional intensity-modulated radiation irradiation (HARVEST-adjuvant): study protocol for a randomised non-inferior multicentre phase III trial.

INTRODUCTION: Short course regimen has become the major trend in the field of adjuvant radiotherapy for patients with breast cancer. Hypofractionated radiotherapy (HF-RT) regimen of 40-42.5 Gy in 15-16 fractions has been established as a preferred option for whole breast irradiation. However, few evidences of hypofractionated regional nodal irradiation (RNI), especially involving internal mammary nodes (IMNs), could be available during the era of intensity-modulated radiation therapy (IMRT). Against this background, we design this trial to explore the hypothesis that HF-RT regimen involving RNI (including infraclavicular, supraclavicular nodes and IMNs) will be non-inferior to a standard schedule by using IMRT technique. METHODS AND ANALYSIS: This is an open-label randomised, non-inferior, multicentre phase III trial. Patients with breast cancer with an indication for RNI after breast conserving surgery or mastectomy are randomised at a ratio of 1:1 into the following two groups: hypofractionated regimen of 2.67 Gy for 16 fractions or conventional regimen of 2 Gy for 25 fractions. The dose was prescribed to ipsilateral chest wall or whole breast and RNI (including infraclavicular, supraclavicular nodes and IMNs, lower axilla if indicated). The trial plans to enrol a total of 801 patients and all patients will be treated using IMRT technique. The primary endpoint is 5-year locoregional recurrence. The secondary endpoints include 5-year distant metastasis free survival, invasive recurrence-free survival, overall survival, accumulative acute radiation-induced toxicity and accumulative late radiation-induced toxicity, cosmetic outcomes and quality of life. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (version 2018-95-3) and approvals from ethical committee of each participating centre have also been obtained. Research findings will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03829553.

IMNI PRECISION trial protocol: a phase II, open-label, non-inferior randomized controlled trial of tailoring omission of internal mammary node irradiation for early-stage breast cancer.

BACKGROUND: Since the publication of MA-20 and EORTC-22922 trials, chest wall (CW)/ whole breast (WB) irradiation + comprehensive regional nodal irradiation (RNI) with internal mammary node irradiation (IMNI) has been the standard adjuvant treatment for early-stage breast cancer (BC). However, one size does not fit all BC, and the risk of recurrence significantly varies among this patient population. In addition, whether all BC patients presented with one to three positive lymph nodes (pN1) could benefit from IMNI remains controversial. Thus, the optimal adjuvant RNI volume for early-stage BC with T1-2N1 remains undetermined. METHODS: The IMNI PRECISION trial is a single institute, open-labeled, non-inferior, randomized controlled trial. A total of 214 clinically "high risk" BC patients which is characterized as having at least two of the five clinically adverse factors (age ≤ 40, three positive LN, T2 stage, grade 3 and Ki-67 index ≥ 14%), but genomic score "low risk" (the genomic score ≤ 44) N1 breast cancers are randomly assigned to omitting IMNI group (experimental group) or with IMNI (control group) with a 1:1 ratio. The primary endpoint of this trial is event-free survival, and secondary endpoints include overall survival and locoregional recurrence-free survival. DISCUSSION: The IMNI PRECISION design allows promising clinical-genomic model to stratify the individualized risk of developing recurrence and guides the optimal RNI treatment for early-stage (pT1-2N1) BC patients. We anticipate that our results would provide high-level evidence to tailor IMNI according to individualized recurrence risk of BC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04517266 . Date of registration: August 18, 2020. Status: Recruiting.

No survival benefit could be obtained from adjuvant radiotherapy in esophageal cancer treated with neoadjuvant chemotherapy followed by surgery: A SEER-based analysis.

Background: The aim of this study is to assess the clinical benefit of postoperative radiotherapy (PORT) in patients with esophageal cancer (EC) who treated with neoadjuvant chemotherapy (NAC) and surgery via a national population-based database. Methods: Patients diagnosed with EC between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis was used to compare the overall survival (OS) and cause-specific survival (CSS) difference between PORT vs. no-radiotherapy (RT) groups before and after propensity score matching (PSM). After PSM for baseline characteristics, Cox proportional hazard regression was performed to investigate the factors associated with OS. Results: A total of 321 patients were included in the analysis. Of them, 91 patients (28%) received PORT. In the unmatched population, the no-RT group had improved OS compared with PORT (44 vs. 25 months, p = 0.002), and CSS was similar in patients undergoing NAC with or without PORT (42 vs. 71 months, p = 0.17). After PSM for baseline characteristics, the OS benefit of the no-RT group over the PORT group remained significant with a median OS of 46 vs. 27 months (p = 0.02), and CSS remained comparable between groups (83 vs. 81 months, p = 0.49). In subgroup analyses, PORT did not improve the OS among patients with adenocarcinoma in the subgroups of cN0, cN1, and cN2-3 (all p > 0.05). In Cox regression, aged ≥71 years old, cT3-4, cN2-3, and receiving PORT were independent predictors of worse OS, whereas cT4 and cN2-3 were independent predictors of worse CSS (all p < 0.05). Conclusions: The present study demonstrated that no survival benefit could be obtained from the additional use of PORT after NAC and surgery in patients with EC. Well-designed prospective trials are needed to confirm our findings.

