Nutri-pharmacogenomics of warfarin anticoagulation therapy: VKORC1 genotype-dependent influence of dietary vitamin K intake.

Warfarin is the most widely prescribed oral anticoagulant, but large interindividual variations exist in the dose required to achieve comparable therapeutic effects. Several clinical and genetic variables have been identified that influence warfarin dosing. However, interactions between genotype and nutrition remain uncertain in terms of dietary vitamin K intake. To investigate genotype-nutrient interactions in warfarin anticoagulation therapy, 202 consecutive outpatients (M/F = 142/60, mean age, 69 years) undergoing treatment with warfarin were enrolled. Prevalent single nucleotide polymorphisms in VKORC1 and CYP2C9 were genotyped, and dietary vitamin K intake during the week preceding the blood sampling was quantitatively estimated by a dietitian-assisted questionnaire. Patients were classified according to low, medium, or high vitamin K intake. The mean daily warfarin dose in subjects with a VKORC1-1639 A/A genotype was significantly smaller than that with a -1639A/G genotype (2.74 vs. 3.91 mg/day, respectively, p < 0.0001). Dose requirements did not differ between subjects with a CYP2C9 *1/*3 genotype versus a CYP2C9 *1/*1 genotype. In subjects with a variant VKORC1-1639 G allele, the mean daily warfarin dose was significantly attenuated by low vitamin K intake compared with medium and high intake after adjustment for covariates (3.4 vs. 5.0 vs. 4.0 mg/day, respectively, p = 0.028). No such genotype effects were observed in homozygous patients for the VKORC1-1639 A allele. The results of the present study suggest that the capacity of dietary vitamin K intake to influence warfarin dose requirements during anticoagulation therapy is VKORC1 genotype-dependent, at least in part.

Hiatal Hernia with Prolapse of the Pancreas Causing Bile Duct Stricture and Liver Function Disorders: A Case Report and Literature Review.

Hiatal hernia is a common condition in elderly patients, but the additional presence of prolapse of the pancreas is extremely rare. We herein report an 89-year-old woman who presented with liver function disorders and abdominal pain. Her laboratory tests revealed cholestasis, and imaging examinations showed stenosis of the common bile duct pulled toward the hernia sac. She was diagnosed with a common bile duct stricture due to pancreatic herniation and underwent laparoscopic surgery. Our review of the literature identified three types of pancreatic herniations: asymptomatic, bile duct complication, and acute pancreatitis. Pancreatic head herniation tends to induce bile duct complications.

Bowel Obstruction due to Shiitake Mushrooms: Diagnostic Features on Computed Tomography.

Shiitake mushrooms are edible mushrooms popular in East Asian cuisine. We herein report a 69-year-old man with abdominal distension and vomiting after ingesting several pieces of sautéed Shiitake mushrooms. Abdominal computed tomography (CT) revealed ring-shaped and crescent-shaped low-density objects (-100 to -300 Hounsfield units) in the ileum. Based on the specific shapes and CT numbers of the foreign bodies, he was diagnosed with small bowel obstruction due to Shiitake mushrooms. After conservative treatment, he passed four pieces of Shiitake mushrooms. Despite the rarity, the condition can be diagnosed before exploratory surgery by careful and detailed interpretation of CT findings.

Conjoined tendon preserving posterior approach in hemiarthroplasty for femoral neck fractures: A prospective multicenter clinical study of 322 patients.

PURPOSE: The posterior approach is widely used in femoral hemiarthroplasty. The major problem with this approach is the high risk of postoperative dislocation. A modified posterior approach, the conjoined tendon preserving posterior approach (CPP), was developed to reduce postoperative dislocations. The objective of this multicenter study was to evaluate the efficacy and safety of hemiarthroplasty performed using the CPP approach for femoral neck fractures. METHODS: A total of 322 patients with femoral neck fracture, from 10 facilities, were prospectively studied. Bipolar hemiarthroplasty using the CPP approach was performed, using the same type of implants. Hip joint movement was not restricted following surgery, regardless of a patient's cognitive status. Final follow-up was performed 9.1 ± 1.5 months after surgery. RESULTS: Hemiarthroplasty was undertaken in 320 patients using the CPP approach. The mean age, operative time, and intraoperative blood loss were 83.3 ± 7.4 years, 70.0 ± 22.7 min, and 134.8 ± 107.9 mL, respectively. No postoperative dislocations were observed during the study period. Intraoperative adverse events related to the hip joint included femoral fractures in five patients (1.6%) and trochanteric fractures in four patients (1.3%). Postoperative hip joint adverse events included a periprosthetic fracture in one patient (0.3%), deep infection in two patients (0.6%), and stem subsidence in one patient (0.3%). Postoperative deaths occurred in 23 patients (7.2%). One patient (0.3%) had a severe non-hip adverse event unrelated to surgery that prevented independent living, while five patients (1.6%) had a moderate non-hip adverse event that required treatment. CONCLUSION: The CPP approach prevented postoperative dislocation following femoral hemiarthroplasty in elderly patients, with no CPP-associated specific adverse events.

