Prognostic value of systemic inflammation and for patients with colorectal cancer cachexia.

BACKGROUND: The development and progression of cancer cachexia are connected to systemic inflammation and physical performance. However, few relevant studies have reported the survival outcomes prediction of systemic inflammation and physical performance in patients with colorectal cancer (CRC) cachexia. This study investigated the prognostic prediction value of systemic inflammation and performance status in patients with CRC cachexia. METHODS: This multicentre cohort study prospectively collected 905 patients with CRC (58.3% males, 59.3 ± 11.5 years old). Cancer cachexia was diagnosed according to the 2011 Fearon Cachexia Diagnostic Consensus. The prognostic value of systematic inflammatory indicators was determined using the area under the curve, concordance index, and multivariate survival analysis. Performance status was evaluated with Eastern Coopertive Oncology Group performance score (ECOG-PS). Survival data were analysed using univariate and multivariate Cox regression analyses. RESULTS: The area under the curve, concordance index and survival analysis showed that C-reactive protein (CRP), lymphocyte to CRP ratio (LCR) and CRP to albumin ratio (CAR) were more stable and consistent with the survival of patients with CRC, both in non-cachexia and cachexia populations. Among patients with CRC cachexia, high inflammation [low LCR, hazard ratio (HR) 95% confidence interval (95% CI) = 3.33 (2.08-5.32); high CAR, HR (95% CI) = 2.92 (1.88-4.55); high CRP, HR (95% CI) = 3.12 (2.08-4.67)] indicated a worse prognosis, compared with non-cachexia patients [low LCR, HR (95% CI) = 2.28 (1.65-3.16); high CAR, HR (95% CI) = 2.36 (1.71-3.25); high CRP, HR (95% CI) = 2.58 (1.85-3.60)]. Similarly, among patients with CRC cachexia, high PS [ECOG-PS 2, HR (95% CI) = 1.61 (1.04-2.50); ECOG-PS 3/4, HR (95% CI) = 2.91 (1.69-5.00]) indicated a worse prognosis, compared with patients with CRC without cachexia [ECOG-PS 2, HR (95% CI) = 1.28 (0.90-1.81); ECOG-PS 3/4, HR (95% CI) = 2.41 (1.32-4.39]). Patients with CRC cachexia with an ECOG-PS score of 2 or 3-4 and a high inflammation had a shorter median survival time, compared with patients with an ECOG-PS score of 0/1 and a low inflammation. CONCLUSIONS: The systemic inflammatory markers LCR, CAR and CRP have stable prognostic values in patients with CRC. The ECOG-PS may be an independent risk factor for CRC. Combined evaluation of systemic inflammation and ECOG-PS in patients with CRC cachexia could provide a simple survival prediction.

The GLIM criteria as an effective tool for nutrition assessment and survival prediction in older adult cancer patients.

BACKGROUND & AIMS: Elderly cancer patients are at particularly high risk for malnutrition because both the disease and the old age threaten their nutritional status. The Global Leadership Initiative on Malnutrition (GLIM) released new universal criteria for diagnosing and grading malnutrition, but the validation of these criteria in elderly cancer population is not well documented. Our objective was to investigate the application of the GLIM criteria in nutrition assessment and survival prediction in elderly cancer patients. METHODS: This retrospective cohort analysis was conducted on a primary cohort of 1192 cancer patients aged 65 years or older enrolled from a multi-institutional registry, and a validation cohort of 300 elderly cancer patients treated at the First Affiliated Hospital of Sun Yat-sen University. Patients considered at-risk for malnutrition based on the NRS-2002 were assessed using the GLIM criteria. The association between the nutritional status and patients' overall survival (OS) was then analyzed by the Kaplan-Meier method and a Cox model. A nomogram was also established that included additional independent clinical prognostic variables. To determine the predictive accuracy and discriminatory capacity of the nomogram, the C-index, receiver operating characteristic (ROC) curve and calibration curve were evaluated. RESULTS: The percentage of patients considered "at-risk" for malnutrition was 64.8% and 67.3% for the primary and validation cohorts, respectively. GLIM-defined malnutrition was diagnosed in 48.4% of patients in the primary cohort and 46.0% in the validation cohort. In the primary cohort, patients at risk of malnutrition (NRS-2002 ≥ 3) showed a worse OS than those with a NRS-2002 < 3 (HR 1.34, 1.10-1.64; p = 0.003). Additionally, patients with GLIM-defined severe malnutrition (HR1.71, 1.37-2.14; p < 0.001) or moderate malnutrition (HR1.35, 1.09-1.66; p = 0.006) showed a significantly shorter OS compared to those without malnutrition. The nomogram incorporating the domains of the GLIM with other variables was accurate, especially for predicting the 1- and 2-year overall survival rates. CONCLUSIONS: The GLIM criteria can be used in elderly cancer patients not only to assess malnutrition, but also to predict survival outcome. The nomogram developed based on the GLIM domains can provide a more accurate prediction of the prognosis than existing systems.

