Trude R. Balstad

Effect of physical exercise on muscle mass and strength in cancer patients during treatment—A systematic review

Cancer treatment and its side effects may cause muscle wasting. Physical exercise has the potential to increase muscle mass and strength and to improve physical function in cancer patients undergoing treatment. A systematic review was conducted to study the effect of physical exercise (aerobic, resistance or a combination of both) on muscle mass and strength in cancer patients with different type and stage of cancer disease. Electronic searches were performed up to January 11th 2012, identifying 16 randomised controlled trials for final data synthesis. The studies demonstrated that aerobic and resistance exercise improves upper and lower body muscle strength more than usual care. Few studies have assessed the effect of exercise on muscle mass. Most studies were performed in patients with early stage breast or prostate cancer. Evidence on the effect of physical exercise on muscle strength and mass in cancer patients with advanced disease is lacking. More exercise studies in patients with advanced cancer and at risk of cancer cachexia are warranted.

Coffee, broccoli and spices are strong inducers of electrophile response element-dependent transcription in vitro and in vivo – Studies in electrophile response element transgenic mice

SCOPE Cytoprotective gene products, e.g. phase II - and antioxidant enzymes, are important in cellular redox homeostasis. A common feature of these genes is binding sites for transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), named electrophile response elements (EpREs) within their promoters. METHODS AND RESULTS To identify dietary bioactive compounds and foods with Nrf2/EpRE inducing properties in an intact organism, we utilized transgenic mice encoding luciferase under control of EpRE from the thioredoxin promoter. We found that 18 of 31 phytochemicals and 10 of 14 dietary plant extracts induced EpRE activity in liver HepG2 cells. Surprisingly, some dietary plant extracts showed profound inducing capability as compared to pure compounds indicating combinatorial effects of compounds found in whole foods. Furthermore, intraperitoneal injections of carnosol, curcumin and tert benzohydroquinine induced EpRE-dependent promoter activity in transgenic mice. In further experiments with curcumin, we found highly induced EpRE activity in intestine, liver, kidney and spleen. Finally, a combination extract made of coffee, thyme, broccoli, rosemary, turmeric and red onion fed orally, induced EpRE mediated luciferase in lung and adipose tissue. CONCLUSION These results show that plant-based foods contain compounds that can be absorbed and induce the antioxidant defence in a living organism in an organ-specific manner.

Degree of roasting is the main determinant of the effects of coffee on NF-κB and EpRE.

Coffee, one of the most popular beverages worldwide, is a major contributor of phytochemicals in the diet and contributes more than 50% of dietary antioxidants in many countries. A moderate intake of coffee has been linked to reduced risk of chronic diseases. Furthermore, experimental studies demonstrate bioactivity of coffee or coffee compounds in inflammation and oxidative stress, two major, related biological processes. We show that the degree of roasting correlates with the efficiency of dampening inflammation-induced NF-kappaB activity and inducing antioxidant defense through Nrf2/EpRE activity. Extracts of dark-roasted coffee inhibit NF-kappaB activity by more than 80% and induce EpRE activity more than 25-fold in vitro. In transgenic NF-kappaB-luciferase mice, a single dose of dark-roasted coffee extract per os inhibits NF-kappaB activation by 63% in the whole mouse, with the liver being the main target, with a 68% reduction in activity. In transgenic EpRE-luciferase mice, the extract of coffee increased overall EpRE activity by 30%, again with the liver as the main contributor, with a 2.7-fold increase. Our results demonstrate that dark-roasted coffee dampens a crucial mechanism in inflammation and induces a pivotal mechanism in oxidative stress defense.