Atypical Clinical Presentation of Crohn's Disease with Superior Mesenteric Vein Obstruction and Protein-losing Enteropathy.

We herein report a 44-year-old man suffering from systemic edema due to protein-losing enteropathy (PLE) with superior mesenteric vein (SMV) obstruction and development of collateral veins, which subsequently proved to be a chronic result of thrombosis and a complication of Crohn's disease (CD). PLE was supposedly induced by both intestinal erosion and thrombosis-related lymphangiectasia, which was histologically proven in his surgically-resected ileal stenosis. Elemental diet and anti-TNFα agent improved his hypoalbuminemia after surgery. The rarity of the simultaneous coexistence of SMV obstruction and PLE and the precedence of these complications over typical abdominal symptoms of CD made the clinical course complex.

Protein profiling in pancreatic juice for detection of intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND/AIMS: Malignant intraductal papillary mucinous neoplasm of the pancreas (IPMN) has a very poor prognosis, and there is no useful biomarker for an early diagnosis at present. A biomarker is expected to allow an early diagnosis of IPMNs and consequently lead to an improvement of the patients' prognosis. Recent advances in proteomic analysis are remarkable; therefore we explored novel biomarkers for IPMN using Surface-Enhanced Laser Desorption and Ionization (SELDI) Mass Spectrometry. METHODOLOGY: We collected pancreatic juice samples from 33 patients with IPMNs, 54 patients with pancreatic ductal carcinoma, and 31 with chronic pancreatitis. We analyzed the pancreatic juice samples using a SELDI ProteinChip system (Ciphergen Biosystems, Fremont, CA). RESULTS: We identified a 6240-Da peak whose expression in pancreatic juice from patients with IPMNs was significantly higher compared with that in other pancreatic diseases (P<0.01). This 6240-Da protein was partially purified and was identified as pancreatic secretory trypsin inhibitor (PSTI) by amino acid sequencing. The pancreatic juice PSTI levels, as measured by radioimmunoassay, were significantly higher in the IPMN group than in the other groups (P<0.001). When the diagnostic cutoff value of PSTI in pancreatic juice was set at 25000 ng/mL, the positive predictive value, negative predictive value, sensitivity, and specificity were respectively 89%, 83%, 48%, and 98%. CONCLUSIONS: PSTI levels of pancreatic juice in patients with IPMN were significantly higher than those in patients with other pancreatic diseases. The PSTI level in pancreatic juice may be useful for the diagnosis of IPMN.

Phase I study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer.

PURPOSE: The primary objective of this study was to determine the maximum-tolerated dose (MTD) of S-1, an oral fluoropyrimidine derivative, with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day from Day 1 to 14 and 22 to 35 at escalating doses from 60 to 80 mg/m(2)/day. RESULTS: Sixteen patients were enrolled in this study. Three patients received S-1 at 60 mg/m(2)/day, 3 at 70 mg/m(2)/day, and 10 at 80 mg/m(2)/day. Though 1 patient at the final dose level (80 mg/m(2)/day) experienced a dose limiting toxicity (biliary infection with Grade 3 neutropenia), the MTD was not reached in this study. The most common toxicities were anorexia and leukocytopenia, with Grade 3 toxicity occurring in 31% and 6.3% of the patients, respectively. CONCLUSIONS: The recommended dose of S-1 with concurrent radiotherapy was determined to be 80 mg/m(2)/day from Day 1 to 14 and 22 to 35 in patients with locally advanced pancreatic cancer. Oral S-1 and radiotherapy is well tolerated and feasible and should be further investigated.

Long-term outcome of endoscopic metallic stenting for benign biliary stenosis associated with chronic pancreatitis.

