A Prospective, Single-arm, Multicenter Trial of Diverting Stoma Followed by Neoadjuvant Chemotherapy Using mFOLFOX6 for Obstructive Colon Cancer: YCOG 1305 (PROBE Study).

OBJECTIVE: We conducted the first prospective clinical trial of neoadjuvant chemotherapy for patients with obstructive colon cancer. BACKGROUND: Obstructive colorectal cancer is locally advanced colorectal cancer with a poor prognosis. The effect of neoadjuvant chemotherapy for obstructive colon cancer is unclear. METHODS: We conducted a single arm, multicenter trial involving patients from the Yokohama Clinical Oncology Group with obstructive colon cancer. All eligible patients underwent diverting stoma formation before neoadjuvant chemotherapy. Patient received 6 cycles of mFOLFOX6 followed by primary tumor surgery and then 6 cycles of adjuvant chemotherapy. The primary endpoint was the objective response rate of all intended neoadjuvant therapy. The study was registered with the Japanese Clinical Trials Registry as UMIN000013198. RESULTS: Between April 2014, and July 2016, 50 patients were registered, and 46 received neoadjuvant chemotherapy. The objective response rate as the primary endpoint was 67.4%. The most common grade >3 adverse event associated with neoadjuvant chemotherapy was neutropenia (28.3%). Forty-five patients underwent surgical resection of the primary lesion (R0 resection in all cases). Grade >2 surgery-related complications occurred in 7 patients (15.6%). The downstaging rate was 48.9%, and the moderate or greater regression rate was 52.2%; no cases showed pathological complete response. Adjuvant chemotherapy with mFOLFOX6 was performed in 34 patients (75.6%). The 3-year relapse-free and overall survival rates were 76.5% and 95.4%, respectively. CONCLUSION: Neoadjuvant chemotherapy using mFOLFOX6 was feasible and might be a treatment option for patients with obstructive colon cancer. Further large-scale studies are warranted to confirm the present findings.

Oenothein B in Eucalyptus Leaf Extract Suppresses Fructose Absorption in Caco-2 Cells.

Inhibition of fructose absorption may suppress adiposity and adiposity-related diseases caused by fructose ingestion. Eucalyptus leaf extract (ELE) inhibits intestinal fructose absorption (but not glucose absorption); however, its active compound has not yet been identified. Therefore, we evaluated the inhibitory activity of ELE obtained from Eucalyptus globulus using an intestinal fructose permeation assay with the human intestinal epithelial cell line Caco-2. The luminal sides of a cell monolayer model cultured on membrane filters were exposed to fructose with or without the ELE. Cellular fructose permeation was evaluated by measuring the fructose concentration in the medium on the basolateral side. ELE inhibited 65% of fructose absorption at a final concentration of 1 mg/mL. Oenothein B isolated from the ELE strongly inhibited fructose absorption; the inhibition rate was 63% at a final concentration of 5 µg/mL. Oenothein B did not affect glucose absorption. In contrast, the other major constituents (i.e., gallic acid and ellagic acid) showed little fructose-inhibitory activity. To our knowledge, this is the first report that oenothein B in ELE strongly inhibits fructose absorption in vitro. ELE containing oenothein B can prevent and ameliorate obesity and other diseases caused by dietary fructose consumption.

A prospective, single-arm, multicenter trial of neoadjuvant chemotherapy with mFOLFOX6 plus panitumumab without radiotherapy for locally advanced rectal cancer.

