Background:Laparoscopic distal gastrectomy (LDG) is a widely used minimally invasive surgery. Following LDG, Billroth-I (B-I) provides physiological reconstruction by preserving the duodenal passage but results in a high incidence of reflux esophagitis that decreases postoperative quality of life. Because of this, Roux-en-Y (R-Y) reconstruction is often considered the first choice after LDG. However, very few studies have investigated differences in physiological function between B-I and R-Y after LDG. We hypothesized that B-I would outperform R-Y in clinical and physiological outcomes, including nutrition parameters. Methods: We compared hemoglobin, ferritin, serum iron, Vitamin B12, 25(OH)-Vitamin D (V-D), body weight, and gastric emptying after LDG in patients with either B-I or R-Y reconstruction. Results: The levels of hemoglobin in the B-I group were significantly higher than that in the R-Y group at all time points later than 6 months postsurgery. The ferritin levels were significantly higher in the B-I group at all time points later than 9 months postsurgery. The concentration of serum V-D in the B-I group was significantly higher than that in the R-Y group at 1 year 6 months, 1 year 9 months, and 2 years after surgery. Gastric emptying in the R-Y group was significantly slower than in the B-I group. Conclusions: Our data indicate that B-I leads to less postsurgical iron deficiency anemia and V-D deficiency compared with R-Y reconstruction. Furthermore, gastric emptying was preserved in B-I reconstruction compared with R-Y reconstruction. In conclusion, after LDG, B-I reconstruction seems to cause fewer nutritional complications than R-Y reconstruction.

Endoscopic submucosal dissection (ESD) has been used to treat patients with early gastric cancer (EGC). Although several endoscopic devices have been developed to ensure easy and safe ESD, this technique still requires an experienced, highly skilled endoscopist, as it is performed through a single gastroscope, thus requiring one-handed surgical techniques. To overcome these limitations, many ESD procedures with counter-traction have been developed, such as the double scope, double channel scope, clip with line, magnetic anchor, percutaneous traction and external grasping forceps methods. We devised a double endoscopic intraluminal operation (DEILO). Two endoscopes were simultaneously inserted into the stomach. One endoscope was used to lift the lesion, and the other was used to excise the lesion. The DEILO procedure was performed on 122 cases of EGC. In this article, we report the efficacy and safety of DEILO in patients with EGC.

BACKGROUND F-Box protein 45 (FBXO45) is reported to be associated with cancer aggressiveness. We investigated the relationship between FBXO45 and clinicopathological factors in gastric cancer (GC). MATERIALS AND METHODS We used immunohistochemistry to investigate FBXO45 expression in 104 GC samples; the prognostic value of FBXO45 was also calculated. RESULTS FBXO45 levels in GC were higher than in normal tissues. Patients with relatively low FBXO45 expression (n=58) had increased cancer progression and poorer prognosis than those with high expression (n=46). Low FBXO45 expression was an independent negative prognostic factor in patients with GC. Using the public Kaplan-Meier plotter database, we showed that survival in patients with low expression of FBXO45 in GC was shorter than that in those with high FBXO45 expression, regardless of lymph node metastasis. CONCLUSION A low FBXO45 expression level in GC tissues may be a powerful predictor of poor prognosis. FBXO45 might, therefore, be a promising candidate for a molecular targeted therapy in GC.

Esophagogastrostomy after proximal gastrectomy (PG) is a simple and safe reconstruction, but it leads to a high incidence of reflux esophagitis and impairs postoperative quality of life. We have already reported gastric tube (GT) reconstruction after PG and performed it on more than 100 patients. No studies have reported long-term outcomes after PG–GT. The aim of this study was to investigate long-term outcomes, including nutrition indices, such as body weight, serum albumin, total protein, hemoglobin, and ferritin after PG, and observe recovery of upper gastrointestinal tract motility.

