Effects of ω-3 Fatty Acid Supplementation in Patients with Bile Duct or Pancreatic Cancer Undergoing Chemotherapy.

BACKGROUND/AIM: Omega-3 fatty acids may improve cancer cachexia, but only in patients with pancreatic and bile duct cancer. Patients with pancreatic cancer commonly suffer from exocrine pancreatic insufficiency, and the ingestion of digestive enzyme supplements may improve absorption. PATIENTS AND METHODS: Racol®, an enteral nutrient formulated with omega-3 fatty acids, was administered to patients with unresectable pancreatic and bile duct cancer. The skeletal muscle mass and blood test data were taken pre-administration and at 4 and 8 weeks after. Patients with pancreatic cancer were given the digestive enzyme supplement LipaCreon® from the fifth week after the start of administration. RESULTS: In all 27 patients, skeletal muscle mass was significantly increased at both 4 and 8 weeks after the start of administration versus pre-administration (p=0.006, p=0.002, respectively). CONCLUSION: Omega-3 fatty acid supplementation in patients with unresectable pancreatic and bile duct cancer may improve cancer cachexia.

New treatment strategy with nuclear factor-κB inhibitor for pancreatic cancer.

BACKGROUND: Because of difficulties with early diagnosis, most patients with pancreatic cancer receive chemotherapy. The National Comprehensive Cancer Network guidelines (version 2.2015) suggest therapy with gemcitabine (GEM) plus nab-paclitaxel (nPTX) as a category 1 recommendation for metastatic pancreatic ductal adenocarcinoma. According to the results of many studies, the activation of chemotherapeutic agents-induced nuclear factor-κB (NF-κB) causes chemoresistance. Hence, we hypothesized that the addition of nafamostat mesilate (NM), a potent NF-κB inhibitor, to GEM/nPTX therapy could enhance the antitumor effect in the treatment of pancreatic ductal adenocarcinoma. MATERIALS AND METHODS: In vitro, we assessed NF-κB activity and apoptosis under treatment with NM alone (80 µg/mL), with GEM/nPTX, or with a combination of NM and GEM/nPTX in human pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and AsPC-1). In vivo, orthotopic pancreatic cancer mice (BALBc nu/nu) were divided into four groups: control (n = 13), NM (n = 13), GEM/nPTX (n = 13), and triple combination (n = 13). NM (30 mg/kg) was delivered intraperitoneally three times a week, and GEM/nPTX was injected intravenously once a week to orthotopic pancreatic cancer model mice. In the triple combination group, mice received NM followed by GEM/nPTX on the first day to avoid GEM/nPTX-induced NF-κB activation. RESULTS: In vitro and in vivo, NM inhibited GEM/nPTX-induced NF-κB activation, and a synergistic effect of apoptosis was observed in the triple combination group. Furthermore, tumor growth was significantly suppressed in the triple combination group compared with the other groups. CONCLUSIONS: NM enhances the antitumor effect of GEM/nPTX chemotherapy for orthotopic pancreatic cancer by inhibition of NF-κB activation.

Effect of NF-κB inhibition on chemoresistance in biliary-pancreatic cancer.

Biliary cancer and pancreatic cancer are considered to be difficult diseases to cure. Although complete resection provides the only means of curing these cancers, the rate of resectability is not high. Therefore, chemotherapy is often selected in patients with advanced unresectable biliary-pancreatic cancer. Many combination chemotherapy regimens have been applied in clinical trials. However, the survival time is not satisfactory. On the other hand, most chemotherapeutic agents induce anti-apoptotic transcriptional factor nuclear factor kappa b (NF-κB) activation, and agent-induced NF-κB activation is deeply involved in the onset of chemoresistance. Recently, novel approaches to potentiating chemosensitivity in cases of biliary-pancreatic cancer using NF-κB inhibitors with cytotoxic agents have been reported, most of which comprise translational research, although some clinical trials have also been conducted. Nevertheless, to date, there is no breakthrough chemotherapy regimen for these diseases. As some reports show promising data, combination chemotherapy consisting of a NF-κB inhibitor with chemotherapeutic agents seems to improve chemosensitivity and prolong the survival time of biliary-pancreatic cancer patients.

