Changes in the negative logarithm of end-tidal hydrogen partial pressure indicate the variation of electrode potential in healthy Japanese subjects.

Molecular hydrogen (H2) is produced by human colon microbiomes and exhaled. End-tidal H2 sampling is a simple method of measuring alveolar H2. The logarithm of the hydrogen ion (H+)/H2 ratio suggests the electrode potential in the solution according to the Nernst equation. As pH is defined as the negative logarithm of the H+ concentration, pH2 is defined as the negative logarithm of the H2 effective pressure in this study. We investigated whether changes in pH2 indicated the variation of electrode potential in the solution and whether changes in end-tidal pH2 could be measured using a portable breath H2 sensor. Changes in the electrode potential were proportional to ([Formula: see text]) in phosphate-buffered solution (pH = 7.1). End-tidal H2 was measured in the morning (baseline) and at noon (after daily activities) in 149 healthy Japanese subjects using a handheld H2 sensor. The median pH2 at the baseline was 4.89, and it increased by 0.15 after daily activities. The variation of electrode potential was obtained by multiplying the pH2 difference, which suggested approximately + 4.6 mV oxidation after daily activities. These data suggested that changes in end-tidal pH2 indicate the variation of electrode potential during daily activities in healthy human subjects.

T tube drainage for spontaneous perforation of the extrahepatic bile duct.

BACKGROUND: Spontaneous perforation of the extrahepatic bile duct is very rare. We report a patient with a spontaneous perforation of the left hepatic bile duct who was diagnosed preoperatively. CASE REPORT: A 65-year-old woman was admitted to our hospital complaining of a right upper quadrant pain lasting for two days. She was diagnosed as having a perforated bile duct and peritonitis and underwent a laparotomy. After a cholecystectomy, T-tube drainage of the left hepatic duct was performed. The postoperative course was uneventful. The T tube was removed 25 days after the surgery. CONCLUSIONS: A more noninvasive procedure, such as endoscopic treatment, should play a central role in the management of extra bile duct perforation. For this case, however, we chose to perform a laparotomy based on the patient's general condition and the presence of peritonitis. T tube decompression is effective and a safe and reliable method. The goal of treatment is to stop the bile leakage, resolve the choledocholithiasis and cholangitis, and reconstruct the bile duct.

Chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine predicts outcome of gastric cancer patients receiving S-1 postoperatively.

BACKGROUND: Chemosensitivity tests have long been discussed but remain a topic of research. In this study, we investigated the correlation between the results of a chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine and the clinical outcomes of gastric cancer patients treated with S-1, an oral fluoropyrimidine, as adjuvant chemotherapy. METHODS: For gastric cancer patients, we performed surgical treatment and a lymph node dissection of D2 or more. Afterwards, a chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine was performed, using the collagen gel droplet embedded culture drug-sensitivity test (CD-DST), in surgical specimens. All the patients received postoperative adjuvant chemotherapy with S-1 for 1 year, and the overall survival (OS), relapse-free survival (RFS), and adverse events were investigated. RESULTS: The chemosensitivity test was performed for 27 patients. The growth inhibition rate (IR) was 50% or more (high-sensitivity group) in 59.3% (16 cases) and it was under 50% (low-sensitivity group) in 40.7% (11 cases). The 3-year OS rate was 100% in the high-sensitivity group and 62.34% in the low-sensitivity group. The 3-year RFS rate was 83.33% in the high-sensitivity group and 24.24% in the low-sensitivity group. Thus, the 3-year OS rate and the 3-year RFS rate were higher in the high-sensitivity group than in the low-sensitivity group. No adverse events of grade 3 or greater severity were observed. CONCLUSIONS: The results of the chemosensitivity test were correlated with the patient outcome. Therefore, such results might be useful for individualizing cancer chemotherapy and for determining future indications for postoperative adjuvant chemotherapy.

Total colonoscopy detects early colorectal cancer more frequently than advanced colorectal cancer in patients with fecal occult blood.