A Novel Nomogram for Predicting Prognosis and Tailoring Local Therapy Decision for Ductal Carcinoma In Situ after Breast Conserving Surgery.

Purpose: We sought to explore the role of nomogram-combined biomarkers, mammographic microcalcification and inflammatory hematologic markers in guiding local therapy decisions in ductal carcinoma in situ (DCIS) subgroups with different ipsilateral breast tumour recurrence (IBTR) risk. Methods: Between January 2009 and December 2018, consecutive patients with DCIS and breast conserving surgery (BCS) were enrolled and randomly assigned to a training cohort (n = 181) and internally validation cohort (n = 78). Multivariate analyses were performed to identify predictors of IBTR. Model performance was evaluated by the concordance index (C-index) and calibration plot. The time-to-event curves were calculated by the Kaplan−Meier methods and compared by the log-rank test. Results: In total, 259 patients were enrolled and 182 of them received whole breast irradiation (WBI). After a median follow-up of 51.02 months, 23 IBTR events occurred in the whole cohort. By multivariate analyses of training cohort, presence of microinvasion, Ki67 index >14%, mammographic-clustered fine linear microcalcifications and neutrophil/lymphocyte ratio before BCS (preop-NLR), >1.1 remained independent risk factors of IBTR to develop a nomogram. The C-indexes of the nomogram were 0.87 and 0.86 in the training and internal validation set, respectively. Calibration plots illustrated good agreement between the predictions and actual observations for 5-year IBTR. Cut-off values of nomogram point were identified as 53 and 115 points, which divided all patients into low-, intermediate- and high-risk groups. Significant differences in IBTR existed between low-, intermediate- and high-risk subgroups (p < 0.01). For the whole cohort and ER-positive tumours, the benefit of WBI was found only in the intermediate-risk subgroup, but not in those with low or high risk. Fourteen out of 23 IBTRs occurred outside the original quadrant and all occurred in the high-risk group. Conclusions: The novel nomogram demonstrated potential to separate the risk of IBTR and locations of IBTR. For the whole cohort and ER-positive tumours, the benefit of WBI was restricted to an intermediate-risk subgroup.

Ki-67 Index Provides Long-Term Survival Information for Early-Stage HER2-Low-Positive Breast Cancer: A Single-Institute Retrospective Analysis.

Aim: It has been reported that more than half of breast cancer (BC) could be identified as HER2-low-positive, which might be a distinct subtype. But the results are controversial. We aim to compare the survival outcomes between HER2-low-positive and HER2-0 BC with Asian women based on HR status or Ki-67 index. Methods: Between January 2009 and December 2017, HER2-nonamplified BC in our single institute was identified. Patients were classified as HER2-low and HER2-0 cohort. Clinical characteristics were compared between these two groups and survival outcomes were calculated by the Kaplan-Meier method. We also performed subgroup analysis according to Ki-67 index and hormone-receptor (HR) status. Results: Of the 2,230 included patients, 536 presented with HER2-0, and 1,694 with HER2-low positive. After a median follow-up of 85 months (range: 1-152 months), the 8-year OS, BCSS, and RFS of the overall cohort were 91%, 95%, and 89%, respectively. In comparison with the HER2-0 cohort, majority of HER2-low-expression BC concurrently presented with HR positive (82.3% vs. 69%, P < 0.001). There was no significant survival difference between the two groups in terms of OS, BCSS, and RFS (all p > 0.05). We then performed subgroup analysis according to HR status and Ki-67 index (<14% vs. ≥14%). Our results indicated that there was no significant survival difference between HER2-low-positive and HER2-0 tumors regardless of HR status (p > 0.05), while OS (p=0.026) and BCSS (p=0.052) of HER2-0 BC with high Ki-67 index were significantly poorer than that of HER2-low positive with high Ki-67, but not for RFS (p=0.17). Conclusion: Among early stage HER2-nonamplified BC, no significant survival difference could be found between HER2-low positive and HER2-0 cohort regardless of HR status. Survival outcomes of HER2-low positive with high Ki-67 seem to be poorer than that of HER2-0 tumors with high Ki-67 index.

A Novel Delivery System of RGD-HSA Loaded GEM/CUR Nanoparticles for the Treatment of Pancreatic Cancer Therapy.

