Association of Sarcopenia With Toxicity and Survival in Postoperative Recurrent Esophageal Squamous Cell Carcinoma Patients Receiving Chemoradiotherapy.

BACKGROUND: Sarcopenia has been associated with treatment-related toxicities and poor survival in cancer patients. Our aim was to investigate the prevalence of sarcopenia in postoperative recurrent esophageal squamous cell carcinoma (ESCC) patients receiving chemoradiotherapy (CRT) and evaluate associations with treatment-related toxicity and prognosis. METHODS: One hundred and eighty-four patients with postoperative locoregional recurrent ESCC receiving CRT between January 2014 and December 2016 were included. The skeletal muscle area (SMA) was measured at the third lumbar vertebra level. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) less than 47.24/cm2/m2 for men and 36.92/cm2/m2 for women. Association of sarcopenia with overall survival (OS) was analyzed using univariate and multivariate cox regression models. RESULTS: Sarcopenia was observed in 94 of 184 (51.1%) patients. Sarcopenic patients had significantly higher rates of grade 3-4 toxicities compared to those without sarcopenia (36.2% vs 21.1%, p = 0.034). The survival rate at 12 and 24 months was 36.2% and 3.2% in the sarcopenic patients and 57.8% and 17.8% in the non-sarcopenic patients (p < 0.001). Multivariate cox regression analysis showed that sarcopenia was significantly associated with decreased OS (HR = 1.729, 95% CI 1.231-2.428, p = 0.002). CONCLUSIONS: Sarcopenia is an independent indicator of poor survival in postoperative locoregional recurrent ESCC patients treated with CRT. Early nutritional interventions before treatment may improve the prognosis.

Concurrent chemoradiotherapy with S-1 compared with concurrent chemoradiotherapy with docetaxel and cisplatin for locally advanced esophageal squamous cell carcinoma.

BACKGROUND: This retrospective study was to assess and compare the toxicity and efficacy of concurrent chemoradiotherapy (CCRT) with S-1 or docetaxel and cisplatin in patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC who received CCRT with S-1 (70 mg/m2 twice daily on days 1-14, every 3 weeks for 2 cycles, S-1 group) or docetaxel (25 mg/m2) and cisplatin (25 mg/m2) on day 1 weekly (DP group) between 2014 and 2016 were retrospectively analyzed. Radiotherapy was delivered in 1.8-2.0 Gy per fraction to a total dose of 50-60 Gy. Treatment-related toxicities (Common Terminology Criteria for Adverse Events version 4.0), response rate, and survival outcomes were compared between groups. RESULTS: A total of 175 patients were included in this study (72 in the S-1 group and 103 in the DP group). Baseline characteristics were well balanced between the two groups. The incidence of grade 3-4 adverse events were significantly lower in the S-1 group than that of the DP group (22.2% vs. 45.6%, p = 0.002). In the DP group, elderly patients (> 60 years) had a significantly higher rate of grade 3-4 adverse events than younger patients (58.1% vs. 31.3%, p = 0.01). The objective overall response rate (complete response + partial response) was 68.1% in the S-1 group, and 73.8% the DP group (p = 0.497). The 3-year overall survival was 34.7% in the S-1 group, and 38.8% in the DP group (p = 0.422). The 3-year progression free survival in the DP group was higher than that in the S-1 group but without significant difference (33.0% vs. 25.0%, p = 0.275). CONCLUSION: CCRT with S-1 is not inferior to CCRT with docetaxel and cisplatin and is better tolerated in in elderly patients with locally advanced ESCC.

Combination of long noncoding RNA MALAT1 and carcinoembryonic antigen for the diagnosis of malignant pleural effusion caused by lung cancer.

PURPOSE: Long noncoding RNAs (lncRNAs) are present in body fluids, but their potential as tumor biomarkers has never been investigated in malignant pleural effusion (MPE) caused by lung cancer. The aim of this study was to assess the clinical significance of lncRNAs in pleural effusion, which could potentially serve as diagnostic and predictive markers for lung cancer-associated MPE (LC-MPE). PATIENTS AND METHODS: RNAs from pleural effusion were extracted in 217 cases of LC-MPE and 132 cases of benign pleural effusion (BPE). Thirty-one lung cancer-associated lncRNAs were measured using quantitative real-time polymerase chain reaction (qRT-PCR). The level of carcinoembryonic antigen (CEA) was also determined. The receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were established to evaluate the sensitivity and specificity of the identified lncRNAs and other biomarkers. The correlations between baseline pleural effusion lncRNAs expression and response to chemotherapy were also analyzed. RESULTS: Three lncRNAs (MALAT1, H19, and CUDR) were found to have potential as diagnostic markers in LC-MPE. The AUCs for MALAT1, H19, CUDR, and CEA were 0.891, 0.783, 0.824, and 0.826, respectively. Using a logistic model, the combination of MALAT1 and CEA (AUC, 0.924) provided higher sensitivity and accuracy in predicting LC-MPE than CEA (AUC, 0.826) alone. Moreover, baseline MALAT1 expression in pleural fluid was inversely correlated with chemotherapy response in patients with LC-MPE. CONCLUSION: Pleural effusion lncRNAs were effective in differentiating LC-MPE from BPE. The combination of MALAT1 and CEA was more effective for LC-MPE diagnosis.