Carbon-ion radiation therapy (C-ion RT) has better dose distribution to the tumor while minimizing surrounding normal tissues compared with photon radiation therapy. The efficacy of C-ion RT for non-small cell lung cancer (NSCLC) has been suggested in several single-institutional studies. We organized a multi-institutional study group of carbon-ion radiation oncology in Japan (J-CROS) and have been conducting various studies regarding C-ion RT. The purpose of this study was to evaluate the treatment outcomes of C-ion RT for stage I NSCLC. This is a retrospective analysis to review 306 patients (male: 172, female 134) with stage I (IA: 225, IB: 81) NSCLC treated with C-ion RT at 4 institutions of J-CROS. The patients' ages were 39–95 (median: 75) years. Histology was proven in 186 patients (adenocarcinoma 145, squamous cell carcinoma 38, others 6). Of total patients, 139 (45%) were considered medically inoperable. The C-ion RT dose was 52.8-64.0 Gy (RBE) / 4 fr in 181 patients, single fraction of 46.0-50.0 Gy (RBE) in 97, and others in 28. No patients received systemic chemotherapy. Common Terminology Criteria for Adverse Events version 3.0 was used to score toxicity. The median follow-up period for all patients was 26 months (range, 6–128 months). The overall and progression-free survival rates at three years were 83.6% (IA: 86.1%, IB: 76.5%) and 69.4% (IA: 72.5%, IB: 60.2%), respectively. The local control rate at three years was 88.6% (IA: 92.2%, IB: 78.0%). The overall and progression-free survival rates (90% and 76% at 3-years) of operable patients were significantly better (P < 0.01) than those (76% and 62% at 3-years) of medically inoperable patients. There was no significant difference in overall survival or progression-free survival between histology proven and unproven patients. Grade 3 or higher CIRT-related toxicities were noted in 1.3% of total patients. The incidences of grade 3 and 4 pulmonary complications were in 0.7% and 0%, respectively. Furthermore, any of grade 3 or higher toxicity was not observed in operable patients. The outcomes of C-ion RT for stage I NSCLC in Japanese multi-institutional large data were retrospectively analyzed. Carbon-ion RT is a low-risk and effective treatment option for patients with stage I non-small cell lung cancer.

Carbon ion radiation therapy (C-ion RT) provides a highly localized deposition of energy that can increase radiation doses to tumors while minimizing irradiation of adjacent normal tissues. However, the relationship between carbon ion dose, change over time and severity of acute radiation mucositis (ARM) has been unclear. In this study, ARM and the dose dependency were assessed changes over time by oral mucosal dose surface model (OMDS-model) in C-ion RT for head and neck tumors developed by Gunma University. Between 2011 and 2012, thirty-nine patients receiving C-ion RT for head and neck tumor were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. Thirty-two patients received 64.0 Gy (RBE) in 16 fractions, 5 patients received 57.6 Gy (RBE) (in these patients, the skin or mucosa was considered to be widely irradiated), and two sarcoma patients received 70.4 Gy (RBE). A maximum dose of palate and tongue was evaluated in each patient by using OMDS-model based on the commercially available deformable registration algorithm software. We assessed a time change of the ARM and made the temporal pattern of ARM. In addition, location of the high dose area was compared to pictures of ARM taken weekly during and after C-ion RT. The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2–3 ARM in the palate and tongue were 43.0 Gy (RBE) and 54.3 Gy (RBE), respectively. RTOG grade 2-3 ARM in the palate and tongue has been gradually rising after about 6 times of irradiation. The RTOG grade for ARM in the palate and tongue gradually increased over an approximate one-week period after initiation of the C-ion RT. Following 16 irradiation procedures, the ARM grade gradually decreased over a one-month period. The ARM recovery period did not differ significantly based on C-ion RT dose. When the ARM healed, dietary intake was restored. The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2–3 ARM. Significant differences were not present for the radiation dose or the healing period. ARM rapidly improved after C-ion RT and none of the patients experienced treatment-related death or impaired quality of life.

Recently, the right gastroepiploic artery (RGEA) has been used in coronary artery bypass graft (CABG) as an alternative arterial graft. Because of the improvement of prognosis after CABG, malignant diseases are more common in older patients. However, there is a serious problem in patients with gastric cancer after CABG with RGEA graft. In these patients, an interruption of coronary blood supply through the RGEA may cause a life-threatening myocardial ischemia. Therefore, an appropriate strategy is very important to avoid risk while retaining the curability of the operation. We herein describe a 76-year-old Japanese man with advanced gastric cancer who underwent CABG using the RGEA. Abdominal computed tomography (CT) showed #6 lymph nodes (sub-pyloric lymph nodes) metastases surrounding the RGEA. We concluded that curative resection was impossible while preserving the RGEA and started combination chemotherapy using S-1 and cisplatin. After 2 courses of that, #6 lymph nodes were reduced extremely. Thereafter the patient underwent distal gastrectomy with regional lymph node dissection around the RGEA without excision of the RGEA. Histologically, there were no metastases in #6 lymph nodes. Neoadjuvant chemotherapy may be effective for preserving the RGEA graft in a patient with advanced gastric cancer after CABG.