Feasibility study of oxaliplatin with oral S-1 or capecitabine as first-line therapy for patients with metastases from colorectal cancer.

BACKGROUND/AIM: The aim of this study was to determine the feasibility of S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (XELOX) as first-line therapy for patients with initially unresectable metastases from colorectal cancer. PATIENTS AND METHODS: Fourteen patients with colorectal cancer who underwent elective colorectal resection between January 2009 and December 2010 at the Department of Surgery, Kashiwa Hospital, the Jikei University School of Medicine, with initially unresectable metastatic lesions were enrolled in this study. After curative resection for the primary colorectal cancer, they underwent adjuvant chemotherapy with SOX or XELOX, starting at one month after surgery. RESULTS: Seven patients (50%) received SOX, and the others received XELOX as first-line therapy for initially unresectable metastases from colorectal cancer. Four (29%) patients had complete response for liver metastases over six months after chemotherapy, and liver metastases were subsequently judged to be completely resected by surgery. For the other ten patients, the median progression-free survival was 9.1 months and median overall survival was 24.1 months. There were no patients with grade 3 or 4 adverse reactions throughout the entire chemotherapy. CONCLUSION: Oxaliplatin with oral S-1 or capecitabine as first-line therapy for patients with initially unresectable metastases from colorectal cancer is safe and feasible.

Feasibility study of adjuvant chemotherapy with S-1 (TS-1; tegafur, gimeracil and oteracil potassium) for colorectal cancer.

BACKGROUND/AIMS: The aim of this study is to evaluate feasibility and safety of 3-week method (3-week administration and 1-week withdrawal) for colorectal cancer as adjuvant chemotherapy with an oral anticancer drug, S-1. METHODOLOGY: Forty-two patients with stage II or III colorectal cancer who underwent curative resection in our hospital during a one year period in 2005 were enrolled in the preliminary pilot study. Between 2006 and 2007, 104 patients with stage II or III colorectal cancer who underwent curative resection in our hospital were chosen and were randomly divided into two groups, 3-week method or 4-week method (4-week administration and 2-week withdrawal) for a prospective randomized trial. RESULTS: The one-year completion rate in the 3-week method group was 98% (50/51) which was significantly better than that in the 4-week method group, 68% (36/53) (p=0.035). There were no grade 3 or 4 adverse reactions in both laboratory and clinical findings in the pilot study and in the prospective randomized trial. CONCLUSIONS: Three-week method of S-1 administration had good feasibility, easily manageable toxicity, high accumulated dose in one year and good compliance. The 3-week method with S-1 may be a standard adjuvant chemotherapy schedule for colorectal cancer.

Serum vitamin D levels and survival of patients with colorectal cancer: post-hoc analysis of a prospective cohort study.

BACKGROUND: Recently, serum 25-hydroxyvitamin D (25OHD) levels were shown to be associated with the survival of patients with colorectal cancer. However, 25OHD levels were measured a median of 6 years before diagnosis or were predicted levels. In this study, we directly measured serum 25OHD levels at surgery and examined the association with survival among patients with colorectal cancer. METHODS: We started a prospective cohort study to find prognostic factors in patients with colorectal cancer from 2003 to 2008 and stored serum samples and clinical data. As part of a post-hoc analysis, serum 25OHD levels were measured by radioimmunoassay. Association between overall survival and serum 25OHD levels were computed using the Cox proportional hazard model adjusted for month of serum sampling as well as age at diagnosis, gender, cancer stage, residual tumor after surgery, time period of surgery, location of tumor, adjuvant chemotherapy and number of lymph nodes with metastasis at surgery. Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were determined. RESULTS: Serum 25OHD levels were measured in 257 patients. Only 3% had sufficient levels (30 ng/ml and greater). Based on month of blood sampling, an annual oscillation of 25OHD levels was seen, with levels being lower in spring and higher in late summer. Higher 25OHD levels were associated with better overall survival under multi-variate analysis (HR, 0.91: 95% CI, 0.84 to 0.99, P = 0.027). CONCLUSIONS: These results suggest that higher 25OHD levels at surgery may be associated with a better survival rate of patients with colorectal cancer.

