Dose escalation of 3D radiotherapy is effective for esophageal squamous cell carcinoma: a multicenter retrospective analysis (3JECROG R-03).

BACKGROUND: To evaluate the impact of radiation dose escalation on overall survival (OS) in patients with non-metastatic esophageal squamous cell carcinoma (ESCC) treated with radical radiotherapy. METHODS: The clinical data of ESCC patients treated with three-dimensional (3D) radiotherapy alone or chemoradiotherapy were collected from multiple institutes and retrospectively analyzed. Patients who received radiation dose ≥40 Gy were included. Radiation dose as a continuous variable was entered into the Cox regression model by using penalized spline regression to allow for a nonlinear relationship between radiation dose and OS to be identified. Patients were stratified into five groups according to EQD2. The Kaplan-Meier method was used to assess the OS in different dose groups. Univariate and multivariate analyses were performed to evaluate the factors associated with OS. RESULTS: A total of 2,469 patients were included from 10 institutes across China. The median follow-up time was 58.3 months [95% confidence interval (CI): 56.4-60.2 months]. The median OS and PFS time were 24.3 months (95% CI: 22.5-26.2 months) and 18.0 months (95% CI: 16.4-19.6 months), respectively. The risk of death decreased sharply with a dose up to 60 to 62 Gy, before increasing slightly after the dose was elevated beyond 62 Gy. Multivariate analysis indicated that the chance of death was significantly decreased in patients who received radiotherapy doses of 60-62 Gy [P=0.028, hazard ratio (HR) 0.85, 95% CI: 0.73-0.98)], compared with those who received radiotherapy doses of 40-60 Gy. CONCLUSIONS: Our results reveal radiation dose is a significant prognostic factor of survival for ESCC patients. Higher radiation dose contributes to much more favorable survival outcomes for ESCC patients receiving radical radiotherapy by modern techniques, and 60 Gy or above might be the most optimal radiation dose.

Stage III Esophageal Squamous Cell Carcinoma Patients With Three-Dimensional Conformal or Intensity-Modulated Radiotherapy: A Multicenter Retrospective Study.

Aim: To evaluate long-term outcome and prognostic factors of stage III esophageal cancer after definitive radiotherapy using three dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) techniques. Methods: Patients with T3N1M0/T4N0-1M0 esophageal squamous cell carcinoma (ESCC) treated with definitive radiotherapy from 2002 to 2016 in 10 Chinese medical centers were retrospectively analyzed. Overall survival (OS) and progression-free survival (PFS) rates were calculated. Prognostic factors were analyzed by Log-rank test and multivariable Cox model. Results: Survival data of 1,450 patients were retrospectively collected. With a median follow-up time of 65.9 months, 1-, 3-, and 5-year OS rates were 69.3, 36.7, and 27.7%, respectively, and PFS rates were 58.6, 32.7, and 27.4%, respectively. Univariable analyses showed that gender, age, lesion location, lesion length, largest tumor diameter, lymph node metastasis, gross tumor volume, EQD2, short-term response, and concurrent chemotherapy were prognostic factors for OS. Multivariable analyses showed that lesion location, T-classification, GTV size, EQD2, and short-term response to RT were independent prognostic factors for OS, and tumor diameter, GTV size, and short-term response were independent prognostic factors for PFS. Conclusions: This study demonstrated that definitive radiotherapy using 3DCRT and IMRT provides promising outcomes for locally advanced ESCC.

Evaluation of heavy metals and metabolites in the urine of patients with breast cancer.

Epidemiologic studies demonstrated that the environment serves a crucial role in cancer development. Heavy metals, including arsenic (As), cadmium (cd), chromium (Cr), lead and mercury, are considered to be carcinogens or co-carcinogens. Furthermore, Cd has been detected in breast cancer (BC) tissue at high concentrations. The present study aimed to investigate the correlation between heavy metals detected in urine and urine metabolome of patients with BC, and their association with cancer development. Nuclear magnetic resonance was used to determine urine metabolites and an inductively coupled plasma mass spectrometry system was used to detect heavy metals in urine samples. The results demonstrated that Cd was markedly increased in the urine of patients with BC compared with the control population (approximately 2-fold). Cr and As were also increased in the urine of patients with BC. In addition, numerous small molecule metabolites were altered in the urine of patients with BC compared with the control population. This study also demonstrated that alterations in small molecule metabolites in the urine of patients with BC were very similar to results from a previous report. These findings indicated that environmental exposure to Cd, As, or Cr could influence the urine levels of metabolites, which may be involved in BC development. Further investigation is therefore required to examine a larger range of samples from different countries or areas in order to understand the impact of heavy metals on metabolism and BC development.

High CD4⁺ T cell density is associated with poor prognosis in patients with non-muscle-invasive bladder cancer.

PURPOSE: The aim of this study was to investigate the clinical significance of CD4(+) T cells in non-muscle-invasive bladder cancer (NMIBC) tissues in situ. METHODS: Immunohistochemistry was used to examine the distribution of CD4(+) T cells in 131 NMIBC tissues. Kaplan-Meier analysis and Cox proportional hazards regression models were applied to estimate overall survival (OS) and recurrence-free survival (RFS). RESULTS: NMIBC patients were divided into two groups based on the median frequency of CD4(+) T cells (median, 1/×400 high resolution). On univariate analysis, CD4(+) T cell density was inversely associated with overall survival (P = 0.01). In those patients with high CD4(+) T density, 5-year OS rates was only 77%, compared with 86% in those with low density, respectively. Although CD4(+) T cell density showed no prognostic significance for RFS (P = 0.36), 5-year RFS rates of patients with high CD4(+) T density (58%) was lower than those of patients with low CD4(+) T density (65%, respectively). By multivariate analysis, tumor infiltrating CD4(+) T cell density emerged as an independent prognostic factor for OS (HR, 2.75; P = 0.004). In addition, no association was found between CD4(+) T cell density and any clinicopathological variables (P > 0.05). CONCLUSION: Our findings suggest that CD4(+) T cells could potentially serve as a poor prognostic marker for patients with NMIBC.