Endoscopic submucosal dissection (ESD) has been used to treat patients with nonulcerated early gastric cancers of 2  cm or less, because the incidence of lymph node metastasis is negligible. However, the standard ESD procedure is long, complex, and associated with high complication rates. To overcome these limitations, we devised a double endoscopic intraluminal operation (DEILO) and assessed its efficacy and safety for superficial gastric neoplasms in a preliminary prospective study.

Some laparoscopic gastrectomy (LG) patients are postoperatively diagnosed with locally advanced disease or lymph node metastasis. Few reports have reviewed the outcomes or validity of LG in such patients.

Background Nesfatin-1 is a novel 82-amino acid anorectic peptide. Acute injection of nesfatin-1 into the third brain ventricle reduces food consumption during the dark phase in rats. Nesfatin-1 is also expressed in gastric X/A-like cells in the peripheral tissues. Nesfatin-1 has been reported to reduce gastric and duodenal motility and to delay gastric emptying. Aim In the present study, we investigated the effects of nesfatin-1 on gastrointestinal motility in conscious dogs. Methods Force transducers were implanted onto the serosal surfaces of the gastric bodies, gastric antra, duodena, and jejuna of healthy beagle dogs, and gastrointestinal motility was monitored. We evaluated the effects of nesfatin-1 on gastrointestinal motility and on the circulating levels of nesfatin-1 in the fasted and fed states. Results The intravenous administration of nesfatin-1 reduced gastric contractions and inhibited cyclical interdigestive migrating contractions in the fasted state. In the fasted state, circulating levels of nesfatin-1 tended to increase during late phase I. In addition, the kinetics of the circulating levels of nesfatin-1 were opposite to those of ghrelin during the fasted state. Conclusions Nesfatin-1 regulates gastrointestinal motility, and, in particular, it inhibits gastric contractions in the fasted state. Interdigestive migrating contractions may be regulated by interactions between nesfatin-1, ghrelin, and motilin.

Recently, the right gastroepiploic artery (RGEA) has been used in coronary artery bypass graft (CABG) as an alternative arterial graft. Because of the improvement of prognosis after CABG, malignant diseases are more common in older patients. However, there is a serious problem in patients with gastric cancer after CABG with RGEA graft. In these patients, an interruption of coronary blood supply through the RGEA may cause a life-threatening myocardial ischemia. Therefore, an appropriate strategy is very important to avoid risk while retaining the curability of the operation. We herein describe a 76-year-old Japanese man with advanced gastric cancer who underwent CABG using the RGEA. Abdominal computed tomography (CT) showed #6 lymph nodes (sub-pyloric lymph nodes) metastases surrounding the RGEA. We concluded that curative resection was impossible while preserving the RGEA and started combination chemotherapy using S-1 and cisplatin. After 2 courses of that, #6 lymph nodes were reduced extremely. Thereafter the patient underwent distal gastrectomy with regional lymph node dissection around the RGEA without excision of the RGEA. Histologically, there were no metastases in #6 lymph nodes. Neoadjuvant chemotherapy may be effective for preserving the RGEA graft in a patient with advanced gastric cancer after CABG.

Background and ObjectivesThis multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent gastrointestinal stromal tumors (GIST).MethodsThe clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001-2011 were retrospectively reviewed. Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The median follow-up period was 4.0 years.ResultsAfter a median follow-up period of 4.0 years, the patients treated with imatinib (n=41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3%, 74.9%, and 53.8%, respectively. In univariate and multivariate analyses, imatinib dose reduction and achieving a complete or partial response were found to be associated with increased OS.ConclusionsLong-term imatinib treatment is recommended for patients with non-progressive disease. If patients experience significant toxicities, temporary dose reduction might be useful. J. Surg. Oncol. 2014; 110:942-946. (c) 2014 Wiley Periodicals, Inc.