The efficacy of total colonoscopy following a positive result of the fecal occult blood test (FOBT) for the early detection of colorectal cancer and polyps was evaluated. A total of 1,491 patients with positive FOBT results underwent total colonoscopy at the Institute of Gastroenterology, Nippon Medical School, Musashi Kosugi Hospital, from April 2002 through July 2009. Abnormalities were found in 1,312 of the 1,491 patients (88.0%). Ninety-six of the 1,491 patients (6.4%) were found to have early cancer, but 59 patients (4.0%) were found to have advanced cancer. The early cancers were treated with endoscopic mucosal resection or endoscopic submucosal dissection in 81 patients, with laparoscopy-assisted colectomy in 10 patients, and with open surgery in 5 patients. Fifty-one of the 59 patients with advanced colorectal cancer underwent conventional open surgery, and 8 patients underwent laparoscopic surgery. The cancers detected were more likely to be early cancers than advanced cancers. In addition to malignancies, other abnormalities found included inner or external hemorrhoids, diverticula of the colon, ulcerative colitis, ischemic colitis, infectious colitis, and colorectal polyps. Our results show that a high percentage of lesions detected with total colonoscopy following a positive FOBT result are early colorectal cancers and polyps.

Mutations in the mitochondrial genome confer resistance of cancer cells to anticancer drugs.

The majority of cancer cells harbor homoplasmic somatic mutations in the mitochondrial genome. We show here that mutations in mitochondrial DNA (mtDNA) are responsible for anticancer drug tolerance. We constructed several trans-mitochondrial hybrids (cybrids) with mtDNA derived from human pancreas cancer cell lines CFPAC-1 and CAPAN-2 as well as from healthy individuals. These cybrids contained the different mitochondrial genomes with the common nuclear background. We compared the mutant and wild-type cybrids for resistance against an apoptosis-inducing reagent and anticancer drugs by exposing the cybrids to staurosporine, 5-fluorouracil, and cisplatin in vitro, and found that all mutant cybrids were more resistant to the apoptosis-inducing and anticancer drugs than wild-type cybrids. Next, we transplanted mutant and wild-type cybrids into nude mice to generate tumors. Tumors derived from mutant cybrids were more resistant than those from wild-type cybrids in suppressing tumor growth and inducing massive apoptosis when 5-fluorouracil and cisplatin were administered. To confirm the tolerance of mutant cybrids to anticancer drugs, we transplanted a mixture of mutant and wild-type cybrids at a 1:1 ratio into nude mice and examined the effect by the drugs on the drift of the ratio of mutant and wild-type mtDNA. The mutant mtDNA showed better survival, indicating that mutant cybrids were more resistant to the anticancer drugs. Thus, we propose that mutations in the mitochondrial genome are potential targets for prognosis in the administration of anticancer drugs to cancer patients.

Two successful curative operations using stomach-preserving distal pancreatectomy with celiac axis resection for the treatment of locally advanced pancreatic body cancer.

Large vessel invasion is a serious factor determining whether an operation for pancreatic body cancer is feasible. The Appleby operation is a radical operation for the treatment of pancreatic body cancer that has infiltrated the celiac axis. Since this procedure includes a total gastrectomy, the operation is associated with a high morbidity, mortality, and deteriorating postoperative quality of life (QOL). We experienced two cases in which radical operations consisting of a stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric artery were performed. The use of adjuvant chemotherapy in these cases led to a good postoperative QOL.

A case of giant mucinous cystic neoplasm of the pancreas resected with laparoscopic surgery.

We report a case of giant mucinous cystic neoplasm (MCN) of the pancreas that was successfully treated with laparoscopic surgery. A 29-year-old woman was admitted to our hospital for evaluation of an abdominal tumor that had been detected during a routine medical examination. The tumor was diagnosed as an MCN of the pancreas. We performed laparoscopic distal pancreatectomy and splenectomy. The patient could begin oral feeding 3 days after the operation. No complications occurred either during or after surgery. The outcome in this patient was excellent, with cosmetically acceptable small scars in the skin. Therefore, laparoscopic distal pancreatectomy may become a therapeutic option for patients with large MCNs of the pancreas.

Acute pulmonary thromboembolism after distal gastrectomy: an appraisal of the guidelines for preventing pulmonary thromboembolism/deep vein thrombosis.