Introduction: Pancreatic cancer is one of the most common malignant tumors and is characterized by high malignancy, occult incidence and poor prognosis. Traditional chemotherapy drugs have limited efficacy and strong side effects. Therefore, there is an urgent need for a better treatment of the malignancy. Methods: The prepared arginine glycine peptide (RGD)-human serum albumin (HSA)-Gemcitabine (GEM)/Curcumin (CUR) nanoparticles (NPs) were characterized for physicochemical properties, stability and in vitro release. Comparisons of HSA-GEM/CUR NPs and RGD-HSA-GEM/CUR NPs regarding tissue distributions and pharmacodynamics were also carried out using mice as the animal models. Results: Transmission electron micrographs showed that RGD peptide-conjugated HSA-NPs had an irregular surface, good dispersion (PDI=0.139±0.03) and a uniform size distribution (Mean PS=115.6±5.7 nm). The ζ-potential was -17.3 mV. As regards in vitro release, non RGD modified NPs showed a faster release rate in 24 hours, yielding a release amount of 75% for GEM and 72% for CUR. RGD-HSA-GEM/CUR NPs exhibited 67% of accumulated release of GEM (63% for CUR) in 24 hours. This may be due to the HSA chain covering the surface of NPs, which hindered the drug release. The cytotoxicity of GEM/CUR co-loaded NPs was significantly higher than that of single-drug NPs (P < 0.05). In vivo study results indicated that RGD-HSA-GEM/CUR NPs had notable targeting effect on subcutaneous tumors, with a potential to actively deliver drugs to tumor tissues. Conclusion: In this study, we prepared RGD-HSA-GEM/CUR NPs that had both good water solubility and tumor-targeting property. The results also showed that the RGD modified NPs had advantages in increasing GEM/CUR concentration at tumor sites and reducing its distribution in peripheral organs.

Influence of Adjuvant Radiotherapy Timing on Survival Outcomes in High-Risk Patients Receiving Neoadjuvant Treatments.

Purpose: To determine the relationship between time to radiotherapy (TTR) and survival outcomes in breast cancer (BC) patients treated with neoadjuvant treatments (NATs). Methods: Continuous non-metastatic BC patients receiving NAT and adjuvant radiotherapy (RT) from 2009 to 2016 were retrospectively reviewed. A multivariable Cox model with restricted cubic splines (RCSs) was used to determine the panoramic relationship between TTR and survival outcomes. Multivariable analysis was used to control for confounding factors between the groups of TTR. Results: A total of 315 patients were included. The RCS modeling demonstrated a non-linear relationship between TTR and survival outcomes. The lowest risk for distant metastasis-free survival (DMFS) and recurrence-free survival (RFS) was observed at the TTR of 12 weeks, and the lowest risk of BC-specific survival (BCSS) at 10 weeks. TTR was accordingly transformed into categorical variables as ≤10, 11-20, and >20 weeks. Multivariable analysis revealed that the TTR of ≤10 weeks was an independent prognostic factor for worse DMFS (HR = 2.294, 95% CI 1.079-4.881) and RFS (HR = 2.126, 95% CI 1.038-4.356) compared with the TTR of 10-20 weeks, while the is no difference in DMFS, RFS, and BCSS between TTR >20 weeks and TTR of 10-20 weeks. Conclusion: There exists a non-linear relationship between TTR after surgery and survival outcomes in patients treated with NAT. Early initiation of RT following surgery does not seem to be associated with a better therapeutic outcome. A relatively flexible recommendation of TTR could be adopted in clinical practice.

Practical Model to Optimize the Strategy of Adjuvant Postmastectomy Radiotherapy in T1-2N1 Breast Cancer With Modern Systemic Therapy.

