Effects of an elemental diet to reduce adverse events in patients with esophageal cancer receiving docetaxel/cisplatin/5-fluorouracil: a phase III randomized controlled trial-EPOC 2 (JFMC49-1601-C5).

BACKGROUND: Oral mucositis (OM) is an unpleasant adverse event in patients receiving chemotherapy. A prospective feasibility study showed that elemental diet (ED), an oral supplement that does not require digestion, may prevent OM. Based on this, we established a central review system for oral cavity assessment by dental oncology specialists blinded to background data. We used this system to elucidate the preventive effect of an ED against OM in patients with esophageal cancer receiving docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy. PATIENTS AND METHODS: In this phase III, multicenter, parallel-group, controlled trial, patients consuming a normal diet orally were randomly assigned (1 : 1) to receive two cycles of DCF with (group A) or without (group B) an ED (Elental® 160 g/day). We assessed the incidence of grade ≥2 OM evaluated by two reviewers, changes in body weight, prealbumin, C-reactive protein, and DCF completion rate based on ED compliance. RESULTS: Of the 117 patients randomly assigned to treatment, four failed to start treatment and were excluded from the primary analysis; thus, groups A and B comprised 55 and 58 patients, respectively. There were no significant differences in background characteristics. Grade ≥2 OM was observed in eight (15%) and 20 (34%) patients in groups A and B, respectively (P = 0.0141). Changes in body weight and prealbumin during the two DCF cycles were significantly higher in group A than B (P = 0.0022 and 0.0203, respectively). During the first cycle, changes in C-reactive protein were significantly lower in group A than B (P = 0.0338). In group A (receiving ED), the DCF completion rate was 100% in patients with 100% ED compliance and 70% in patients failing ED completion (P = 0.0046). CONCLUSIONS: The study findings demonstrate that an ED can prevent OM in patients with esophageal cancer receiving chemotherapy.

MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells.

BACKGROUND: We reported recently the clinical efficiency of interferon (IFN)-α/5-fluorouracil (5-FU) combination therapy in advanced hepatocellular carcinoma (HCC). However, prediction of the response to the combination therapy remains unsatisfactory. The aim of this study was to investigate the anti-tumour effects of microRNA (miR)-21 on the sensitivity of HCC cells to IFN-α/5-FU and whether miR-21 can be used as a predictor of the response to such therapy in HCC. METHODS: Changes in the sensitivity of HCC cells (PLC/PRF/5 and HepG2) to IFN-α/5-FU were examined after transfection with pre-miR-21 or anti-miR-21. The correlation between miR-21 expression level, evaluated by qRT-PCR, and response to the therapy was also investigated in clinical HCC specimens. RESULTS: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-α/5-FU. Annexin V assay showed that the percentage of apoptotic cells was significantly lower in cells transfected with pre-miR-21 than control cells. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-α/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4. miR-21 expression in clinical HCC specimens was significantly associated with the clinical response to the IFN-α/5-FU combination therapy and survival rate. CONCLUSIONS: The miR-21 in HCC cell lines and clinical HCC samples is a significant modulator of the anti-tumour effect of IFN-α and 5-FU. This suggests that miR-21 is a potentially suitable marker for the prediction of the clinical response to the IFN-α/5-FU combination therapy.

Identification of proteolytic bacteria from thai traditional fermented foods and their allergenic reducing potentials.

This study aimed to identify proteolytic bacteria from Thai traditional fermented foods and investigate their allergenic reducing potentials to wheat and milk allergens. Nine bacteria were isolated from fermented foods as follows: fermented soybean seeds (Thua Nao), fermented soybean paste (Thua Nao), wheat flour dough of steamed stuffed bun (Sa La Pao), and soaked rice from Thai fermented rice-noodle (Kha Nhom Jeen) processing. Both phenotypic and genotypic identifications were used in this study. It was found that all isolates were Gram-positive rods. Seven isolates were matched and identified as Bacillus subtilis by both techniques, and the remaining 2 isolates were phenotypically and genotypically identified as B. licheniformis and B. subtilis, respectively. The concentrated crude enzyme of B. subtilis DB and SR could reduce allergenicity of gliadin by hydrolyzing the allergenic gliadin fragments detected by immunoblotting. Furthermore, the enzyme of B. subtilis DB could also reduce allergenicity of beta-lactoglobulin (beta-LG) detected by hydrolyzing the major allergenic epitope of beta-LG at Gln(35)-Ser(36) position. B. subtilis DB and SR can be applied for the production of hypoallergenic wheat flour or milk food products.

[A case of postoperative multiple hepatic metastasis from esophageal cancer successfully treated by surgical resection and hepatic arterial infusion chemotherapy].

A 66-year-old male who underwent radical resection for esophageal cancer (stage IV) was diagnosed with multiple hepatic metastasis 1 year and 3 months after the surgery. He underwent hepatic resection and received systemic chemotherapy (FAP: 5-FU, ADR, CDDP), as the post-operative adjuvant therapy. One year and 3 months later, there was a huge recurrence in the residual liver and hepatic arterial infusion chemotherapy (FAP) was performed. The recurrent lesion disappeared completely after 3 sessions of arterial infusion chemotherapy. The arterial infusion chemotherapy was continued in the outpatient clinic and the recurrent lesion is well controlled. At present, this patient has returned to social life, 2 years and 3 months after the hepatic resection. The utility of hepatic arterial infusion chemotherapy and hepatectomy for postoperative multiple hepatic metastasis from esophageal cancer was shown in the present case.