High level of microtubule-associated protein light chain 3 predicts poor prognosis in resectable esophageal squamous cell carcinoma.

Microtubule-associated protein light chain 3 (LC3) is a key mediator bridging autophagy, apoptosis and differentiation. However, its role and clinical significance in resectable esophageal squamous cell carcinoma (ESCC) is still scanty. The purpose of this study was to investigate the clinical significance of LC3 by immunohistochemistry in a group of patients with ESCC treated with surgical resection. Tissue microarray that included 253 surgically resected ESCC specimens was successfully generated for immunohistochemical evaluation. The clinical/prognostic significance of LC3 expression was analyzed statistically. The association of LC3 expression with the ESCC survival rate was assessed by Kaplan-Meier and Cox proportional-hazards regression. The results showed that the immunostaining of LC3 was distributed in cytoplasm and plasma-membrane. Significantly high LC3 expression was found in ESCC cells compared with that of normal esophageal epithelial cells. Patients with low expression of LC3 demonstrated higher overall survival compared with those with high expression of LC3 (mean of 71.1 months versus 55.5 months, P = 0.022). A similar result was observed for disease-free survival (mean of 68.7 months versus 51.8 months, P = 0.021). In subgroup analysis, LC3 expression could stratify pN0 patients with ESCC. Multivariate analysis showed that the level of LC3 expression was an independent prognostic factor in ESCC (RR = 1.407, P = 0.049). This paper shows high level of LC3 suggests poor prognosis for resectable ESCC patients.

The predictive value of histological tumor regression grading (TRG) for therapeutic evaluation in locally advanced esophageal carcinoma treated with neoadjuvant chemotherapy.

Response criteria remain controversial in therapeutic evaluation for locally advanced esophageal carcinoma treated with neoadjuvant chemotherapy. We aimed to identify the predictive value of tumor regression grading (TRG) in tumor response and prognosis. Fifty-two patients who underwent neoadjuvant chemotherapy followed by esophagectomy and radical 2-field lymphadenectomy between June 2007 and June 2011 were included in this study. All tissue specimens were reassessed according to the TRG scale. Potential prognostic factors, including clinicopathologic factors, were evaluated. Survival curves were generated by using the Kaplan-Meier method and compared with the log-rank test. Prognostic factors were determined with multivariate analysis by using the Cox regression model. Our results showed that of 52 cases, 43 (83%) were squamous cell carcinoma and 9 (17%) were adenocarcinoma. TRG was correlated with pathologic T(P = 0.006) and N (P < 0.001) categories. Median overall survival for the entire cohort was 33 months. The 1- and 2-year overall survival rates were 71% and 44%, respectively. Univariate survival analysis results showed that favorable prognostic factors were histological subtype (P = 0.003), pathologic T category (P = 0.026), pathologic N category (P < 0.001), and TRG G0 (P = 0.041). Multivariate analyses identified pathologic N category (P < 0.001) as a significant independent prognostic parameter. Our results indicate that histomorphologic TRG can be considered as an alternative option to predict the therapeutic efficacy and prognostic factor for patients with locally advanced esophageal carcinoma treated by neoadjuvant chemotherapy.

A new alternative for bony chest wall reconstruction using biomaterial artificial rib and pleura: animal experiment and clinical application.

OBJECTIVE: To evaluate a new method for chest wall reconstruction using porcine-derived artificial rib and pleura in an animal experiment. Further, the clinical application was performed in five patients with large defects in the chest wall as a preliminary observation. METHODS: In animal experiments, a full-thickness chest wall defect of 7 cm × 8 cm was created in 12 adult mongrel dogs. Six dogs underwent reconstruction with porcine-derived artificial ribs and pleura (test group), and six with methylmethacrylate and double polyester mesh in the form of traditional Marlex sandwich technique (control group). At follow-up of each for 3, 6, and 12 months postoperatively, a general performance assessment and thoracic radiography were performed. Gross and histopathological examinations were carried out following humane euthanasia at the time of last follow-up. In clinical application, five patients with wide tumor resection in the chest wall underwent reconstruction with porcine-derived artificial ribs and pleura as well. RESULTS: In animal experiment, no perioperative death or hyperpyrexia occurred and no difference in either infection or dyspnea was noted between the two groups. Postoperative radiography revealed good thoracic integrity with no evidence of collapse, deformation, or abnormal movement in the test group. In the control group, similar results were observed, except that two dogs had abnormal movement in the chest wall associated with respiration. Severe adhesions between the 'sandwich' complex and the host tissues were identified in the control group, but by contrast, only mild adhesions were noted in the test group. The non-degradable polyester mesh induced fibrous proliferation and rejection, whereas the artificial pleura was absorbed with mild fibrous hyperplasia after 12 months. In clinical application, no thoracic deformity, chronic pain, or respiratory discomfort were observed at 1 or 12 postoperative months. CONCLUSIONS: Porcine-derived ribs and pleura can be employed safely to create an artificial chest wall to repair bony chest defects. The clinical results corresponded well with those of animal experiments, and thus confirmed the safety and feasibility of this new alternative of chest wall reconstruction. However, a long-term study in a large number is needed due to the small number of animals in this study.