Effects of half-solid nutrients on gastroesophageal reflux in beagle dogs with or without cardioplasty and intrathoracic cardiopexy.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) has become an important modality to provide enteral access for long-term nutritional support. Nevertheless, aspiration of liquid nutrients due to vomiting and reflux esophagitis caused by gastroesophageal reflux (GER) is a significant problem associated with tube feeding by PEG. MATERIALS AND METHODS: First, gastrostomy as an access for enteral nutrition and esophagostomy for gastroesophageal pH and Bilitec monitoring were performed in eight beagle dogs, in which the influence of viscosity of an enteral formula on the degree of GER was investigated using a commercially available liquid meal and a nearly isocaloric half-solid diet that was prepared by adding a solution mixed with dextrin, pectin, and calcium lactate. Second, similar studies were accomplished in seven beagle dogs that underwent cardioplasty and intrathoracic cardiopexy (a model of GER disease [GERD]). RESULTS: There was no difference in the degree of GER evaluated by Bilitec monitoring between liquid and half-solid nutrients in eight normal dogs, whereas solidifying nutrients significantly reduced the frequency of reflux during the feeding periods (P=0.0180) and post-feeding periods (P=0.0277) in a model of GERD. CONCLUSION: The use of half-solid nutrients for enteral feeding reduced the frequency of reflux in a dog model of GERD.

The herbal medicine Dai-Kenchu-To directly stimulates colonic motility.

Dai-kenchu-to (DKT) has attracted attention as a drug that improves the symptoms of postoperative ileus. However, the detailed mechanism of its action still remains unknown. The effect of DKT on colonic motility was herein evaluated using an original method. Eight healthy male volunteers who understood the purpose of this study were enrolled. Dai-kenchu-to (5 g) was dissolved in saline and administered into the cecum using a colonoscope until the ascending colon became distended. Colonic motility was observed by extrasomatic ultrasonography for 30 min. Colonic contractions were observed 129.4 (range 110-145) s after DKT administration into the ascending colon. Every segment in the right colon divided by the crescentic folds contracted independently. On the other hand, no colonic contractions were observed in the right colon after saline solution alone was administered to the ascending colon. In conclusion, DKT stimulates colonic motility immediately after administration, in the same manner as it does for the upper alimentary tract.

Preoperative Diagnosis of Adult Intussusception Caused by Small Bowel Lipoma.

Adult intussusception is rare, accounting for only 5% of all intussusceptions, for which preoperative diagnosis is difficult. We herein report a preoperatively diagnosed case of adult intussusception caused by a small bowel lipoma. A 33-year-old man was admitted to our hospital with three weeks history of colicky epigastric pain. Computed tomography revealed thickening of the ileal wall suggestive of intussusception. Colonoscopy revealed an ileocolic intussusception. Barium enema for reduction of ileocolic intussusception demonstrated a small bowel tumor in the ileum 15 cm proximal to the ileocecal valve. The intussusception was reduced, and the patient underwent partial resection of the ileum encompassing the small bowel tumor. Histological findings confirmed the diagnosis of lipoma of the small bowel. The patient made a satisfactory recovery and remains well.

The use of nonpharmacological interventions to reduce anxiety in patients undergoing gastroscopy in a setting with an optimal soothing environment.