[Chemoembolization for liver metastasis from colorectal cancer].

Chemoembolization using Lipiodol, cisplatin, angiotensin II and Gelfoam (modified sandwich therapy) was carried out for the patients with liver metastasis from colorectal cancer. 1. Ten of 30 patients who underwent hepatic resection received TAE before operation, and the remaining 20 underwent surgery without preoperative TAE. Three-year survival of the former was 66%, and that of the latter was 44% (not significant). 2. Twenty-two patients who were assessed as non-resectable were surgically catheterized into the hepatic artery. Thirteen patients received TAE (totally 38 times) and intra-arterial infusion chemotherapy, and the remaining 9 underwent intra-arterial chemotherapy alone. The 50% survival of the former and the latter was 545 and 285 days, respectively. One year survival of the former was significantly better than that of the latter. 3. Fourteen patients had intrahepatic recurrences after hepatic resections. Eight patients received TAE and the remaining 6 did not. The 50% survival of the former was 615 days and that of the latter was 190 days. For one-year survival, the former was significantly better than the latter. These results suggested that TAE is an effective modality for liver metastasis from colorectal cancer.

[Intraarterial and intraportal chemotherapy combined with decollateralization for cholangiocellular carcinoma and metastatic liver cancer].

Two patients with cholangiocarcinoma and one patient with liver metastasis from inflammatory breast cancer underwent catheterization into both hepatic artery and portal vein following decollateralization using silicone rubber sheeting. They received arterial chemoembolization and chemotherapy and portal chemotherapy through the catheters repeatedly. Two patients with cholangiocarcinoma are still alive more than one year after the beginning of the treatments without regrowth of the tumors. The patient with metastatic liver cancer died of lung metastasis, although the liver foci were controlled by procedure. Thus, both intraarterial and intraportal chemotherapy combined with decollateralization by silicone rubber sheeting seems to be effective for advanced cholangiocarcinoma and metastatic carcinoma.

[Evaluation of preoperative chemoembolization using ethiodized oil, cisplatin and gelatin sponge (sandwich therapy) for hepatocellular carcinoma].

The significance of preoperative chemoembolization using ethiodized oil, cisplatin and gelatin sponge (Sandwich therapy) for resectable hepatocellular carcinoma (HCC) was evaluated. One hundred and thirteen patients with solitary and less than 10 cm sized HCC who underwent radical hepatic resection were chosen for this study. Fifty-three patients received Sandwich therapy before surgery (Group A), and the remaining 60 patients under-went surgery without any preoperative treatments (Group B). Any background factors between two groups were not significantly different. The anticancer effects of this therapy were evaluated by histologic examination in 31 patients who had preoperative Sandwich therapy. In 22 of 31 patients (71%), the main nodules were completely necrotic. The ratios of patients with complete necrosis in daughter nodules were 7/12 (58%), in portal vein tumor emboli, 7/10 (70%), in intracapsular invasions, 11/21 (52%), in extracapsular invasions, 4/11 (36%). The 4-year disease-free survival rates in Group A and Group B were 56% and 27% respectively, and the rate of the former was significantly higher than that of the latter (p less than 0.05). The 4-year survival rates in Group A and Group B were 83% and 53% respectively. The rate of Group A was also significantly higher than that of Group B (p less than 0.01). We concluded that preoperative Sandwich therapy was very significant to obtain successful long-term disease-free survival and survival in regard to relatively early stage HCC.

[Adjuvant surgery to enhance therapeutic effects of chemo-embolization in advanced hepatocellular carcinoma].

Different kinds of adjuvant surgery were carried out in three patients with advanced hepatocellular carcinoma (HCC) to enhance the therapeutic effects of chemo-embolization (TAE). The first patient, who had multiple foci localized in the right lobe, underwent ligation of the right portal vein in order to eliminate the small intrahepatic spreads and to protect against transportal metastasis to the left lobe. Afterward, TAEs were repeated a total of 5 times. The patient is still alive 24 months after the surgery with partial remission of the lesions. The second patient with severe cirrhosis had received TAE twice. Since one of the tumors, which existed in the hepatic hilus, did not respond to TAE, only the non-respondent tumor was removed surgically. This patient remains alive 28 months after the surgery with complete remission of the lesions. In the third patient, repeated TAEs resulted in collateral feeding arteries. Permanent decollateralization using silicone rubber sheeting was carried out following ligation of collaterals. Thus adjuvant surgery to enhance the therapeutic effects of TAE may be a significant palliative treatment for HCC.

[Selective anticancer effects of intra-arterial infusion of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine (TT82) in hepatocellular carcinoma].

