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BackgroundAcidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxel + cisplatin regimen in patients with metastatic breast cancer (MBC).MethodsPatients enrolled were randomly assigned to three arms: Arm A, docetaxel 75 mg/m2 followed by cisplatin 75 mg/m2 on d4, repeated every 21 days with a maximum of 6 cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80 mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3 days on 4 days off) was maintained up to maximum 66 weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100 mg p.o. bid. The primary endpoint was response rate.ResultsNinety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5 %, respectively. Median TTP for arm A (n = 32), B (n = 31), C (n = 31) were 8.7, 9.4, and 9.7 months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (46.9 % vs. 67.7 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045). Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8 months, respectively (p = 0.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2 months, p = 0.090). No additional toxicity was observed with PPI.ConclusionsThe results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial.Trial registrationClinicaltrials.gov identifier: NCT01069081.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0194-x) contains supplementary material, which is available to authorized users.

Introduction Systemic nutrition and inflammation are the critical factors in cancer initiation, evolution, and progression. This study aimed to evaluate the prognostic value of the prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) in hepatocellular carcinoma (HCC) patients who underwent liver resection. Methods A total of 202 HCC patients met the criteria and were included in the study. The receiver operating characteristic (ROC) curve was used to calculate the optimal PNI and SII cutoff values. The relationship between PNI/SII and clinicopathologic parameters was analyzed. The effect of PNI and SII on recurrence-free survival (RFS) and overall survival (OS) was investigated by Kaplan-Meier curves and Cox proportional hazards models. Results The areas under the ROC curve for PNI and SII were 0.64 and 0.58. The ideal preoperative PNI and SII cutoff values were 50.25 and 461.5, respectively. Multivariate Cox regression analysis identified that the PNI (P = 0.001) and tumor diameter (P = 0.018) were significant prognostic markers for RFS, and that the PNI (P = 0.049), SII (P = 0.039) and tumor diameter (P = 0.001) were significant prognostic markers for OS. The median RFS in the PNI-low and PNI-high groups was 13.5 months and 23 months (P = 0.001), and that in the SII-low and SII-high groups was 18 months and 15 months (P = 0.03), respectively. The median OS in the PNI-low and PNI-high groups was 24 months and 39 months (P = 0.001), and that in the SII-low and SII-high groups was 36 months and 22 months (P = 0.002), respectively. Conclusion Interestingly, we found that PNI and SII could be important prognostic parameters for HCC patients who under hepatectomy.

Background Many recent studies have demonstrated the predominant role chronic inflammation plays in cancer cell propagation, angiogenesis and immunosuppression. Cancer-related inflammation (CRI) has been shown to correlate with poor cancer prognosis. Our study aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with hepatocellular carcinoma (HCC) who have undergone liver resection. Methods Between 2012 and 2015, 239 patients with HCC who had undergone liver resection at XiangYa Hospital Central South University were included in this study. The values of simple inflammatory markers, including the NLR and PLR, used in predicting the long-term outcomes of these patients were evaluated using Kaplan–Meier curves and Cox regression models. Results The cutoff values of the NLR and PLR were 2.92 and 128.1, respectively. In multivariate Cox regression analysis, high NLR (≥2.92) and high PLR (≥128.1) were independent risk factors predicting poorer outcomes in patients with HCC. However, high NLR and high PLR were prognostic factors in tumor size and tumor number. Conclusions In this study, we identified that high NLR (≥2.92) and high PLR (≥128.1) are useful prognostic factors in predicting outcomes in patients with HCC whom underwent liver resection.

Esophageal squamous cell carcinomas (ESCC) have become a severe threat to health and the current treatments for ESCC are frequently not effective. Recent epidemiological studies suggest that the anti-hyperglycemic agent metformin may reduce the risk of developing cancer, including ESCC, among diabetic patients. However, the antitumor effects of metformin on ESCC and the mechanisms underlying its cell cycle regulation remain elusive. The findings reported herein show that the anti-proliferative action of metformin on ESCC cell lines is partially mediated by AMPK. Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1. In vivo experiments further showed that metformin inhibited tumor growth in a ESCC xenograft model. Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo. In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model. AMPK, p53, p21CIP1, p27KIP1 and cyclinD1 are involved in the inhibition of tumor growth that is induced by metformin and cell cycle arrest in ESCC. These findings indicate that metformin has the potential for use in the treatment of ESCC.