PURPOSE: The present study evaluated the safety and efficacy of neoadjuvant chemotherapy with modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab in clinical stage III rectal cancer with KRAS wild-type. METHODS: We conducted a prospective multicenter phase II trial. KRAS wild-type clinical stage III rectal cancer patients were enrolled. Patients received 6 cycles of mFOLFOX6 with 6 mg/kg panitumumab as neoadjuvant chemotherapy. The primary outcome was the response rate (RR) defined by RECIST. Lateral lymph node dissection (LLDN) was performed when patients had a locally advanced tumor < 9 cm from the anal margin. RESULTS: A total of 50 patients were enrolled. Twelve (24.0%) experienced grade 3-4 adverse events during neoadjuvant chemotherapy. The RR was 88.0% (complete response 2.0%, partial response 86.0%), which met the primary outcome. All patients underwent laparoscopic surgery and achieved R0 resection. Seven patients underwent resection of other adjacent organs, and 43 underwent LLND. Twelve patients (24.0%) experienced grade 3-4 postoperative complications, and 4 (8.0%) had pathological complete response (pCR). Thirteen patients (26.0%) had lymph node metastasis. Forty-five patients (90.0%) received postoperative adjuvant chemotherapy. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 79.0% and 93.7%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy of mFOLFOX6 plus panitumumab without radiotherapy resulted in a low pCR rate but a high PR rate, low local recurrence rate, and good long-term outcome, suggesting that this treatment strategy may be a viable option for patients unable or unwilling to receive radiotherapy. The trial was registered with the UMIN Clinical Trials Registry, number 000006039.

Hyperthermic Effect of Ginger (Zingiber officinale) Extract-Containing Beverage on Peripheral Skin Surface Temperature in Women.

Ginger is known to warm the body. Therefore, we conducted a placebo-controlled crossover trial to investigate the hyperthermic effect of a palatable ginger-containing beverage in healthy women with cold-sensitive extremities. Six women drank 280 mL of 0.07% ginger extract-containing or placebo beverage in a temperature-controlled room (21°C). Their palm temperatures were measured as measure of surface body temperature using a thermographic camera before intake and every 10 min after intake for 60 min. Palm temperature increased immediately following intake of the ginger and placebo beverages. However, palm temperature following intake of the ginger beverage increased for 20 min, while palm temperature following placebo intake decreased again after 10 min. The increased palm temperature following ginger intake was maintained significantly longer than after placebo intake (p < 0.05). In response to a questionnaire, some subjects answered that their increased body temperature was maintained after drinking the ginger beverage. Ginger extract-containing beverage may thus improve cold sensitivity.

Determination and purification of sesamin and sesamolin in sesame seed oil unsaponified matter using reversed-phase liquid chromatography coupled with photodiode array and tandem mass spectrometry and high-speed countercurrent chromatography.

In Asian countries, sesame seed oil unsaponified matter is used as a natural food additive due to its associated antioxidant effects. We determined and purified the primary lignans sesamin and sesamolin in sesame seed oil unsaponified matter using reversed-phase liquid chromatography coupled with photodiode array and tandem mass spectrometry and high-speed countercurrent chromatography. Calibration curves showed good correlation coefficients (r2 > 0.999, range 0.08 and/or 0.15 to 5 µg/mL) with a limit of detection (at 290 nm) of 0.02 µg/mL for sesamin and 0.04 µg/mL for sesamolin. Sesame seed oil unsaponified matter contained 2.82% sesamin and 2.54% sesamolin, respectively. Direct qualitative analysis of sesamin and sesamolin was achieved using quadrupole mass spectrometry with positive-mode electrospray ionization. Pure (>99%) sesamin and sesamolin standards were obtained using high-speed countercurrent chromatographic purification (hexane/ethyl acetate/methanol/water; 7:3:7:3). An effective method for determining and purifying sesamin and sesamolin from sesame seed oil unsaponified matter was developed by combining these separation techniques for standardized food additives.

Inhibitory effects of eucalyptus and banaba leaf extracts on nonalcoholic steatohepatitis induced by a high-fructose/high-glucose diet in rats.