We report a case of acute pulmonary thromboembolism after gastrectomy. A 67-year-old woman was found to have gastric cancer and a giant lipoma in the ascending colon. We performed distal gastrectomy and enucleation of the ascending colon lipoma. On postoperative day 9, an acute pulmonary thromboembolism developed, and thrombolytic therapy was urgently performed. The 2004 Japanese guidelines for preventing pulmonary thromboembolism/deep vein thrombosis are discussed in relation to the present case.

Experience with direct Kugel patch method for repair of adult inguinal hernia.

The direct Kugel Patch method is a minimally invasive but nonlaparoscopic preperitoneal method of hernia repair which has various ideal characteristics including all the benefits of laparoscopic hernia repair without the risks of complications. In this retrospective study, we report our experience with this method for adult inguinal hernia repair. Forty-four hernias, including 35 indirect, 7 direct inguinal hernias, and 1 recurrent indirect inguinal hernia, in 41 patients were surgically repaired using the direct Kugel patch method. The average operation time was 45.6 +/- 11.3 min, and the average hospitalization time was 6.2 +/- 5.0 days. There were 5 complications of seroma and only 1 recurrence of hernia which were successfully managed. We concluded that the direct Kugel patch method provides an ideal approach to adult inguinal hernia repair with short operation time and hospital stay and a very low risk of complications or recurrence.

Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization.

The linear ubiquitin chain assembly complex (LUBAC) participates in inflammatory and oncogenic signaling by conjugating linear ubiquitin chains to target proteins. LUBAC consists of the catalytic HOIP subunit and two accessory subunits, HOIL-1L and SHARPIN. Interactions between the ubiquitin-associated (UBA) domains of HOIP and the ubiquitin-like (UBL) domains of two accessory subunits are involved in LUBAC stabilization, but the precise molecular mechanisms underlying the formation of stable trimeric LUBAC remain elusive. We solved the co-crystal structure of the binding regions of the trimeric LUBAC complex and found that LUBAC-tethering motifs (LTMs) located N terminally to the UBL domains of HOIL-1L and SHARPIN heterodimerize and fold into a single globular domain. This interaction is resistant to dissociation and plays a critical role in stabilizing trimeric LUBAC. Inhibition of LTM-mediated HOIL-1L/SHARPIN dimerization profoundly attenuated the function of LUBAC, suggesting LTM as a superior target of LUBAC destabilization for anticancer therapeutics.

Expression and roles of keratinocyte growth factor and its receptor in esophageal cancer cells.

The keratinocyte growth factor receptor (KGFR), also known as FGFR2 IIIb, is mainly localized in epithelial cells and is activated by the keratinocyte growth factor (KGF) that is predominantly synthesized by mesenchymal cells. In this study, we examined the roles of KGFR and KGF in human esophageal cancer (EC). In noncancerous esophageal tissues, KGFR was localized in epithelial cells from the basal region of the epithelium to the lower one-third of the epithelium, and KGF was weakly localized in the basal to parabasal epithelial cells. On the other hand, Ki-67 was localized in the parabasal cells. In EC tissues, KGFR and KGF were expressed in cancer cells in 22 and 37 of 54 patients, respectively. The coexpression of KGFR and KGF in cancer cells was detected in 14 of 54 (26%) patients. Clinicopathologically, KGFR expression correlated with the well-differentiated cell type of EC (p<0.001), and KGF expression correlated with lymphatic invasion and lymph node metastasis (p=0.004 and 0.021, respectively). The coexpression of KGFR and KGF in cancer cells correlated with the well-differentiated cell type of EC (p=0.001). KGFR-positive, KGF-positive and KGFR/KGF coexpression patients tended to have shorter survival rates, but the survival rates were not statistically significantly different (p=0.44, 0.059 and 0.112, respectively). In human EC cell lines (TE-1, TE-8 and TE-11), KGFR mRNA was expressed but no KGF mRNA was detected. The KGFR mRNA level was highest in TE-1 cells, derived from well-differentiated SCC and lowest in TE-8 cells. KGFR was detected in the cancer cell lines by Western blot analysis. Recombinant human KGF significantly stimulated the growth of TE-8 and -11 cells, derived from moderately differentiated SCC, but had no effect on TE-1 cell growth. These results suggest that KGFR expression correlates with the differentiation of a normal esophageal epithelium and the well-differentiated cell type of EC. On the other hand, KGF may induce the growth of some EC cells in a paracrine manner and closely correlates with lymphatic invasion and lymph node metastasis.