Patients develop anxiety before undergoing gastroscopy. By removing such distressing feelings, patients are more likely to experience gastroscopy more smoothly. This study was designed to examine changes in anxiety levels in patients undergoing gastroscopy and the effect of an optimal soothing environment (OSE) as a new nonpharmacological intervention to reduce patient anxiety prior to gastroscopy. During a 6-month period, 50 outpatients referred for gastroscopy were randomly assigned to two groups (control group, n = 24 patients; OSE group, n = 26 patients). This study was performed at the digestive endoscopy service of a 150-bed acute care hospital in Japan. The patient anxiety was assessed using the Face Scale score. Pre- and postprocedural systolic blood pressures were measured and values were compared with blood pressure upon arrival at the hospital. The tools for an OSE, including a safe essential oil burner with lavender essential oil and a digital video disk program entitled "Flow" manufactured by NHK (Japan Broadcasting Corporation) software, were provided to patients in the waiting room before gastroscopy. The score for self-assessed anxiety level just before gastroscopy was significantly higher than that on arrival at the hospital but returned to baseline after gastroscopy in the control group, whereas the score did not increase before starting gastroscopy in the OSE group. Systolic blood pressure measurements just before and after gastroscopy were significantly higher than those on arrival at the hospital and the baseline values in the control group, whereas it was not increased before starting gastroscopy in the OSE group. Providing an OSE before and during gastroscopy is useful to minimize patient anxiety regarding experiencing a gastroscopy. This nonpharmacological method is a simple, inexpensive, and safe method of minimizing anxiety before and during gastroscopy.

Blood transfusion requirement for gastric cancer surgery: reasonable preparation for transfusion in the comprehensive health insurance system.

We investigated the necessity of preparation for blood transfusion in gastric cancer surgery to save costs for blood typing, antibody screening, cross-matching, and disposal of the blood product. The subjects of the study were 52 patients who underwent gastric cancer surgery at our department between 2000 and 2004. The requirement for blood transfusion during surgery was investigated in terms of patient characteristics, hemoglobin before surgery, and performance status as well as treatment regimen. Furthermore, economic effects were investigated when typing and screening (T&S) were performed instead of typing and cross-matching (T&X). Of 9 patients who received blood transfusion, 8 had gastric cancer of stage IIIB or higher, or underwent combined resection. Blood transfusion was not used in surgery for patients with early gastric cancer. The volumes of blood prepared, lost, and disposed of in 28 patients who underwent T&X were 831.3+/-249.4, 219.3+/-228.5 and 600+/-333.1 ml, respectively, whereas the blood loss in 24 patients who underwent T&S was 161.1+/-95.6 ml; this difference had a major economic effect. The practice of T&S for patients undergoing gastric surgery in the absence of combined resection for early gastric cancer seems to be a safe and cost-effective practice that abrogates disposal of blood in hospital management.

Adenovirus vector-mediated gene therapy using iodized oil esters for hepatocellular carcinoma in rats.

BACKGROUND: When gene therapy is performed for malignant tumors, gene transfer efficiency and selectivity are extremely important. The usefulness of gene therapy by intraarterial injection of an adenovirus vector with iodized oil esters (IOEs) for hepatocellular carcinoma (HCC) was studied. MATERIALS AND METHODS: HCC was induced in rats with diethyl nitrosamine and phenobarbital, after which either adenovirus vector expressing the herpes simplex virus thymidine kinase (AxCAHSVtk) and IOEs or AxCAHSVtk alone was injected through the hepatic artery. On postoperative days 2, 4 and 6, gancyclovir was injected into the peritoneum; blood sampling was performed on day 7. RESULTS: Aspartate aminotransferase and alanine aminotransferase levels in the AxCAHSVtk with IOEs group were lower than in the AxCAHSVtk alone group (p = 0.0274, p = 0.0323). However, the survival rate was not significantly different between groups (p = 0.7122). CONCLUSION: Intra-arterial injection of an adenovirus vector with IOEs can result in cancer-selective but not effective gene therapy for HCC.

Impact of appropriateness of initial antibiotic therapy on outcome of postoperative pneumonia.