Neutrophil-to-lymphocyte ratio as a prognostic biomarker for patients with locally advanced esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

The present study evaluated the clinical and prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy (dCRT). A total of 517 patients with ESCC were enrolled and analysed retrospectively. The NLR was calculated at three time points: baseline, post-treatment, and at the time of tumor progression. Elevated NLR was defined as a ratio ≥5. High NLR at baseline was present in 204 (39%) patients and was significantly correlated with larger tumour size, advanced TNM stage, worse ECOG performance status, and dCRT response (p < 0.05). At a median follow-up of 17 months, patients with higher NLR at baseline had poorer progression-free survival (PFS) and overall survival (OS). On multivariate analysis, elevated NLR at baseline was independently associated with PFS and OS (HR = 1.529, p < 0.001 for PFS; HR = 1.856, p < 0.001 for OS). In addition, patients with high pre- and post-treatment NLR demonstrated worse clinical outcomes than other groups. Our results suggest that NLR is an independent prognostic indicator for patients with ESCC undergoing dCRT and changes in NLR level with treatment may indicate therapeutic benefit.

High expression of long non-coding RNA AFAP1-AS1 predicts chemoradioresistance and poor prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

To evaluate the clinical significance of lncRNAs in the resistance to cisplatin-based chemoradiotherapy in esophageal squamous cell carcinoma (ESCC). We focused on lncRNAs which were frequently reported in ESCC or were involved in chemoradiotherapy resistance. LncRNA expressions were examined in paired cisplatin-resistant and parental ESCC cell lines. Dysregulated lncRNAs were further measured in 162 pretreatment biopsy specimens of ESCC who received definitive chemoradiotherapy (dCRT). Then the correlations between lncRNA expression and response to dCRT and prognosis were analyzed. Three lncRNAs (AFAP1-AS1, UCA1, HOTAIR) were found to be deregulated in cisplatin-resistant cells compared with their parent cells. AFAP1-AS1 was significantly up-regulated in tumor tissues compared with adjacent normal tissues (P = 0.006). Furthermore, overexpression of AFAP1-AS1 was closely associated with lymph node metastasis (P < 0.001), distant metastasis (P = 0.016), advanced clinical stage (P = 0.002), and response to dCRT (P < 0.001). Kaplan-Meier survival analysis revealed that high expression of AFAP1-AS1 was significantly associated with shorter progression free survival (PFS) (median, 15 months vs. 27 months, P < 0.001) and overall survival (OS) (median, 29 months vs. 42 months, P < 0.001). In the multivariate analysis, high expression of AFAP1-AS1 was found to be an independent risk factor to predict poor PFS (HR, 1.626; P = 0.027) and OS (HR, 1.888; P = 0.004). Thus, high expression of AFAP1-AS1 could serve as a potential biomarker to predict tumor response and survival. Determination of this lncRNA expression might be useful for selection ESCC patients for dCRT. © 2016 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

[A randomized controlled trial of intensity-modulated radiation therapy plus docetaxel and cisplatin versus simple intensity-modulated radiation therapy in II-III stage esophageal carcinoma].

OBJECTIVE: To compare the efficacy and toxicity of intensity- modulated radiation therapy plus chemotherapy (IMRT-TP) with simple intensity-modulated radiation therapy (IMRT) in the treatment of locally advanced esophageal carcinoma. METHODS: A total of 170 eligible patients with locally advanced esophageal carcinoma were recruited prospectively from September 2004 to April 2008 and randomly divided into IMRT-TP group and IMRT group. Two groups were treated with IMRT of 6MV-X. The radiation dose was 60 Gy in 30 fractions in IMRT-TP group and 66 Gy in 30 fractions in IMRT group. The regimen of chemotherapy consisted of docetaxel and cisplatin in IMRT-TP group for 2 cycles. RESULTS: Of 170 patients, 160 completed the trial, including 75 patients of IMRT-TP group and 85 of IMRT group. As compared to IMRT group, total recurrence rate [69.3% (52/75) vs. 84.7% (72/85), P=0.020] and local recurrence rate [50.7% (38/75) vs. 67.1% (57/85), P=0.035] decreased in IMRT-TP group, the 5-year overall survival (29.3% vs. 15.3%, P=0.031) and 5-year recurrence free survival (24.0% vs. 10.6%, P=0.015) increased in IMRT-TP group. While severe side effect ratio increased obviously in IMRT-TP group [54.7% (41/75) vs. 4.7% (4/85), P=0.000]. CONCLUSION: As compare to simple IMRT, IMRT plus docetaxel and cisplatin can decrease the local recurrence rate, prolong the overall survival and regression-free survival, but bring more side effects.