Purpose: The effect of adjuvant irradiation after mastectomy in early-stage breast cancer patients remains controversial. The present study aims to explore the clinical benefit obtained from adjuvant radiotherapy among post-mastectomy pT1-2N1 breast cancer patients who received adjuvant modern systemic therapy. Methods: Medical records of consecutive patients with pT1-2N1 breast cancer who received mastectomy in our institution between January 2009 and December 2016 were retrospectively reviewed. High-risk features consist of patient age, number of positive lymph nodes, T stage, and Ki67 index, which were developed previously at our institution using early-stage breast cancer patients after mastectomy without adjuvant radiotherapy. Differences of survival and local recurrence were compared between no-postmastectomy radiotherapy (PMRT) and PMRT group according to number of risk factors. The time-to-event curves were calculated by the Kaplan-Meier methods and compared by the log-rank test. Propensity score matching (PSM) was performed to reduce the imbalances in patient characteristics. Results: A total of 548 patients were enrolled (no-PMRT: 259 and PMRT: 289). After a median follow-up of 69 months, the 5-year rate of DFS, BCSS, and LRR in the overall cohort was 90.2%, 97.4%, and 3.6%, respectively. PMRT did not significantly improve DFS, BCSS, and LRRFS in the whole cohort. Patients were divided into low-risk (with no or one risk factor) and high-risk (with two or more risk factors) groups. According to the univariable and multivariable analysis, high-risk group (HR = 1.81, 95% CI 1.11-2.98, p = 0.02) was demonstrated as an independent risk factor for DFS. For the high-risk group, PMRT significantly improved DFS from 81.4% to 91.9% and BCSS from 95.5% to 98.6% and decreased the 5-year rate of LRR from 5.6% to 1.4%, respectively (p < 0.01, p = 0.05, and p = 0.06). However, no survival benefit from PMRT was observed in the low-risk group in terms of DFS, BCSS, and LRR (p = 0.45, p = 0.51, and p = 0.99, respectively). In multivariate analysis, PMRT remained an independent prognostic factor for DFS (HR = 0.50, 95% CI 0.24-1.00, p = 0.05) in the high-risk group. After PSM analysis, the survival benefit of PMRT was sustained in high-risk patients. Conclusion: PMRT significantly improved DFS in high-risk pT1-2N1 breast cancer patients, but not in low-risk patients. Independent validation of our scoring system is recommended.

Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for the treatment of locally advanced esophageal cancer: a population-based analysis.

AIM: Currently, the optimal treatment strategy for locally advanced esophageal cancer (LAEC) remains controversial. We perform the present study to compare the outcomes of LAEC treated with neoadjuvant chemotherapy (neo-CT) or chemoradiotherapy (neo-CRT). MATERIALS AND METHODS: A population cohort with histologically diagnosed of esophageal cancer was identified from SEER database between 2004 and 2015. The Kaplan-Meier method and Cox-regression proportional hazards model were used to assess the impact of neoadjuvant treatment regimens on the cause-specific survival (CSS) and overall survival (OS) of LAEC. A propensity score model was utilized to balance baseline covariates. RESULTS: After propensity score matching, a total of 1986 LAEC patients were included for analysis, 1,655 patients treated with neo-CRT and 331 with neo-CT, respectively. The survival outcomes of LAEC treated with neo-CRT were comparable to those treated with neo-CT in terms of 5-year OS (39% vs. 36%, p = 0.63) and CSS (51% vs. 51%, p = 0.77). In the multivariate Cox analyses, sex, histological grade, ypT stage, ypN( +), and number of LN examined were independent factors for predicting OS and CSS among LAEC treated with neoadjuvant treatment. CONCLUSION: The present study based on large cohort demonstrated that no significant survival difference was observed between LAEC patients treated with neo-CRT versus neo-CT. However, the results needed to be confirmed in well-designed prospective trials.

Postoperative Radiotherapy Contributes to the Survival Benefit of Breast-Conserving Therapy over Mastectomy.

Purpose: A survival benefit of breast-conserving therapy (BCT) over mastectomy has been shown in recent studies. This study aimed to explore differences in recurrence patterns between BCT and mastectomy and clarify the contribution of radiotherapy (RT) to the survival benefit of BCT. Methods: Consecutive patients with pT1-2/pN0-1/M0 breast cancer between 2009 and 2015 in our institution were retrospectively reviewed and compared in matched cohorts using 1 : 1 propensity score matching (PSM). Results: A total of 2370 patients were enrolled with a median follow-up of 75 (3-148) months. In the cohort without regional nodal irradiation (RNI), WBI was associated with significantly increased 10-year relapse-free survival (RFS), distant metastasis-free survival (DMFS), and regional recurrence-free survival (RRFS) compared with mastectomy alone. There were 419 pairs in the cohort without RNI and 87 pairs in the cohort with RNI after PSM. In the PSM cohort, improved 10-year RFS (95.4% vs. 82.7%, p < 0.05), DMFS (97.4% vs. 84.1%, p < 0.05), and RRFS (99.1% vs. 95.5%, p < 0.05) were observed in WBI compared with mastectomy alone. Regarding the first recurrence event, WBI demonstrated a significantly lower cumulative rate of distant metastases than mastectomy alone. There was no significant difference in survival outcomes between WBI plus RNI and PMRT before and after the PSM. In patients without RNI, mastectomy alone was significantly associated with unfavorable RFS (HR = 2.3, 95% CI 1.2-4.5, p < 0.05) and DMFS (HR = 2.5, 95% CI 1.1-5.8, p < 0.05). Conclusion: This study found the benefit of RFS and DMFS in BCT patients compared with those treated with mastectomy without RNI but not in those treated with RNI. We hypothesized that RT played an important role in reducing the risk of regional recurrence and distant metastases.