AIM: Endoscopic metal stenting (EMS) offers good results in short to medium term follow-up for bile duct stenosis associated with chronic pancreatitis (CP); however, longer follow-up is needed to determine if EMS has the potential to become the treatment of first choice. METHODS: EMS was performed in eight patients with severe common bile duct stenosis due to CP. After the resolution of cholestasis by endoscopic naso-biliary drainage three patients were subjected to EMS while, the other five underwent EMS following plastic tube stenting. The patients were followed up for more than 5 years through periodical laboratory tests and imaging techniques. RESULTS: EMS was successfully performed in all the patients. Two patients died due to causes unrelated to the procedure: one with an acute myocardial infarction and the other with maxillary carcinoma at 2.8 and 5.5 years after EMS, respectively. One patient died with cholangitis because of EMS clogging 3.6 years after EMS. None of these three patients had showed symptoms of cholestasis during the follow-up period. Two patients developed choledocholithiasis and two suffered from duodenal ulcers due to dislodgement of the stent between 4.8 and 7.3 years after stenting; however, they were successfully treated endoscopically. Thus, five of eight patients are alive at present after a mean follow-up period of 7.4 years. CONCLUSION: EMS is evidently one of the very promising treatment options for bile duct stenosis associated with CP, provided the patients are closely followed up; thus setting a system for their prompt management on emergency is desirable.

[Assessment of immunotoxicity of irinotecan determined by the novel method, by which productivity of TNF-alpha from whole blood is stimulated by lipopolysaccharide].

Irinotecan hydrochloride shows much different responses in each patient, and it has severe adverse effects. Therefore, a sensitive marker for the side effect of irinotecan on immunotoxicity may be able to prevent the severe complications by the early detection. We have recently developed a method to assess the immunotoxicity by measuring the productivity of TNF-alpha from whole blood containing monocytes when stimulated by lipopolysaccharide. By using this method, the effects of continuous low-dose irinotecan therapy on immunotoxicity were assessed in 10 patients with advanced gastric or colon cancer. When compared this method with the others such as white blood cell count, lymphocyte blastoid transformation by phytohem agglutinin (PHA), and natural killer cell activity in terms of the sensitivity, immunotoxicity by this method was found earlier than the other methods. Because our original method is easy to perform and sensitive as compared to the conventional methods, it can be widely used as one of the laboratory tests useful for patients treated with immunosuppressive agents.

[Efficacy of TS-1 in patients with peritonitis carcinomatosa from gastric cancer].

Medical treatment with TS-1 was performed in patients with gastric cancer with peritonitis carcinomatosa. The median survival time for the patients who underwent distal or total gastrectomy was 14.0 months, and that for the patients who underwent exploratory laparotomy was 9.3 months. Compared with other medical care, the anti-cancer drug TS-1 enabled prolonged survival time and shortened hospitalization. Since TS-1 had few side effects, it was useful to patients suffering from gastric cancer with peritonitis carcinomatosa.

Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer.

PURPOSE: The aim of this study was to evaluate efficacy and safety of gemcitabine plus S-1 (GS) combination chemotherapy in patients with unresectable pancreatic cancer. METHODS: Patients were randomly assigned to receive GS (oral S-1 60 mg/m(2) daily on days 1-15 every 3 weeks and gemcitabine 1,000 mg/m(2) on days 8 and 15) or gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks). The primary endpoint was progression-free survival (PFS). RESULTS: One hundred and one patients were randomly assigned. PFS was significantly longer in the GS arm with an estimated hazard ratio (HR) of 0.65 (95 % CI 0.43-0.98; P = 0.039; median 5.3 vs 3.8 months). Objective response rate (ORR) was also better in the GS arm (21.6 vs 6 %, P = 0.048). Median survival was 8.6 months for GS and 8.6 months for GEM (HR 0.93; 95 % CI 0.61-1.41; P = 0.714). Grade 3-4 neutropenia (44 vs 19.6 %, P = 0.011) and thrombocytopenia (26 vs 8.7 %, P = 0.051) were more frequent in the GS arm. CONCLUSIONS: GS therapy improved PFS and ORR with acceptable toxicity profile in patients with unresectable pancreatic cancer.

Usefulness of multidetector computed tomography for detecting protruding lesions in intraductal papillary mucinous neoplasm of the pancreas in comparison with single-detector computed tomography and endoscopic ultrasonography.