Successful treatment of a colonic ulcer penetrating the urinary bladder caused by the administration of calcium polystyrene sulfonate and sorbitol.

A 77-year-old woman was urgently admitted for the treatment of diabetic ketoacidosis and a duodenal ulcer hemorrhage in March 1999. She had a history of diabetes and angina pectoris. After admission, she received oral calcium polystyrene sulfonate and sorbitol to treat hyperkalemia. Nine days later, severe abdominal pain developed. A colonoscopic examination revealed a sigmoid colonic ulcer and stenosis; the patient was treated conservatively. At a 1-year follow-up examination, the colonic stenosis was found have worsened; pneumaturia developed in January 2001. The patient was found to have a sigmoidovesical fistula and underwent sigmoidectomy and partial resection of the ileum and urinary bladder. The histological findings were a benign colonic ulcer with the infiltration of inflammatory cells, mainly lymphocytes. Rhomboidal, dark violet Kayexalate crystals were observed on microscope examination in the submucosa in both the first and second colonic biopsy specimens. We concluded that the colonic ulcer and the sigmoidovesical fistula had been caused by the administration of calcium polystyrene sulfonate and sorbitol. Reports of colonic perforation as a result of the administration of calcium polystyrene sulfonate and sorbitol are rare. Here, we report the successful treatment of a colonic ulcer that had penetrated the urinary bladder.

Case of intra-abdominal endocrine tumor possibly arising from an ectopic pancreas.

We report an intra-abdominal endocrine tumor possibly arising from an ectopic pancreas. A 45-year-old woman visited the Nippon Medical School Musashi-Kosugi Hospital because of right-sided hypochondralgia and upper abdominal discomfort of 1 years duration. An intra-abdominal tumor was diagnosed on the basis of the results of an ultrasound examination, computed tomography and magnetic resonance. Surgery was subsequently performed using laparoscopic techniques, and a tumor without firm adhesions was found near the wall of the duodenal bulbus. The tumor was easily removed; the resected specimen (55 x 45 x 25 mm, 50 g) was composed of bloody fluid within a cystic tumor. Histological and immunohistochemical examinations of the tumor showed a type 3 ectopic pancreas, according to the classification proposed by Heinrich. The patients recovery was uneventful.

Significance of gastrectomy as palliative surgery for gastric carcinoma with pyloric stenosis.

We conducted a clinicopathological study of cases of gastric carcinoma with pyloric stenosis and examined treatment outcomes and the prognosis of cases of stage IV gastric carcinoma with pyloric stenosis and the validity of gastrectomy as palliative surgery in these cases. The outcomes of 49 surgeries for gastric carcinoma with pyloric stenosis were compared with those of 671 surgeries for gastric carcinoma without pyloric stenosis. The diagnosis of pyloric stenosis was confirmed with both upper gastrointestinal endoscopy and an upper gastrointestinal barium series. The frequency of pyloric stenosis in patients with gastric carcinoma was 7.3%. Serosal invasion was observed in about 70% of all cases. Of these cases, 53.1% were classified as stage IV. The resection rate was 73.5%, and the resection was classified as curative in 44.9% of cases. The incidence of complications after surgery in cases of stage IV gastric carcinoma was 47.1%. The median survival time was significantly greater in patients undergoing resection group than in those not undergoing resection (p=0.025). Most patients with gastric cancer and pyloric stenosis can be considered to have stage IV disease, which is associated with high rates of morbidity and mortality; thus, prevention of complications, and therefore, avoidance of gastrectomy is recommended in such patients. Nonetheless, in this study, gastrectomy was shown to improve prognoses in these patients.

Successful use of endoscopic argon plasma coagulation for patients with early gastric cancer and diabetes mellitus.

