A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol.

BACKGROUND: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study. METHODS: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. DISCUSSION: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. TRIAL REGISTRATION: Registered at August 23, 2017. Registry number: UMIN000028801 .

Rikkunshito for Preventing Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients: Results from 2 Prospective, Randomized Phase 2 Trials.

The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)-that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0-24 h) and delayed (>24-120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC. Clinical Trial Registry Information: This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry, identification numbers UMIN 000014239 and UMIN 000014240.

Plasma homocysteine levels and hematological toxicity in NSCLC patients after the first cycle of pemetrexed under folate supplementation.

Although baseline plasma homocysteine levels are related to pemetrexed toxicities in patients treated without folate supplementation, the relationship between these parameters in patients treated with folate supplementation is not well understood. The pretreatment plasma homocysteine levels were measured in non-small-cell lung cancer patients treated with pemetrexed alone under folate supplementation. Pemetrexed (500 mg/m) was administered every 3 weeks. As folate supplementation, folic acid (0.5 mg) was orally administered daily and vitamin B12 (1 mg) was injected intramuscularly every 9 weeks starting at least 1 week before treatment. The rate of toxicities during the first cycle of pemetrexed treatment with folate supplementations was evaluated and the relationship between the plasma homocysteine levels and toxicities was examined. Between June 2009 and November 2010, 58 patients were enrolled in this study. The median pretreatment plasma homocysteine level was 7.7 µmol/ml (3.5-34.6 µmol/ml). The pretreatment plasma homocysteine levels were above 11.5 µmol/ml in nine patients (15.5%). The pretreatment plasma homocysteine level correlated significantly with the nadir of the absolute counts of leukocytes, neutrophils, and thrombocytes (r = -0.374, P = 0.004; r = -0.286, P = 0.028; r = -0.324, P = 0.012, respectively). In addition, the rates of decrease in leukocytes, neutrophils, and thrombocytes correlated significantly with the pretreatment plasma homocysteine level (r = +0.378, P = 0.003; r = +0.335, P = 0.009; r = +0.363, P = 0.005, respectively). The plasma homocysteine level is associated with hematological toxicities in patients receiving pemetrexed with folate supplementation.

Anti-allergic effects of enzymatically modified isoquercitrin (α-oligoglucosyl quercetin 3-O-glucoside), quercetin 3-O-glucoside, α-oligoglucosyl rutin, and quercetin, when administered orally to mice.

Quercetin, a flavonol distributed widely in edible and medicinal plants, has beneficial biological activities in vitro. However, the low water solubility of quercetin limits its bioavailability to exhibit activity in vivo. We evaluated the anti-allergic effects of quercetin, quercetin 3-O-glucoside (isoquercitrin, IQC), α-oligoglucosyl rutin (αOR), and enzymatically modified isoquercitrin (α-oligoglucosyl isoquercitrin; EMIQ) in the murine ear passive cutaneous anaphylaxis (PCA) reaction using ovalbumin as an antigen. The substances to be tested were dissolved or suspended in water, and administered orally to mice (4 mmol 10 ml⁻¹ kg⁻¹). EMIQ exhibited a significant inhibitory effect on the PCA reaction. We detected 600 µM IQC and 95.1 µM Q3Glcn in the plasma of mice 30 min after EMIQ treatment, suggesting that IQC and Q3Glcn might be the genuine active compounds mediating the anti-allergic effects of EMIQ. Oral treatments of quercetin and αOR at this dosage exhibited no anti-allergic effect, and IQC showed less effect than EMIQ. Since IQC and quercetin cannot completely dissolve in water at this concentration, the water solubilities of these substances might affect their biological activities. αOR dissolved well in water at the concentration used but plasma concentrations of quercetin metabolites in mice orally treated with αOR were low, suggesting that αOR might not be converted to IQC or quercetin by the enzymes in small intestine and thus not exhibit any activity. Glycosyl conjugation of quercetin with specific sugar motifs is an effective strategy to improve the biological activity of quercetin in vivo.

