Nobuo Omura

Establishment of Surgically Induced Chronic Acid Reflux Esophagitis in Rats

BACKGROUND The purpose of the study was to establish an animal model of chronic acid reflux esophagitis which could be used for further investigations of the pathophysiology of reflux esophagitis. METHODS Esophagitis was produced by ligating the transitional region between the forestomach and the glandular portion with a 2-0 silk thread and covering the duodenum near the pylorus ring with a small piece of an 18Fr Nélaton catheter. The histologic features of the esophagus were examined, and the survival rate of these animals was investigated. Moreover, the effects of lansoprazole on this model was studied. RESULTS The 3-week survival rate was 90%, and esophagitis was noted in all rats. Esophagitis was found 2 or 3 cm above the esophagogastric junction in most cases and at 4.0+/-2.3 sites per animal. Histopathologically, there were increased thickness of the esophageal epithelium, elongation of the lamina propria papillae, which extended upward into the epithelium, marked inflammatory cell infiltration, interruption of the lamina muscularis mucosae, and increase of collagen fibers in the lamina propria and submucosa. These signs were in accord with the histologic features of typical chronic esophagitis. No signs of esophagitis were observed, except in one animal, in the rats given 1 mg/kg/day of lansoprazole. CONCLUSIONS This experimental rat model is considered useful as a model of chronic acid-type esophagitis for the evaluation of the pathophysiology of reflux esophagitis and the evaluation of drug efficacy.

Sentinel lymph node navigation surgery for early stage gastric cancer

We attempted to evaluate the history of sentinel node navigation surgery (SNNS), technical aspects, tracers, and clinical applications of SNNS using Infrared Ray Electronic Endoscopes (IREE) combined with Indocyanine Green (ICG). The sentinel lymph node (SLN) is defined as a first lymph node (LN) which receives cancer cells from a primary tumor. Reports on clinical application of SNNS for gastric cancers started to appear since early 2000s. Two prospective multicenter trials of SNNS for gastric cancer have also been accomplished in Japan. Kitagawa et al reported that the endoscopic dual (dye and radioisotope) tracer method for SN biopsy was confirmed acceptable and effective when applied to the early-stage gastric cancer (EGC). We have previously reported the usefulness of SNNS in gastrointestinal cancer using ICG as a tracer, combined with IREE (Olympus Optical, Tokyo, Japan) to detect SLN. LN metastasis rate of EGC is low. Hence, clinical application of SNNS for EGC might lead us to avoid unnecessary LN dissection, which could preserve the patients quality of life after operation. The most ideal method of SNNS should allow secure and accurate detection of SLN, and real time observation of lymphatic flow during operation.

Adipose Tissue-Derived Mesenchymal Stem Cells in Long-Term Dialysis Patients Display Downregulation of PCAF Expression and Poor Angiogenesis Activation

We previously demonstrated that mesenchymal stem cells (MSCs) differentiate into functional kidney cells capable of urine and erythropoietin production, indicating that they may be used for kidney regeneration. However, the viability of MSCs from dialysis patients may be affected under uremic conditions. In this study, we isolated MSCs from the adipose tissues of end-stage kidney disease (ESKD) patients undergoing long-term dialysis (KD-MSCs; mean: 72.3 months) and from healthy controls (HC-MSCs) to compare their viability. KD-MSCs and HC-MSCs were assessed for their proliferation potential, senescence, and differentiation capacities into adipocytes, osteoblasts, and chondrocytes. Gene expression of stem cell-specific transcription factors was analyzed by PCR array and confirmed by western blot analysis at the protein level. No significant differences of proliferation potential, senescence, or differentiation capacity were observed between KD-MSCs and HC-MSCs. However, gene and protein expression of p300/CBP-associated factor (PCAF) was significantly suppressed in KD-MSCs. Because PCAF is a histone acetyltransferase that mediates regulation of hypoxia-inducible factor-1α (HIF-1α), we examined the hypoxic response in MSCs. HC-MSCs but not KD-MSCs showed upregulation of PCAF protein expression under hypoxia. Similarly, HIF-1α and vascular endothelial growth factor (VEGF) expression did not increase under hypoxia in KD-MSCs but did so in HC-MSCs. Additionally, a directed in vivo angiogenesis assay revealed a decrease in angiogenesis activation of KD-MSCs. In conclusion, long-term uremia leads to persistent and systematic downregulation of PCAF gene and protein expression and poor angiogenesis activation of MSCs from patients with ESKD. Furthermore, PCAF, HIF-1α, and VEGF expression were not upregulated by hypoxic stimulation of KD-MSCs. These results suggest that the hypoxic response may be blunted in MSCs from ESKD patients.

Surgical treatment for achalasia: when should it be performed, and for which patients?