We report on two patients with gastric tumors (early cancer and adema) and diabetes mellitus who were treated with argon plasma coagulation (APC) therapy. Case 1. A 78-year-old woman visited the Nippon Medical School Musashi Kosugi Hospital because of epigastric pain. An early gastric cancer (IIc) in the anterior wall of the gastric antrum was diagnosed on the basis of the results of a gastric endoscopy examination. The patient had had diabetes mellitus for 18 years and had injected insulin (NovoRapid 30 Mix, 72 units/day) by herself everyday for 10 years. Case 2. A 61-year-old man was referred to our hospital because of a gastric tumor. A gastric adenoma in the anterior of the gastric antrum was diagnosed on the basis of the results of a gastric endoscopy examination. The patient had had diabetes mellitus for 12 years and had been taking oral medication for 2 years. Endoscopic APC was performed in both patients to remove the gastric tumors. These patients have been well for 28 months and 30 months, respectively, after undergoing APC treatment. APC therapy appears to be a safe and useful treatment for patients with diabetes and gastric mucosal lesions.

Quantification of cibenzoline by enzyme-linked immunosorbent assay.

We have developed an enzyme-linked immunosorbent assay (ELISA) suitable for routine monitoring of serum levels of cibenzoline. Anti-cibenzoline antibody was obtained by immunizing rabbits with cibenzoline conjugated with bovine serum albumin using N-(4-maleimidobutyryloxy)succinimide as a heterobifunctional coupling agent. An enzyme marker was prepared by coupling 2,2-diphenylethylamine with beta-D-galactosidase using glutaraldehyde. The detection limit of cibenzoline by ELISA was approximately 640 pg/ml with 50-microl samples. Cross-reactivity data showed that the antibody well recognizes both the diphenyl and cyclopropyl moieties, and is thus specific enough to the structure of cibenzoline. The values for the cibenzoline concentrations detected using this assay were comparable with those detected using HPLC. There was a good correlation between the values determined by the two methods. Moreover, ELISA was about 15-fold more sensitive in detecting cibenzoline at lower concentrations. Using this assay, drug levels were easily measured in the serum of rabbits after oral administration of cibenzoline at a single dose of 3 mg/kg.

Expression of keratinocyte growth factor receptor correlates with expansive growth and early stage of gastric cancer.

The keratinocyte growth factor receptor, also known as KGFR/FGFR2 IIIb, is mainly localized in epithelial cells, and participates in the proliferation of these cells. In contrast, a recent study has revealed that the overexpression of KGFR in salivary adenocarcinoma induces growth inhibition, cell differentiation and apoptosis. We attempted to clarify the expression and role of KGFR in normal and cancerous human gastric tissues and cancer cell lines. Reverse-transcription polymerase chain reaction and Western blot analyses showed KGFR mRNA and its protein expression in NUGC-4, KATO-III and MKN-7 gastric cancer cell lines, but not in the NS-8 cell line. Immunohistochemically, KGFR immunoreactivity was weakly detected in the luminal surface of normal gastric epithelial cells. In addition, KGFR immunoreactivity was strongly detected in the nucleus and cytoplasm of many parietal cells. In gastric cancer tissue, KGFR was expressed in the cell membrane and cytoplasm of cancer cells in 46 of 126 (36.5%) cases. KGFR expression in gastric cancer cells was significantly associated with early-type macroscopic findings, shallow invasion of the gastric wall and expansive growth type. KGFR expression tended to correlate with a good prognosis in gastric cancer. These findings indicate that KGFR expression plays important roles in the differentiation of normal gastric epithelial cells and parietal cell functions. Furthermore, a decreased expression level or the non-expression of KGFR in gastric cancer cells may be associated with the proliferation and invasion of gastric cancer cells and a poor prognosis for the patient.

Simple and accurate (13)C-urea breath test for detection of Helicobacter pylori in the remnant stomach after surgery.