Anthocyanin-rich purple potato flake extract has antioxidant capacity and improves antioxidant potential in rats.

Anthocyanins from various vegetables and fruits have antioxidant activities, however, the bioactivities of coloured potato anthocyanins are not well studied. We examined the antioxidant capacities of pigmented fractions from purple potato flakes in vitro, and the antioxidant potentials of purple potato flakes in vivo. 1,1-Diphenyl-2-picrylhydrazyl radical scavenging activity of the pigmented fraction from Hokkai no. 92 (H92) potato flakes was higher than that from Kitamurasaki (KM) potato flakes. Extracts equivalent to 600 microg pigmented fractions from KM and H92 potato flakes inhibited linoleic acid oxidation in the order trolox>H92> or =KM>control. Rats were fed 25% KM or H92 potato flake diets for 4 weeks. The major anthocyanin was identified as petanin. Control rats were fed a diet with cornstarch instead of potato flakes for 4 weeks. The serum antioxidant potential level in the H92 group was significantly higher than that in the control group. The degree of hepatic lipid peroxidation in the H92 group was significantly lower than that in the control group. Hepatic Cu/Zn-superoxide dismutase (SOD), Mn-SOD and glutathione peroxidase (GSH-Px) mRNA levels in the H92 group were significantly higher than those in the control group. Similar significant differences in Cu/Zn-SOD and Mn-SOD mRNA levels between the KM and control groups were found. The present results suggest that purple potato flakes have antioxidant functions with regard to radical scavenging activity and inhibition of linoleic acid oxidation, and that they improve the antioxidant potentials in rats by enhancing hepatic Mn-SOD, Cu/Zn-SOD and GSH-Px mRNA expression.

Determination of transverse relaxation rate for estimating iron deposits in central nervous system.

To determine the amount of iron deposits in the basal ganglia, we examined 13 healthy volunteers with a 1.5 T MRI system using three transverse relaxation rates measured with two sequences. The transverse relaxation rates comprise the reversible contribution (R2') and irreversible contribution (R2) to a phase-reversal 180 degrees -pulse sequence. The transverse relaxation rates with the estimated iron indicated that both R2 and R2' had a robust relationship with brain iron level as determined from published post mortem data. This was the case only when the analyses are limited to the subcortical gray matter regions, however. R2' was affected by macroscopic magnetic field inhomogeneity arising from the skull bases, so that it was less robust for estimating the amount of iron deposits in the basal ganglia.

Effect of stage 1 sleep on auditory cortex during pure tone stimulation: evaluation by functional magnetic resonance imaging with simultaneous EEG monitoring.

BACKGROUND AND PURPOSE: Responses of the auditory cortex to sound during sleep have been explored with somewhat discrepant results. The purpose of this study was to investigate the effect of stage 1 sleep on signal intensity changes in the auditory cortex in response to pure tone stimulus measured by functional MR imaging. METHODS: Six sleep-deprived subjects were exposed to a series of echo-planar images for 30-40 minutes. No medication was used to help the subjects go to sleep. A long repetition time of 12 seconds and a 1.9-second clustered multisection acquisition were used to minimize the effect of imager acoustic noise from the preceding acquisition and to make it possible to obtain electroencephalographs between image acquisitions. A pure tone stimulus (beep, 1,000-Hz sine waves, 30-millisecond duration, five beeps per second) was alternated with the baseline every 36 seconds. RESULTS: All subjects fell asleep. The effect of habituation evaluated by comparing the percentage of signal intensity change between the first and second half was not significant. The percentage of signal intensity changes in the right and left transverse temporal gyri were 0.49% and 0.43% during wakefulness and 0.05% and 0.07% during stage 1 sleep. The differences between wakefulness and stage 1 sleep were significant. CONCLUSION: Transition to stage 1 sleep coincides with a decrease in functional MR imaging-determined signal intensity changes in the auditory cortex in response to pure tone stimulus. The limited response of the brain at this stage may protect the brain from sound and facilitate deepening of the sleep stage.