Deregulation of MicroRNA-375 Inhibits Proliferation and Migration in Gastric Cancer in Association With Autophagy-Mediated AKT/mTOR Signaling Pathways.

Gastric cancer is a deadly disease. Some microRNAs are involved in tumor invasion and metastasis. Underexpression of miR-375 has been correlated with tumorigenesis, treatment resistance, and poor prognosis. In this study, we first analyzed the profiles and prognostic values of miR-375 expression in gastric cancer tissues from a public database, and the expression level of miR-375 in gastric cancer samples and gastric cancer cell lines was then analyzed by quantitative real- time polymerase chain reaction. Significant underexpression of miR-375 was seen in all the gastric cancer samples compared to paired paracarcinoma tissues, and the expression level of miR-375 in the gastric cancer cell lines was negatively associated with the cell migration ability. A Cell proliferation (CCK-8) assay was performed to examine cell viability. Overexpression of miR-375 suppressed the proliferation of gastric cancer cells. A Western blot analysis was carried out to test protein expression. Overexpression of miR-375 inhibited autophagy through the AKT/ mammalian target of rapamycin signaling pathway. MiR-375 regulated invasion and migration via AKT/ mammalian target of rapamycin pathway-mediated epithelial-to-mesenchymal transition. Wound healing and migration assays were used to determine the motility of gastric cancer cells. A gastric cancer xenograft nude mouse model was used for an in vivo efficacy evaluation. Overexpression of miR-375 significantly suppressed cell proliferation in the established gastric cancer xenograft nude mouse model. Our results demonstrate that increasing the expression level of miR-375 suppresses proliferation in vitro and in vivo, and they provide a mechanistic and applicable rationale for the future clinical evaluation of miR-375 in gastric cancer treatment. Our findings provide not only new information about the molecular mechanism of microRNAs in regulating invasion and migration in gastric cancer but also a theoretical principle for a potential targeted therapy for gastric cancer.

Determinants and nutritional assessment value of hand grip strength in patients hospitalized with cancer.

BACKGROUND AND OBJECTIVES: Hand grip strength (HGS) has emerged as a predictor of the nutritional status. However, many factors may modify the malnutrition-HGS association. This study explored the nutritional assessment value and determinants of HGS in patients hospitalized with cancer. METHODS AND STUDY DESIGN: In this multicenter, retrospective, observational study (11,314 patients), the Receiver operator characteristic curve was used to observe HGS and nutritional status sensitivity/specificity. Sex; age; height; weight; mid-upper arm circumference (MAMC); Patient-Generated Subjective Global Assessment (PG-SGA) score; Karnofsky score; physical function (PF) domain; cognitive function (CF) domain; global health and quality of life (QL) domain of EORTC QLQ-C30 (a quality of life instrument designed by the European Organization for Research and Treatment of Cancer); and albumin, prealbumin, and hemoglobin levels were included in a Stepwise analysis model to identify the factors influencing HGS. RESULTS: HGS showed a very low diagnostic value and accuracy for identifying severe malnourishment (area under the curve, 0.615-0.640; p<0.01). HGS positively correlated with sex; height; weight; MAMC; Karnofsky score; QL, PF, and CF domains; and hemoglobin and prealbumin levels (Beta= 0.02-0.42, p<=0.05), and negatively with age (Beta=-0.19, p<0.01). However, the PG-SGA score was excluded because of its very limited contribution to HGS variability. CONCLUSIONS: HGS is a mutifactorial index. The use of HGS cutoff values to identify malnutrition is markedly challenging. Thus, HGS may be of limited use as a predictor of nutritional status.