Extract of Oregano, Coffee, Thyme, Clove, and Walnuts Inhibits NF-κB in Monocytes and in Transgenic Reporter Mice

The transcription factor NF-κB is a promising target for chemoprevention. Several dietary plants are efficient inhibitors of NF-κB activation in vitro and could act synergistically on the NF-κB signaling pathway. In this study, we tested whether dietary plant extracts could inhibit NF-κB activation in a synergistic manner in vitro. Second, we investigated the potency of the same dietary plant extracts in the inhibition of NF-κB activation in vivo. A combined extract of clove, oregano, thyme, walnuts, and coffee synergistically inhibited lipopolysaccaride (LPS)-induced NF-κB activation in a monocytic cell line, compared with the sum of effects from the single extracts. Transgenic NF-κB luciferase reporter mice were given a single dose of the combined extract and subsequently challenged with LPS. NF-κB activation was monitored by in vivo imaging for 6 hours. In addition, NF-κB activity in organs and the expression of immune-related genes in liver were investigated. Based on the area under the curve, the extract decreased whole body LPS-induced NF-κB activity the first 6 hours by 35% compared with control mice. Organ-specific NF-κB activation was inhibited in intestine, liver, testis, and epididymis of the mice receiving the combination extract. In addition, dietary plants reduced the expression of genes related to inflammation, cell migration, and proliferation in liver. This study shows that dietary plants may be potent modulators of NF-κB signaling both in vitro and in vivo, and thus support further investigation of consumption of these plant foods as part of a healthy diet or as a mode of chemoprevention. Cancer Prev Res; 3(5); 653–63. ©2010 AACR.

Dietary treatment of weight loss in patients with advanced cancer and cachexia: A systematic literature review

PURPOSE A systematical literature review evaluating the effect of dietary counseling in treating weight loss and improving energy intake in patients with advanced cancer with different stages of cachexia. PRINCIPAL RESULTS Five publications were retrieved, of which three were randomized. Two out of five studies showed less weight loss with dietary counseling (+1% weight gain vs. -1.5% weight loss, p=0.03, 1.4kg vs. -2kg, p<0.05), two presented positive effect on energy intake (92% of total caloric need vs. 73%, p<0.01, 1865±317kcal vs. 1556±497kcal, ns). CONCLUSION Dietary counseling can effect energy intake and body weight, however, apparent heterogeneity between studies is present. Based on these results there is not enough proof of evidence that dietary counseling given to patients with cancer is beneficial for improving weight or energy balance in the different cachexia stages. Nutrition is an essential part of cachexia treatment as it is not considered possible to increase or stabilize weight if nutritional needs are not met.

A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer

Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n‐3 polyunsaturated fatty acid nutritional supplements, exercise, and anti‐inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy.

Activation and inhibition of nuclear factor kappa B activity by cereal extracts: role of dietary phenolic acids.

The transcription factor nuclear factor kappa B (NF-kappaB) plays a critical role in stress, immune, and inflammatory responses, and the modulation of its activity can be a potentially effective preventive strategy for controlling certain diseases. Cereal grains contain phenolic compounds in concentrations comparable to those in fruits and vegetables, well-known for their beneficial effect on human health. In this study we aimed to examine the effect of different phenolic extracts from barley, oat, wheat, and buckwheat on the modulation of basal and lipopolysaccharide (LPS)-induced NF-kappaB activity and elucidate the role of phenolic acids in this modulation. Three extracts were prepared: extracts of free phenolic compounds (M1), extracts of free phenolic acids (M2), and extracts of bound phenolic acids (HY). Generally, extracts M2 showed the highest effect on modulation of NF-kappaB activity with strong inhibition of LPS-induced NF-kappaB activity at all concentrations and of the basal NF-kappaB activity at concentrations equal to or lower than 3 mg/mL. Most of extracts M1 and HY slightly increased both the basal and the LPS-induced NF-kappaB activation. However, at the highest concentrations (3 or 15 mg/mL) extracts HY inhibited LPS-induced NF-kappaB activation. Similar experiments with standard solutions of phenolic acids indicated their ability to modulate the NF-kappaB activity.