Nonalcoholic steatohepatitis (NASH) is a liver disease associated with metabolic syndrome. The aim of this work was to examine whether eucalyptus (Eucalyptus globulus) leaf extract (ELE) and banaba (Lagerstroemia speciosa L.) leaf extract (BLE) inhibited NASH induced by excessive ingestion of fructose in rats. Wistar rats were divided into four groups according to four distinct diets: starch diet (ST), high-fructose/high-glucose diet (FG), FG diet supplemented with ELE, or FG diet supplemented with BLE. All rats were killed after 5 weeks of treatment. Serum alanine aminotransferase and total cholesterol levels were significantly lower in the BLE group than in the FG group. Liver histopathology, including steatosis, lipogranulomas, and perisinusoidal fibrosis, was significantly attenuated in the ELE and BLE groups compared with the FG group. Levels of 2-thiobarbituric acid reactive substances (TBARS), which reflect oxidative injury to the liver, were significantly suppressed by ELE and BLE. Western blotting analysis indicated that interleukin-6 expression levels were significantly lower in the ELE and BLE groups than in the FG group. These results suggest that ELE and BLE reduced lipogenesis, oxidative stress, and inflammatory cytokine expression and thus inhibited NASH induced by excessive ingestion of fructose in rats.

Probable novel MEP pathway inhibitor and its binding protein, IspG.

A second isoprene unit biosynthetic pathway, via 2-C-methyl-D-erythritol 4-phosphate (MEP), was discovered in the 1990s. We screened and isolated the cyclic dipeptide, maculosin, which is a probable novel MEP pathway inhibitor, from the culture broth of Bacillus subtilis strain KN07. To identify the target enzyme of maculosin, we applied an avidin-biotin complex method using biotinylated maculosin and the lysates of seven Escherichia coli strains, each overexpressing one enzyme of the MEP pathway, and performed quartz crystal microbalance (QCM) experiments using maculosin and each enzyme. The results indicate that IspG, the sixth enzyme on the MEP pathway, was bound to maculosin.

[Circadian chronotherapy for metastatic liver tumor].

Efficacy of circadian chronotherapy for liver metastases from colorectal cancer was evaluated. Chronomodulated infusion of anticancer drugs via the hepatic artery(HAI) was applied for patients with marginally resectable or unresectable liver metastases at initial diagnosis. Response rate of chemotherapy and frequency of liver resection after chemotherapy of patients treated with chronomodulated HAI were higher than those treated with flat HAI. Further, combination of chronomodulated regional HAI and systemic chemotherapy was the most effective prehepatectomy chemotherapy for the treatment of patients with advanced colorectal liver metastases. Based on these results, we are now performing phase II non-randomized open labeled trial of chronomodulated HAI with systemic administration of panitumumab for patients with such advanced liver metastases (ccFLAP trial). Circadian chronotherapy is an effective prehepatectomy chemotherapy for the treatment of patients with advanced and aggressive liver metastases from colorectal cancer.

Eucalyptus leaf extract inhibits intestinal fructose absorption, and suppresses adiposity due to dietary sucrose in rats.

Sucrose is more lipogenic than starch, and the extreme ingestion of sucrose induces adiposity and obesity. The aim of this study was to examine the effect of the eucalyptus (Eucalyptus globulus) leaf extract (ELE) on adiposity due to dietary sucrose in rats. In addition, in this study, the effect of ELE on intestinal fructose absorption was also examined. Rats were fed a high-sucrose diet (75 % in calorie base) with or without ELE (10 g/kg diet) for 5 weeks. Body weight was lower in the rats receiving ELE than in the controls (342 (sd 37.9) v. 392 (sd 26.0) g (n 7); P<0.05). Furthermore, ELE resulted in decreases in the triacylglycerol concentrations in the plasma (1.44 (sd 0.448) v. 2.79 (sd 0.677) mmol/l (n 7); P<0.05) and liver (19.1 (sd 5.07) v. 44.1 (sd 16.28) micromol/g (n 7); P<0.05). In contrast, ELE did not show any significant effects in the rats fed a starch diet. When rats were orally given ELE 10 min before fructose administration, the intestinal fructose absorption, which was examined by measuring the elevated concentration of fructose in the portal vein at 30 min after the fructose administration, was significantly inhibited in a dose-dependent manner. Furthermore, in rats fed a high-fructose diet, the plasma and hepatic triacylglycerol concentrations were significantly decreased by ELE. These results indicate that ELE, which inhibits the intestinal fructose absorption, can suppress adiposity in rats that ingest large amounts of sucrose or fructose.