BACKGROUND: Although delay in the administration of appropriate antibiotic treatment for ventilator-associated or community-acquired pneumonia is associated with increased hospital mortality, impact of appropriateness of initial antibiotic therapy on outcome of postoperative pneumonia has been poorly investigated. MATERIALS AND METHODS: Of 7,275 patients who had undergone intraabdominal surgery under general anesthesia between January 1998 and December 2005, we compiled a list of 101 patients with microbiologically confirmed postoperative pneumonia. We analyzed the influence of the appropriateness of initial antibiotic therapy on outcome of postoperative pneumonia using logistic regression analysis. RESULTS: Among the patients with postoperative pneumonia, about a half received inadequate initial antimicrobial therapy. As well as the presence of concomitant intraabdominal abscess [odds ratio (OR) = 28.83), prolonged duration of anesthesia at surgery (OR = 22.41), and the isolation of methicillin-resistant Staphylococcus aureus (OR = 8.86), inadequate initial antibiotic therapy was a determinant of death from postoperative pneumonia (OR = 16.75). CONCLUSION: The outcomes of patients with postoperative pneumonia could be improved by avoiding concomitant intraabdominal abscess, reducing surgical insult, and administering appropriate antimicrobial agents.

Effect of Dai-kenchu-to on gastrointestinal motility based on differences in the site and timing of administration.

The purpose of this study was to investigate the effects of the herbal medicine dai-kenchu-to on gastrointestinal motility based on differences in the administration site and timing. We sutured strain-gauge transducers to the stomach (three), duodenum (one), jejunum (one), ileum (one), and colon (two) and inserted indwelling tubes into the stomach, jejunum, and proximal colon of beagles. Dai-kenchu-to was administered to each site during the fasting or fed state. During the fasting state, the prokinetic effects of dai-kenchu-to were evident at all administration sites. The effects were attenuated during the fed state. With intracolonic administration, a contraction similar to the giant migrating contraction-like contraction was induced during the fasting and the fed state, and defecation occurred. Despite the differences in administration site and timing, no contraction complex appeared orad to the administration sites. These results indicate that the prokinetic effects of dai-kenchu-to differ with the site or timing of administration.

Implantation of rectal cancer in an anal fistula: report of a case.

A 53-year-old man who had had an anal fistula for 20 years was admitted to our hospital with a large intestinal obstruction. Barium enema and colonoscopy confirmed advanced rectal cancer and we palpated a soft tumor, 3 cm in diameter, with inflammatory induration on the right side of the rectum. After draining a perianal abscess caused by the anal fistula, we performed low anterior resection. Histological examination of the perianal necrotic tissue obtained during resection of the perianal tumor encompassing the anal fistula revealed adenocarcinoma. Since the histology of the perianal lesion was identical to that of the rectal cancer, a diagnosis of cancer implantation rather than carcinoma originating in the anal fistula was entertained. Although the recurrence of rectal cancer by mucosal implantation is not uncommon, the coincidental implantation of rectal cancer in an anal fistula is extremely rare.

New approach for the establishment of an hepatocyte cell line derived from rat early embryonic stem cells.

A cell line with the characteristics of hepatocytes was established from rat early embryonic stem cells (REES). This cell line was established using a new novel method of Ishiwata et al. from two cell embryos taken from the spontaneous dwarf rat (SDR). The hepatocyte cell line (REES-hep) was instituted from dark red colored tissue in embryos during embryogenesis using REES cell line cultured in the presence of embryotrophic factors. These cell lines were cultured with DMEM/F12 medium supplemented 10% FBS and 1 ng/ml of LIF. They were found to maintain their diploid state, were characterized with 42 normal chromosomes and proliferated to confluence; contact inhibition was also present. These cells produced albumin when cultured using a collagen sponge gel system and reconstructed in a funicular form resembling the cell cords of liver. The cells also produced albumin and bilirubin when transplanted into the spleen of SDR Reconstruction of a REES-hep cell line from early embryonic stem cells should help in treating hepatic insufficient patients. It will be valuable for further research, as an introduction to cell transplantation and application for use in a bio-hybrid typed liver apparatus.