BACKGROUND: The efficacy of the (13)C-urea breath test (UBT) for diagnosis of Helicobacter pylori (H. pylori) infection in the remnant stomach after surgery is a matter of controversy. We report a simple and accurate method of (13)C-UBT for diagnosis of H. pylori infection in the remnant stomach after gastrectomy. METHODS: Eighty patients who had undergone gastrectomy with or without subsequent H. pylori eradication therapy were examined a total of 134 times for H. pylori infection by the (13)C-UBT. (13)C-Urea, 10mg per test, was used in powdered form or in the form of film-coated tablets. Breath samples were collected before and 10, 20, and 3 min after ingestion. Mucosal biopsy specimens for bacterial culture and histological examination of the remnant stomach were collected endoscopically after each (13)C-UBT test. RESULTS: Factors that confounded the (13)C-UBT results in the remnant stomach were oral bacteria, posture, and residual food. Lying horizontally on the left side was the best position, and film-coated tablets indicated no necessity for use of mouthwash. The method of anastomosis had no significant effect on the results of the (13)C-UBT. Thirty minutes and a cutoff of 4.5 per thousand were optimal conditions for detection of H. pylori in the remnant stomach. Under these conditions, sensitivity, specificity, and accuracy were 79.4% (27/34 cases), 95.7% (44/46 cases), and 88.8% (71/80 cases), respectively, in ordinary H. pylori diagnosis, and 100% (2/2 cases), 93.3% (14/15 cases), and 94.1% (16/17 cases), respectively, in evaluating eradication at 4 weeks after treatment of H. pylori. CONCLUSIONS: Having the patient lie horizontally on the left side, using a film-coated (13)C-urea tablet without using mouthwash, and measurement at 3 min provided a simple and accurate method of (13)C-urea breath test for detection of H. pylori in the remnant stomach after gastrectomy.

Factor XIII therapy of anastomotic leak, and circulating growth factors.

Wound healing is far more rapid in the gastrointestinal tract than in the skin. Once dehiscence of a surgical anastomosis in the gastrointestinal tract occurs, the high collagenase activity in the gastrointestinal tract may delay wound healing and promote the formation of a nonhealing fistula. Because factor XIII promotes cross-linking of fibrin during the early phase of wound healing, we investigated the effect of factor XIII concentrate on 16 anastomotic leaks and a nonhealing fistula. A 240-U dose of factor XIII concentrate (Fibrogammin P) was administrated intravenously for 5 days. Factor XIII activity and plasma levels of epidermal growth factor (EGF), transforming growth factor (TGF)-beta, and interleukin-6 were measured before treatment and 1 day and 7 days after the end of treatment. Clinical outcomes were evaluated on the basis of the findings of contrast radiography, computed tomography, and drainage volume. Improvement relevant to the therapy was observed in 15 cases (88.2%). Factor XIII activity increased to more than 70% of the normal value in 11 cases (64.7%) but remained at 40% to 70% of the normal value in 6 cases (35.3%). Plasma EGF and TGF-betalevels increased in patients with improvement but were unchanged in patients without improvement. Our findings suggest that factor XIII significantly accelerates wound healing of anastomotic leaks and nonhealing fistulas by increasing circulating growth factors after systemic administration.

Helicobacter pylori infection with a duodenal ulcer in a 6-year-old boy.

A 6-year-old boy was hospitalized because of dark feces and facial pallor of 1 weeks duration. Other gastrointestinal symptoms, including vomiting and abdominal pain, were absent, but he felt dizziness when standing and fatigue on effort. Hematologic studies revealed iron-deficiency anemia, and endoscopy showed gastric erosions and a duodenal ulcer. All test results for Helicobacter pylori infection, including H. pylori antigen in stool, anti-H. pylori IgG immunoassay in serum, and the (13)C-urea breath test, were positive. Because an H. pylori-associated gastric ulcer had been diagnosed with endoscopy in the patients father 3 years earlier, father-son transmission was suspected. The patient was treated with triple-agent eradication therapy (proton pump inhibitor [lansoprazol], amoxicillin, and clarithromycin) for 2 weeks. One month after therapy was completed, eradication of H. pylori was confirmed by negative results on the stool antigen test. Peptic ulcer disease can occur in young children, as in this case. The stool antigen test kit is a useful and reliable method that can be used even in preschool children to diagnose H. pylori infection.