AIM:To investigate whether 5-hydroxytryptamine (serotonin; 5-HT) is involved in mediating abnormal motor activity in dogs after cisplatin administration.METHODS:After the dogs had been given a 2-wk recovery period, all of them were administered cisplatin, and the motor activity was recorded using strain gauge force transducers. Blood and intestinal fluid samples were collected to measure 5-HT for 24 h. To determine whether 5-HT in plasma or that in intestinal fluids is more closely related to abnormal motor activity we injected 5-HT into the bloodstream and the intestinal tract of the dogs.RESULTS:Cisplatin given intravenously produced abnormal motor activity that lasted up to 5 h. From 3 to 4 h after cisplatin administration, normal intact dogs exhibited retropropagation of motor activity accompanied by emesis. The concentration of 5-HT in plasma reached the peak at 4 h, and that in intestinal fluids reached the peak at 3 h. In normal intact dogs with resection of the vagus nerve that were administered kytril, cisplatin given intravenously did not produce abnormal motor activity. Intestinal serotonin administration did not produce abnormal motor activity, but intravenous serotonin administration did.CONCLUSION:After the intravenous administration of cisplatin, abnormal motor activity was produced in the involved vagus nerve and in the involved serotonergic neurons via another pathway. This study was the first to determine the relationship between 5-HT and emesis-induced motor activity.

BACKGROUND:The primary aim of this study was to examine the motor activity (motility) of a gastric tube after laparoscopic-assisted proximal gastrectomy (LPG). A secondary objective was to ascertain whether a correlation exists between gastric tube motor activity and reflux esophagitis.PATIENTS AND METHODS:A total of 41 patients who underwent LPG for early gastric cancer were studied. The motility of the gastric tube and the status of reflux esophagitis were evaluated. Manometric recording was performed 2 weeks and 1 year after surgery.RESULTS:In a fasting state, the motilities of the distal gastric tube and duodenum recovered within 1 year after surgery but that of the proximal gastric tube did not recover. Improvement of the motility of the gastric tube was associated with a decreased number of patients with reflux esophagitis 1 year after surgery. In patients with reflux esophagitis, the motility of the distal gastric tube was significantly lower than that in patients without reflux esophagitis.CONCLUSION:After LPG, the motility of the gastric tube recovered, and the incidence of reflux esophagitis decreased with time, in parallel to recovery of gastrointestinal motility.

PURPOSE:To describe our initial experiences with the standardized introducer technique for percutaneous endoscopic gastrostomy and to compare clinical outcomes and complications with the pull technique.METHODS:The introducer technique was used on 91 patients. The clinical outcomes of procedures were retrospectively collected and compared with those of 22 patients who had procedures using the pull technique.RESULTS:Mean operation time was significantly longer in the introducer technique group as compared with the pull technique group. Increased inflammation markers (body temperature, white blood cell count, and C-reactive protein) were observed in the pull technique group as compared with the introducer technique group. Incidences of peristomal infection and pneumonia were lower in the introducer method group than in the pull method group.CONCLUSIONS:The introducer technique is a useful and safe method for percutaneous endoscopic gastrostomy in terms of reduced incidences of peristomal infection, pneumonia, pain, and discomfort.

Karyopherin-α2 (KPNA2) functions as an adaptor that transports several proteins to the nucleus. We investigated the clinical and functional significance of KPNA2 in gastric cancer (GC). Immunohistochemistry was performed to examine KPNA2 expression in primary GC and metastatic lymph nodes. Next, KPNA2 was suppressed by small interfering RNA (siRNA) to examine KPNA2 function in proliferation and cisplatin-induced apoptosis of GC cell lines. Nuclear expression of KPNA2 in marginal regions of primary GC was stronger than in central regions of GC and normal tissues. The high expression of marginal KPNA2 was significantly associated with β-catenin accumulation in the nucleus and poor prognosis in two independent GC cohorts (discovery cohort, n = 90, P = 0.018; validation cohort, n = 89, P = 0.0125). We detected correlations between nuclear KPNA2 expression in marginal region and progression of macroscopic type (P = 0.036), tumor depth (P = 0.013), lymph node metastasis (P = 0.0064), venous invasion (P = 0.034) and clinical stage (P = 0.0006). Nuclear KPNA2 expression in marginal regions of metastatic lymph nodes was significantly higher than in the central region. It was associated with poor survival of GC patients with lymph node metastasis (n = 96; center, P = 0.4384; marginal, P < 0.0001). KPNA2 suppression enhanced cisplatin-induced apoptosis and reduced proliferation in the KPNA2 siRNA group compared with the control siRNA group. The expression of the DNA repair gene NBS1 (NBN) in the nucleus was suppressed in KPNA2-suppressed cells. KPNA2 might be a useful prognostic marker and an effective therapeutic target for GC.