[Application of simplified intensity modulated radiation therapy in gastric cancer after operation].

OBJECTIVE: To elucidate the application and the dosimetry characteristic of the simplified intensity modulated radiation therapy (sIMRT) for gastric cancer after operation, and to compare the dose distribution with intensity modulated radiation therapy (IMRT) and three-dimension conformal radiation therapy (3D-CRT). METHODS: Twelve patients with gastric cancer after operation were enrolled in this study. 3D-CRT plan, 5-field IMRT plans (20 degree, 80 degree, 180 degree, 280 degree, 340 degree) and 5-field sIMRT plans (20 degree, 80 degree, 180 degree, 280 degree, 340 degree) were performed for each patient. The conformal index (CI), heterogeneity index (HI) of the planning target volume (PTV) and the dose of normal organs were analyzed with the dose volume histogram (DVH). The total MU and treatment time were also compared. RESULTS: The sIMRT and IMRT plans had comparable CI (sIMRT>IMRT>3D-CRT), and showed better dose conformity but worse homogeneity than 3D-CRT. The percentage of volume receiving 20 Gy, 25 Gy, 30 Gy and 40 Gy by liver were significantly lower in sIMRT than that in 3D-CRT, and comparable to IMRT. All the dose volumes to kidneys with sIMRT were still significantly lower as compared to 3D-CRT, and comparable to IMRT. The sIMRT plan was better than IMRT plan in total MU and treatment time. CONCLUSIONS: sIMRT has comparable dose distribution in patients with gastric cancer to IMRT, but is significantly better than 3D-CRT. Treatment time of sIMRT is the shortest. So sIMRT technique can be applied more simply.

A randomized controlled study of single-agent cisplatin and radiotherapy versus docetaxel/cisplatin and radiotherapy in high-risk early-stage cervical cancer after radical surgery.

BACKGROUND: This study explored whether docetaxel/cisplatin and radiotherapy (TP-R) increases overall survival (OS) and recurrence-free survival (RFS) compared to single-agent cisplatin and radiotherapy (C-R) in patients with high-risk early-stage cervical cancer post surgery. METHODS: Patients with clinical stage IB and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or the diameter of the primary tumor ≥4 cm and/or depth of interstitial infiltration ≥1/2 and/or lymphovascular space invasion were eligible for this study. Patients were randomized to receive C-R or TP-R. Radiotherapy in both groups was external radiation (46-54 Gy) followed by high-dose rate brachytherapy (12-24 Gy). Patients were given cisplatin (40 mg/m(2)) every week for five cycles (C-R group) or docetaxel (30 mg/m(2)) and cisplatin (30 mg/m(2)) every week for five cycles (TP-R group). RESULTS: Between 2003 and 2008, 320 patients were entered onto the study. Final analyses included 285 patients. One hundred and forty patients comprised the C-R group and 145 were in the TP-R group. The 5-year OS were 74.3 % in the C-R group and 82.8 % in the TP-R group. The hazard ratio (HR) for death was 0.65 in the TP-R group (95 % CI: 0.39-1.09, P = 0.098). The RFS were 69.3 % in the C-R group and 79.3 % in the TP-R group, and the HR for recurrence was 0.64 in the TP-R group (95 % CI: 0.40-1.03, P = 0.061). Recurrence rates were similar in both groups (27 in the C-R group and 18 in the TP-R group, P = 0.112). The seriousness of late side effects was similar in the two groups, with a higher rate of reversible hematological effects in the TP-R group. CONCLUSIONS: Compared with single-agent cisplatin and radiotherapy, docetaxel/cisplatin in combination with radiotherapy does not increase OS but has the trend of increasing RFS in patients with high-risk early-stage cervical cancer. However, docetaxel/cisplatin in combination with radiotherapy is associated with a higher incidence of side effects, this effect was reversible, and the incidence of late side effects was similar in the two treatment groups.