3'-5'-Dioctanoyl-5-fluoro-2'-deoxyuridine (TT 82), one of the lipophilic prodrugs of 5-fluoro-2'-deoxyuridine mixed with Lipiodol (LPD), was injected into the hepatic artery before hepatic resection in 4 patients with hepatocellular carcinoma. Later, the anti-cancer effects of the drug were evaluated mainly by the examination of resected specimens. The serum alpha-fetoprotein levels of three patients in whom the values were over normal range fell to less than 50% of pretreatment values from 7 to 14 days after the injections. In pathological observation of the specimens, the necrosis rates of main tumors were 100%, 70%, 30% and 0%, respectively. In three patients whose main tumors showed complete or partial necrosis, selective depositions of LPD in the tumors were observed on soft X-ray photographs. The concentrations of TT 82 and its metabolites in the tissues of LPD-depositing areas were markedly higher than those in tissue of the regions without LPD deposits. These findings suggested that TT82-Lipiodol mixture remained selectively in the cancerous tissues and exhibited anticancer effects following injection into the hepatic artery.

[Effects of intravenous alimentation on adjuvant chemotherapy--an experimental study on the distribution of 5-FU after injection of tegafur (2)].

The stomach, small and large intestines, heart, lungs, bone and kidneys were removed from 48 Sato lung cancer-bearing rats used in the previous experiments and given 90 mg/kg of tegafur (FT-207) by single intravenous administration and tissue 5-FU and FT-207 concentrations were measured. FT-207 concentration in the alimentary canal was somewhat lower than the blood concentration, but both were lowered in parallel. 5-FU concentration in the stomach and large intestines showed virtually identical changes in both IVH and PO groups, but IVH group tended to have higher concentration. IVH group showed higher values than PO group anytime, particularly in the large intestines. A reduction of the side effects on the digestive system via intravenous alimentation was thought due to the elimination of mechanical stimulation via a cessation of oral feeding. 5-FU concentration in the bone was highest in PO group at six hours after administration and blood concentration changes were parallel, but there was virtually no change in IVH group. Maximum values were found one hour after administration and slowly declined thereafter; at 24 hrs the values were 0.059 +/- 0.013 microgram/g, relatively high compared to the PO group at 0.041 +/- 0.022 microgram/g. In the present study under intravenous alimentation, the concentration changes were slight in spite of 5-FU maximum concentration being lower than that by oral feeding and the long-term high concentration which was maintained; this is thought to be a disadvantageous action with regard to the bone marrow. FT-207 concentration in the kidney, heart and lungs was the same as that for the blood, with a gradual reduction in IVH group. 5-FU concentration was the same for the kidneys and IVH group quickly reached to the high levels compared to PO group with only slight changes thereafter. Effects of continuous water load might be involved but not clear.

Vasodilator effects of cepharanthine, a biscoclaurine alkaloid, on cutaneous microcirculation in the rabbit.

Cutaneous microcirculatory responses to intravenous administration of cepharanthine (CT), a biscoclaurine alkaloid, isolated from Stephania cepharantha, were studied in a transparent round chamber installed in a rabbit ear, under conscious conditions. Vital-microscopic observations were made visually with a microscope-closed TV system and microphotoelectric plethysmography. Following the CT administration in doses of 1.0 and 3.0 mg/kg, an enhancement of rhythmic perfusion of microvascular blood due to vasomotion was developed for a period of 1 h or longer, although no appreciable change was observed following CT administration at 10.0 mg/kg. The microvascular dilator effect of CT appeared to have no direct association with systemic hemodynamics, based on the additional measurements of heart rate, blood pressure, carotid blood flow and auricular arterial blood flow.

[Effects of intravenous feeding on adjuvant chemotherapy--an experimental study on the distribution of 5-FU after injection of tegafur (1)].

Forty-eight male Donryu rats inoculated with Sato lung cancer were used to experimentally determine the effects of intravenous feeding on the concentrations of the chemotherapeutic agents FT-207 and 5-FU in the blood, as well as in the liver and tumorigenic tissue. Following FT-207 administration, the blood, tumor and liver tissue levels were lower than in the IVH group (oral administration). The liver 5-FU concentration, at 0.10 +/- 0.02 microgram/g, was significantly higher in the intravenous feeding group than in the p.o. group (0.05 +/- 0.01 micrograms/g). The 5-FU blood concentration rose quickly, reaching 0.051 +/- 0.013 micrograms/ml and 0.035 +/- 0.004 micrograms/ml at 9 and 12 hours, respectively, following treatment. This was significantly higher than in the p.o. group, which showed corresponding levels of 0.031 +/- 0.004 microgram/ml and 0.022 +/- 0.002 microgram/ml, respectively. The increase in the 5-FU level within the tumor was markedly high in the IVH group compared to the p.o. group, and it peaked at 9 hours following administration. The concentration in the IVH group was thus higher than in the p.o. group at any given time. At 24 hours after treatment, the IVH group level was 0.35 +/- 0.09 microgram/g, against 0.27 +/- 0.05 microgram/g in the p.o. group. The blood concentration of 5-FU following intravenous feeding maintained a high value for a long time, and the 5-FU tumor concentration also remained at a high level. The intravenous route was therefore considered to be advantageous for antitumor chemotherapy.