AIM To study the effects of 5-hydroxytryptamine (5-HT) receptor antagonists on normal colonic motor activity in conscious dogs. METHODS Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B, 5-HT3 and 5-HT4 receptor antagonist administration. The force transducers were implanted on the serosal surfaces of the gastric antrum, terminal ileum, ileocecal sphincter and colon. Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state. The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed. RESULTS 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum. The 5-HT3 and 5-HT4 receptor antagonists inhibited phase III of the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity. In the proximal colon, the inhibitory effect was dose dependent. Dose dependency, however, was not observed in the distal colon. The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity. CONCLUSION The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity. The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.

BACKGROUND:Traditional Japanese medicine, known as Kampo medicine, consists of mixtures of several medicinal herbs widely used to treat upper gastrointestinal disorders in Japan. Rikkunshito, one of these medicines, has not been evaluated with respect to its influence on gastrointestinal motor activity. We investigated the effect of rikkunshito on upper gastrointestinal motility and plasma ghrelin concentrations in conscious dogs.METHODS:Contractile response to intragastric administration of rikkunshito was studied via surgically implanted force transducers. A powdered extract of rikkunshito (1.3, 2.7, and 4.0 g) dissolved in water was administered into the stomachs of normal and vagotomized dogs before feeding and gastric emptying was evaluated. Several inhibitors of gastrointestinal motility (atropine, hexamethonium, and ondansetron) were injected intravenously before intragastric administration of rikkunshito. Plasma acylated ghrelin levels after intragastric administration of rikkunshito were measured.RESULTS:In a fasting state, intragastric administration of rikkunshito induced phasic contractions in the duodenum and jejunum in normal dogs. Rikkunshito-induced contractions were inhibited by atropine, hexamethonium and ondansetron. In vagotomized dogs, rikkunshito induced phasic contractions, similar to normal dogs. Gastric emptying was accelerated by intragastric administration of rikkunshito in a dose-dependent manner. The plasma acylated ghrelin level 150 min after intragastric administration of 4.0 g of rikkunshito was significantly higher than the control value.CONCLUSIONS:Intragastric administration of rikkunshito stimulates gastrointestinal contractions in the interdigestive state through cholinergic neurons and 5-HT type 3 receptors. Moreover, rikkunshito increases plasma acylated ghrelin levels. Rikkunshito may alleviate gastrointestinal disorders through its prokinetic effects.

Ogawa A, Mochiki E, Yanai M, Morita H, Toyomasu Y, Ogata K, Ohno T, Asao T, Kuwano H. Interdigestive migrating contractions are coregulated by ghrelin and motilin in conscious dogs. Am J Physiol Regul Integr Comp Physiol 302: R233–R241, 2012. First published November 9, 2011; doi:10.1152/ajpregu.00078.2011.— During fasting, gastrointestinal (GI) motility is characterized by cyclical motor contractions. These contractions have been referred to as interdigestive migrating contractions (IMCs). In dogs and humans, IMCs are known to be regulated by motilin. However, in rats and mice, IMCs are regulated by ghrelin. It is not clear how these peptides influence each other in vivo. The aim of the present study was to investigate the relationship between ghrelin and motilin in conscious dogs. Twenty healthy beagles were used in this study. Force transducers were implanted in the stomach, duodenum, and jejunum to monitor GI motility. Subsequent GI motility was recorded and quantified by calculating the motility index. In examination 1, blood samples were collected in the interdigestive state, and levels of plasma ghrelin and motilin were measured. Plasma motilin peaks were observed during every gastric phase III, and plasma ghrelin peaks occurred in nearly every early phase I. Plasma motilin and ghrelin levels increased and decreased cyclically with the interdigestive states. In examination 2, saline or canine ghrelin was administered intravenously during phase II and phase III. After injection of ghrelin, plasma motilin levels were measured. Ghrelin injection during phases II and III inhibited phase III contractions and decreased plasma motilin levels. In examination 3, ghrelin was infused in the presence of the growth hormone secretagogue receptors antagonist [D-Lys3]GHRP-6. Continuous ghrelin infusion suppressed motilin release, an effect abrogated by the infusion of [D-Lys3]-GHRP-6. Examination 4 was performed to evaluate the plasma ghrelin response to motilin administration. Motilin infusion immediately decreased ghrelin levels. In this study, we demonstrated that motilin and ghrelin cooperatively control the function of gastric IMCs in conscious dogs. Our findings suggest that ghrelin regulates the function and release of motilin and that motilin may also regulate ghrelin.