A randomized, controlled, multicenter study comparing intensity-modulated radiotherapy plus concurrent chemotherapy with chemotherapy alone in gastric cancer patients with D2 resection.

BACKGROUND AND PURPOSE: The role of postoperative chemoradiotherapy in the treatment of patients with gastric cancer with D2 lymph node curative dissection is not well established. In this study, we compared postoperative intensity-modulated radiotherapy plus chemotherapy (IMRT-C) with chemotherapy-only in this patient population. MATERIALS AND METHODS: We randomly assigned patients with D2 lymph node dissection in gastric cancer to IMRT-C or chemotherapy-only groups. The adjuvant IMRT-C consisted of 400 mg of fluorouracil per square meter of body-surface area per day plus 20mg of leucovorin per square meter of body-surface area per day for 5 days, followed by 45 Gy of IMRT for 5 weeks, with fluorouracil and leucovorin on the first 4 and the last 3 days of radiotherapy. Two 5-day cycles of fluorouracil and leucovorin were given 4 weeks after the completion of IMRT. Chemotherapy-only group was given the same chemotherapy regimens as IMRT-C group. RESULTS: The median overall survival (OS) in the chemotherapy-only group was 48 months, as compared with 58 months in the IMRT-C group; the hazard ratio for death was 1.24 (95% confidence interval, 0.94-1.65; P=0.122). IMRT-C was associated with increases in the median duration of recurrence-free survival (RFS) (36 months vs. 50 months), the hazard ratio for recurrence was 1.35 (95% confidence interval, 1.03-1.78; P=0.029). COX multivariate regression analysis showed that lymph node metastasis and TNM stage were both the independent prognostic factors. Rates of all grade adverse events were similar in the two treatment groups. CONCLUSIONS: IMRT-C improved RFS, but did not significantly improve OS among patients with D2 lymph node dissection in gastric cancer. Using IMRT plus chemotherapy was feasible and well tolerated in patients with gastric cancer after D2 resection.

Efficacy analysis of simplified intensity-modulated radiotherapy with high or conventional dose and concurrent chemotherapy for patients with neck and upper thoracic esophageal carcinoma.

For patients with neck and upper thoracic esophageal carcinoma, it is difficult to control lymph node metastases with conventional dose therapy. In this study, we assessed the feasibility of simplified intensity-modulated radiotherapy (sIMRT) and concurrent chemotherapy for 44 patients and boosted high-dose to metastatic lymph nodes.Three radiation treatment volumes were defined: PGTVnd, with which 68.1 Gy was delivered in high dose group (hsIMRT group), and 60 Gy in the conventional dose group (csIMRT group); PTV1, featuring 63.9 Gy in the hsIMRT group and 60Gy in the csIMRT group; PTV2, with 54 Gy given to both groups. The sIMRT plan included 5 equi-angular coplanar beams. All patients received the cisplatin and 5-FU regimen concurrently with radiotherapy. The treatment was completed within six weeks and one case with grade three acute bronchitis was observed in hsIMRT group. For esophageal lesions, 80% complete response (CR) and 20% partial response (PR) rates were found in the hsIMRT group, and 79.2% CR, with 20.8% PR, in the csIMRT group; for lymph node lesions, 75% CR and 25% PR rates were observed in the hsIMRT group, with 45.8% and 37.5% respectively in the csIMRT group (P <0.05). The differences in 1-, 2- and 3-year relapse-free survival rates were all statistically significant (P <0.05). The major toxicity observed in both groups was Grade I~II leucopenia. sIMRT can generate a desirable dose distribution in treatment of neck and upper thoracic esophageal carcinoma with a better short-term efficacy. Boosted high dosing to metastatic lymph nodes can increase the relapse-free survival rate.

Berberine elicits anti-arrhythmic effects via IK1/Kir2.1 in the rat type 2 diabetic myocardial infarction model.

The purpose of this study was to explore the anti-arrhythmic mechanisms of berberine in diabetic rats with myocardial infarction. Sixty rats were divided into four groups: (1) normal control; (2) myocardial infarction group (MI); (3) Type 2 diabetes with myocardial infarction group (T2DM+MI); and (4) Type 2 diabetic with myocardial infarction berberine-treated group (BBR). Berberine (60 mg/kg/day) was administered after coronary artery ligation in the T2DM+MI group for 14 days. Currents were measured using whole-cell patch-clamp techniques. Western blot was performed for quantification of target proteins. The study showed that arrhythmias induced by myocardial infarction were aggravated in diabetic rats. Arrhythmia scores in the MI group were significantly higher than in the control group. Interestingly, the administration of berberine at a dose of 60 mg/kg/d recovered arrhythmia scores (P > 0.05). RMP (Resting membrane potential) which could be recovered by berberine (P < 0.05), was significantly reduced in both the infarction groups. I(K1) current and current density markedly decreased in the MI and T2DM+MI groups (P < 0.05) and could be reversed by berberine (P < 0.05). The relative expression of Kir2.1 in rats in the MI and T2DM+MI group were both significantly decreased (P < 0.05); berberine recovered depressed Kir2.1 to nearly normal levels. The results suggest that the effects of berberine on I(K1)/Kir2.1 may be an important mechanism for producing anti-arrhythmic effects.