Metformin is used as a first-line therapy for type 2 diabetes, with reports of its usefulness for the prevention and control of several types of cancers. This study investigated the effects of metformin on hepatocellular carcinoma (HCC). The human HCC cell lines HepG2 and PLC/PRF/5 were cultured and treated with metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of adenosine monophosphate (AMP)-activated protein kinase. Changes in cell viability and cell cycle distribution were evaluated by MTT and flow cytometry, respectively. Apoptosis was assessed by fluorescent-dye staining. An HCC model was established in 6- to 8-week-old BALB/c-nu mice by subcutaneous injection of PLC/PRF/5 cells. After 1 week, mice were treated intragastrically with metformin or vehicle. Tumor xenograft tissues were examined using immunohistochemistry for evaluation of the the expression of cyclin D1, p21CIP and p27KIP. HCC cells and tissues from the in vitro and in vivo experiments, respectively, were subjected to protein extraction and western blotting. We found that metformin treatment reduced HCC cell viability in a dose-dependent manner similar to AICAR treatment. In addition, metformin treatment induced HCC cell cycle arrest at G1/G0 phase and apoptosis. Intragastric treatment of the mouse PLC/PRF/5 cell xenograft model with metformin showed that metformin not only blocked tumor progression, but also reduced tumor morbidity. Treatment with metformin upregulated the expression of p21CIP and p27KIP, but downregulated cyclin D1 levels, both in vitro and in vivo. Metformin treatment also upregulated the expression of phosphorylated AMPK protein in xenograft tissues. These findings indicate that metformin warrants further evaluation as a novel therapeutic and preventive strategy against HCC.

The effects of fructooligosaccharide (FOS) on growth performance, immunity and predominant autochthonous intestinal microbiota of shrimp (Litopenaeus vannamei) fed diets with fish meal (FM) partially replaced by soybean meal (SBM) were evaluated. After acclimation, shrimps (1.82 ± 0.01 g/kg) were allocated into 15 tanks (25 shrimps per tank) and fed five different diets including positive control diet (C0, containing 250 g/kg FM and 285 g/kg SBM), control diet (C, containing 125 g/kg FM, 439 g/kg SBM) and three experimental diets supplemented with 1.0 g/kg FOS (T1), 2.0 g/kg FOS (T2) and 4.0 g/kg FOS (T3) to control diet (C) respectively. Shrimps were fed diets to apparent satiation three times per day, and 15 shrimps from each aquarium were randomly sampled and analysed at the end of the 6-week feeding trial. The results showed that FBW, WGR, SGR and SR decreased, while FCR and FI increased significantly in control (C) compared with positive control (C0). Besides, significantly decreased trypsase and lipase activities, and SOD, AKP and ACP activities were recorded in control (C) compared with positive control (C0). On the other hand, significantly improved SGR and decreased FCR were observed in groups T1, T2 and T3 compared with control (C). Moreover, lipase and amylase activities enhanced significantly in group T3 compared with the control (C), while GOT and GPT activities dropped significantly with the increment supplementation of FOS in diets. Compared with the control (C), SOD activity enhanced significantly and MDA level decreased significantly in groups T2 and T3, and improved AKP and ACP activities were observed in group T3. In addition, dietary FOS improved the microbial diversity, and suppressed several potential pathogens, such as Vibrio tubiashii, Vibrio parahaemolyticus and Photobacterium damselae-like strains in the intestine of shrimp. Overall, these results proved FOS could relieve the side effects induced by SBM and supported the use of 2.0-4.0 g/kg FOS in shrimp diets with FM partially replaced by SBM. K E Y W O R D S Fructooligosaccharide, growth performance, immunity, intestinal microbiota, Litopenaeus vannamei | 195 HU et al.

Aim: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. Methods: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. Results: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm ( p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240–0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm ( p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). Conclusion: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population. Trial Registration: ClinicalTrials.gov identifier: NCT02763566.