OBJECTIVES: To retrospectively evaluate the usefulness of multidetector computed tomography (MDCT) with multiplanar reformations (MPRs) and curved planar reformations (CPRs) for detecting protruding lesions in intraductal papillary mucinous neoplasms of the pancreas (IPMNs) as compared with single-detector CT (SDCT) and endoscopic ultrasonography (EUS). METHODS: Eighty-six patients with IPMNs were imaged either with SDCT (n = 52) or MDCT with MPRs/CPRs and EUS (n = 34). The diagnostic accuracy of each imaging modality for identifying protruding lesions was compared with histological samples. RESULTS: Among the patients in whom protruding lesions were histopathologically identified, the lesions were detected in 9 of the 33 patients subjected to SDCT (51.9% accuracy), in 17 of the 25 patients subjected to MDCT with MPRs and CPRs (76.5% accuracy), and in 21 of the 25 patients subjected to EUS (70.6% accuracy). Thus, significant difference was observed between MDCT and SDCT regarding accuracy (P < 0.05); however, no significant difference was seen between MDCT and EUS. Protruding lesions of less than 10 mm in height were better visualized with MDCT (53.3%) than with SDCT (13.0%; P < 0.05). CONCLUSIONS: Multidetector computed tomography proved more useful than SDCT and equivalent to EUS in detecting protruding lesions in IPMNs.

Pancreatic juice cytology in the diagnosis of intraductal papillary mucinous neoplasm of the pancreas: significance of sampling by peroral pancreatoscopy.

BACKGROUND: The examination of pancreatic juice cytology could hypothetically contribute to the establishment of a definite diagnosis of malignant intraductal papillary mucinous neoplasm of the pancreas (IPMN), but to the authors' knowledge, its significance has not been confirmed to date. The current study was conducted to assess the diagnostic value of pancreatic juice cytology in IPMN and to examine the usefulness of peroral pancreatoscopy (POPS) in sampling pancreatic juice. METHODS: The study subjects were comprised of 103 patients with IPMN who underwent surgical resection of pancreatic tumors (adenoma in 29 patients, borderline in 17 patients, carcinoma in situ in 25 patients, and invasive carcinoma in 32 patients). Pancreatic juice was collected with a catheter in 71 patients and by POPS in 32 patients. Patients with pancreatic carcinoma (n = 81) and chronic pancreatitis (n = 76) also were investigated. RESULTS: The cytologic diagnosis was found to be of nondiagnostic value in only one patient with an IPMN, whereas it was of no diagnostic value in 14 of the patients with pancreatic carcinoma (17.3%), a difference that was statically significant (P < 0.001). The location of the IPMN (either in the pancreas or the pancreatic ducts) was not found to significantly affect the diagnostic value of the test. The sensitivity for IPMN was 62.2% when pancreatic juice was collected by POPS, and was 38.2% when it was collected using a catheter. In the case of pancreatic carcinoma, the sensitivity of pancreatic juice cytology was found to be 25.4%, which was significantly lower than that for IPMN when the pancreatic juice was collected by POPS (P < 0.001). CONCLUSIONS: Pancreatic juice cytology was found to have better diagnostic value in the patients with IPMNs compared with those with pancreatic carcinoma. POPS was found to be useful for the collection of pancreatic juice.

Assessment of portal vein invasion in pancreatic cancer by fusion 3-dimensional ultrasonography.

OBJECTIVE: The purpose of this study was to assess the usefulness of a newly developed imaging technique, fusion 3-dimensional ultrasonography (3DUS) in the diagnosis of portal vein (PV) invasion in patients with pancreatic cancer (PC). METHODS: Fourteen patients with proven PC were examined by fusion 3DUS presented as shaded volume-rendering and multiplanar reconstruction images. The surgical findings were obtained in all patients (12 with resection and 2 without). The findings were compared with those of 2-dimensional ultrasonography (2DUS), contrast-enhanced computed tomography (CT), dynamic CT (DCT), angiography, and surgical findings. Portal vein invasion was assessed by 3 independent radiologists for each modality, and objectivity of the assessment was examined by interobserver variability analysis (kappa value). RESULTS: On the basis of surgical findings, the accuracy rates of 2DUS, fusion 3DUS, DCT, and angiography were 78.6%, 92.9%, 85.3%, and 66.7%, respectively. The kappa values of 2DUS, fusion 3DUS, DCT, and angiography for PV invasion were 0.57, 0.90, 0.63, and 0.49, respectively, being most objective in fusion 3DUS. CONCLUSIONS: Fusion 3DUS is useful for diagnosis of PV invasion of PC.