[Feasibility and short-term efficacy of simplified intensity-modulated radiotherapy and concurrent chemotherapy for neck and upper thoracic esophageal carcinoma].

BACKGROUND AND OBJECTIVE: For neck and upper thoracic esophageal carcinoma, three dimensional conformal radiation therapy (3D-CRT) does not necessarily meet all clinical requirements while intensity modulated radiation therapy (IMRT) may take up a lot of labour power and material resources. This study was to explore the feasibility of simplified IMPT(sIMRT) and concurrent chemotherapy for neck and upper thoracic esophageal carcinoma, and to investigate the acute toxicities and short-term efficacy of this treatment modality. METHODS: sIMRT plans were designed for 30 patients with neck and upper thoracic esophageal carcinoma. Two target volumes were defined: PTV1, which was designed to irradiate to 64 Gy (2.13 Gy x 30 fractions); PTV2, which was given to 54 Gy (1.8 Gy x 30). The sIMRT plan included five equiangular coplanar beams. All patients concurrently received DDP+5-FU regimen with radiotherapy on d1-5 and d29-33. Chemotherapy was repeated for two cycles 28 days after radiotherapy. RESULTS: The treatment was completed for all patients within 6 weeks, and only one patient had Grade 3 acute bronchitis. The complete response (CR) rate was 90.0% (27/30) and the partial response (PR) rate 10.0% (3/30). Overall response was 100% for esophageal lesions and the CR rate 76.5% (13/17). The PR rate was 23.5% (4/17) in lymph node lesions. The major toxicities observed were Grades I-II leukocytopenia. CONCLUSIONS: sIMRT can generate desirable dose distribution for neck and upper thoracic esophageal carcinoma, which is similar to sophisticated IMRT but obviously better than 3D-CRT. The short-term efficacy of sIMRT is satisfactory and its acute toxicities are tolerable.

Inhibition of lung metastasis in mice by intravascular injection of dendritic cells and natural killer cells.

To investigate the efficacy of dendritic cells and natural killer cells in the inhibition of lung metastasis, we injected dendritic cells and natural killer cells intravascularly into mice bearing B16F10 tumour melanoma cells. This efficiently inhibited tumor growth and prolonged survival. In addition, surviving mice developed a long-lasting memory response against the original tumor when re-challenged with live tumor cells. Intravenous administration of dendritic cells and natural killer cells may be a potential way to treat lung metastasis in patients.

Alterations of sarcolemmal phospholipase D and phosphatidate phosphohydrolase in congestive heart failure.

Phospholipase D 2 (PLD2) is the major PLD isozyme associated with the cardiac sarcolemmal (SL) membrane. Hydrolysis of SL phosphatidylcholine (PC) by PLD2 produces phosphatidic acid (PA), which is then converted to 1,2 diacylglycerol (DAG) by the action of phosphatidate phosphohydrolase type 2 (PAP2). In view of the role of both PA and DAG in the regulation of Ca(2+) movements and the association of abnormal Ca(2+) homeostasis with congestive heart failure (CHF), we examined the status of both PLD2 and PAP2 in SL membranes in the infarcted heart upon occluding the left coronary artery in rats for 1, 2, 4, 8 and 16 weeks. A time-dependent increase in both SL PLD2 and PAP2 activities was observed in the non-infarcted left ventricular tissue following myocardial infarction (MI); however, the increase in PAP2 activity was greater than that in PLD2 activity. Furthermore, the contents of both PA and PC were reduced, whereas that of DAG was increased in the failing heart SL membrane. Treatment of the CHF animals with imidapril, an angiotensin-converting enzyme (ACE) inhibitor, attenuated the observed changes in heart function, SL PLD2 and PAP2 activities, as well as SL PA, PC and DAG contents. The results suggest that heart failure is associated with increased activities of both PLD2 and PAP2 in the SL membrane and the beneficial effect of imidapril on heart function may be due to its ability to prevent these changes in the phospholipid signaling molecules in the cardiac SL membrane.