Apple, Cherry, and Blackcurrant Increases Nuclear Factor Kappa B Activation in Liver of Transgenic Mice

Nuclear factor kappa B (NF-κB) is essential in normal physiology, and several human disorders involve inappropriate regulation of NF-κB. Diets dominated by plant-based foods protect against chronic diseases, and several food derived compounds have been identified as promising NF-κB modulators. We investigated the effects of diets supplemented with apple, blackcurrant, or cherries on lipopolysaccharide (LPS)-induced NF-κB activation in transgenic NF-κB-luciferase mice. Whole body and organ specific NF-κB activities were determined. The mice had ad libitum access to the respective experimental diets for 7 days. On Day 7, all mice were given an LPS-injection (2.5 mg/kg), and NF-κB activation was monitored by in vivo imaging for 6 h. After imaging, blood samples were taken, the mice were euthanized, and ex vivo imaging of organs was performed. Compared to the control group, the apple and cherry groups had slightly higher whole-body NF-κB activation at 4 h, and all 3 experimental groups had higher NF-κB activation at 6 h. LPS-induced NF-κB activation in liver was increased with all 3 experimental diets, but no effects were observed in other organs. Our findings indicate that high intakes of lyophilized fruits modulate in vivo NF-κB signaling in the liver following LPS-induced stress; however, consequences of this NF-κB modulation in hepatic tissue needs further investigation.

Plant extracts of spices and coffee synergistically dampen nuclear factor-κB in U937 cells.

A large array of bioactive plant compounds (phytochemicals) has been identified and synergy among these compounds might contribute to the beneficial effects of plant foods. The transcription factor nuclear factor-κB (NF-κB) has been suggested as a target for many phytochemicals. Due to the complexity of mechanisms involved in NF-κB regulation, including numerous feedback loops, and the large number of phytochemicals which regulate NF-κB activity, we hypothesize that synergistic or antagonistic effects are involved. The objectives of our study were to develop a statistical methodology to evaluate the concept of synergy and antagonism and to use this methodology in a monocytic cell line (U937 expressing an NF-κB-luciferase reporter) treated with lipopolysaccharide and phytochemical-rich plant extracts. Both synergistic and antagonistic effects were clearly observed. Observed synergy was most pronounced for the combinations of oregano and coffee, and thyme and oregano. For oregano and coffee the synergistic effect was highest at 5 mg/mL with 13.9% (P < .001), and for thyme and oregano the highest synergistic effects was at 3 mg/mL with 13.7% (P < .001). Dose dependent synergistic and antagonistic effects were observed for all combinations tested. In conclusion, this work presents a methodological tool to define synergy in experimental studies. Our results support the hypothesis that phytochemical-rich plants may exert synergistic and antagonistic effects on NF-κB regulation. Such complex mechanistic interactions between phytochemicals are likely to underlie the protective effects of a plant-based diet on life-style related diseases.

Development of the EORTC QLQ-CAX24, a questionnaire for cancer patients With cachexia

CONTEXT Cachexia is commonly found in cancer patients and has profound consequences; yet there is only one questionnaire that examines the patients perspective. OBJECTIVE To report a rigorously developed module for patient self-reported impact of cancer cachexia. METHODS Module development followed published guidelines. Patients from across the cancer cachexia trajectory were included. In Phase 1, health-related quality of life (HRQOL) issues were generated from a literature review and interviews with patients in four countries. The issues were revised based on patient and health care professional (HCP) input. In Phase 2, questionnaire items were formulated and translated into the languages required for Phase 3, the pilot phase, in which patients from eight countries scored the relevance and importance of each item, and provided qualitative feedback. RESULTS A total of 39 patients and 12 HCPs took part in Phase 1. The literature review produced 68 HRQOL issues, with 22 new issues arising from the patient interviews. After patient and HCP input, 44 issues were formulated into questionnaire items in Phase 2. One hundred ten patients took part in Phase 3. One item was reworded, and 20 items were deleted as a consequence of patient feedback. CONCLUSIONS The QLQ-CAX24 is a cancer cachexia-specific questionnaire, comprising 24 items, for HRQOL assessment in clinical trials and practice. It contains five multi-item scales (food aversion, eating and weight-loss worry, eating difficulties, loss of control, and physical decline) and four single items.