Bifidobacterium infantis attenuates colitis by regulating T cell subset responses.

AIM: to investigate the effect of Bifidobacterium infantis (B. infantis) on the T cell subsets and in attenuating the severity of experimental colitis in mice. METHODS: Normal BALB/c mice were fed different doses of B. infantis for 3 wk, and T cell subsets and related cytokine profiles in mesenteric lymph nodes (MLNs) were detected by flow cytometry and real-time RT-PCR. Colitis was induced by administration of trinitrobenzene sulfonic acid (TNBS) in mice. Before colitis induction, mice were fed high dose B. infantis for 3 wk. Cytokine profiles in MLNs and histological changes of colonic tissue were examined 6 d after colitis induction. RESULTS: No significant change in cytokine profiles was observed in normal mice fed low dose B. infantis. However, Th1-related cytokines (IL-2, IFN-γ, IL-12p40), Th17-related transcription factor and cytokines (RORγt, IL-21, IL-23), regulatory T cell (Treg)-related transcription factor and cytokines (Foxp3, IL-10) were increased in normal mice fed high dose B. infantis. Furthermore, flow cytometry assay showed B. infantis increased the numbers of CD4(+)Foxp3(+) Tregs and Th17 cells in MLNs. Colitis was successfully induced by TNBS in mice, characterized by colonic inflammation and aberrant Th1 and Th17 responses. Feeding high dose B. infantis for 3 wk before colitis induction decreased the inflammatory cell infiltration and goblet cell depletion and restored the intestinal epithelium. In addition, B. infantis feeding reduced Th1-related cytokines (T-bet, IL-2 and IFN-γ) and Th17-related cytokines (IL-12p40, RORγt, IL-17A, IL-21 and IL-23), and increased Treg-related molecules (Foxp3, IL-10 and TGF-ß) in colitis mice. CONCLUSION: B. infantis effectively attenuates TNBS-induced colitis by decreasing Th1 and Th17 responses and increasing Foxp3(+) Treg response in the colonic mucosa.

N-3 PUFAs have antiproliferative and apoptotic effects on human colorectal cancer stem-like cells in vitro.

The n-3 polyunsaturated fatty acids have been shown to inhibit the induction and progression of many kinds of tumor and to increase the therapeutic effects of numerous chemotherapeutics, but their anticancer effect on cancer stem cells from colorectal cancer has not been described previously. In the present study, we cultivated spheres from the SW620 cell line in serum-free medium and evaluated the features of the spheres by immunofluorescence, cell cycle distribution, resistance to chemotherapeutics and soft agar clone formation, and the spheres were shown to be cancer stem-like cells through tumorigenicity in athymic nude mice. Reverse transcriptase polymerase chain reaction analysis of pluripotency genes, such as Sox-2, Oct-4 and Bmi-1, showed that the spheres were generated by dedifferentiation of SW620 cells. The study explored the use of n-3 polyunsaturated fatty acids (PUFAs) in spheres, which were treated with two n-3 PUFAs [docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA)]. Treatment of the spheres with DHA and EPA alone or in combination for 72 h led to apoptosis and the progressive loss of viability and DNA fragmentation and an increase in annexin V expression. DHA and EPA can enhance the chemotherapeutic sensitivity effect of 5-Fu and mitomycin C, especially DHA combined with EPA. Taken together, these results provide evidence that n-3 PUFAs exert a direct anticancer action that may contribute to their antiproliferative and proapoptotic effect on the cancer stem-like cells.