Achalasia is a rare motor disorder of the esophagus, characterized by the absence of peristalsis and impaired swallow-induced relaxation. In the past decade, evidence has been accumulated suggesting that achalasia may be an immune-mediated inflammatory disorder. With the advent of minimally invasive surgery, laparoscopic Heller myotomy (LHM) has slowly shifted the treatment of achalasia toward the greater use of surgical therapy. The goal of both surgical and nonsurgical treatment is to eliminate the outflow obstruction afforded by a nonrelaxing sphincter, relieving dysphagia and maintaining a barrier against gastroesophageal reflux (GER). Endoscopic botulinum toxin injection (EBTI) is safe, easy to perform, inexpensive, and effective in aged patients, and it is especially effective when the lower esophageal pressure is hypertonic. This therapeutic option is reserved for patients too ill to undergo any surgical procedure. Pneumatic dilation (PD) has been shown to be an effective and inexpensive treatment with few adverse effects. The long-term success rate of PD seems to drop progressively over time. Heller myotomy (HM) has shown the best clinical efficacy in achalasia as a first-line treatment. Multiple endoscopic treatments are associated with poorer outcomes after HM. EBTI also makes LHM more difficult and results in a worse surgical outcome. The inferior symptomatic outcomes after thoracoscopic HM may be caused by the difficulty in extending an adequate myotomy onto the stomach from the chest and the inability to create a fundoplication. LHM with Dor’s fundoplication (LHM + Dor) is effective and is safer procedure for avoiding GER, dysphagia, mucosal perforation, and a pseudodiverticulum. LHM + Dor is also effective in the presence of sigmoid achalasia, but the clinical result is not as good as nonsigmoid achalasia. A few patients need esophagectomy for surgical failure of HM. However, considering the risk of esophagectomy, LHM + Dor is the first treatment option for patients with achalasia regardless of the degree of esophageal dilatation. This procedure is therefore considered to be an effective and safe treatment for patients of any age or with any condition.

Alendronate improves vitamin d-resistant osteopenia triggered by gastrectomy in patients with gastric cancer followed long term

Gastrectomy/gastric bypass has been used for patients with gastric cancer, and its application is now expanding to treating patients with morbid obesity, the prevalence of which is increasing worldwide. It is well known that gastrectomy leads to osteopenia, but the underlying pathophysiology and optimum treatments for this disorder have not been delineated. We followed 13 patients who showed progressive osteopenia (bone mineral density T-score <-2.4 SD) after gastrectomy/gastric bypass due to gastric cancer and who were resistant to long-term treatment (mean, 6 years) of active vitamin D3 and prospectively studied the effects of alendronate, a bisphosphonate, on osteopenia-related parameters for 2 years. Oral administration of alendronate in addition to vitamin D3 led to remarkable improvement within 2 years, not only in clinical symptoms, such as radial bone fractures and lumbar pain, but also in parameters for osteopenia, including decreased bone mineral density of the lumbar spine (P < 0.01), decreased concentrations of calcium (P < 0.05), increased urine levels of deoxypyridinoline (P < 0.01), increased serum levels of bone-specific alkaline phosphatase (P < 0.01), increased serum levels of osteocalcin (P < 0.01), and increased serum levels of intact parathyroid hormone (P < 0.05), although body weight did not alter. These results suggest that bisphosphonate may improve osteopenia after gastrectomy/gastric bypass.

A case of granulocyte-colony stimulating factor producing gallbladder cancer

Ever since the identification of the colony-stimulating factor (CSF), granulocyte-CSF (G-CSF)-producing tumors have often been reported, and have been attracting attention, especially in pulmonary cancer. However, there have been only a small number of reports of G-CSF-producing tumors in cases of gastrointestinal cancer, and only four cases of G-CSF-producing gallbladder cancer have been reported so far. Recently, we encountered a 73-yr-old man with G-CSF-producing gallbladder cancer. The leukocyte count in the peripheral blood increased to the maximum of 75,200/mm3 during the course of observation, and mature neutrophils accounted for 97% (segmented forms: 89%, band forms: 8%). The serum G-CSF concentration was high (129 pg/ml). The leukocyte count became normalized postoperatively, and the serum G-CSF concentration also decreased (50 pg/ml). The tumor was diagnosed as undifferentiated adenocarcinoma of the pleomorphic type on the histopathologic examination. Numerous tumor cells were stained with the anti-G-CSF antibody. Detailed findings of the patient are presented here together with some discussion of the literature.

Preoperative dilatation does not affect the surgical outcome of laparoscopic Heller myotomy and Dor fundoplication for esophageal achalasia.

Background Laparoscopic Heller myotomy and Dor fundoplication are now widely performed for achalasia. In patients who have had dilatation in the past, inflammation between the esophageal mucosal and muscular layers may make it difficult to perform myotomy. Purpose We investigated the effects of preoperative dilatation on the surgical outcomes. Method : One hundred and twelve patients were divided into 2 groups: 37 patients with a past history of preoperative dilatation and 75 patients who had no history of preoperative dilatation. The operating time, intraoperative blood loss, days required to resume postoperative oral intake, postoperative hospital stay, improvement in dysphagia, and incidence of postoperative esophagitis were compared. Results The operating time, intraoperative blood loss, postoperative hospital stay, and improvement of dysphagia were no significant differences between these groups. Furthermore, there were no significant differences in the incidence of postoperative esophagiatis. Conclusions The therapeutic outcome of laparoscopic Heller myotomy and Dor fundoplication is not affected by preoperative pneumatic dilatation.

Therapeutic Effects of a Laparoscopic Heller Myotomy and Dor Fundoplication on the Chest Pain Associated with Achalasia

PurposeThe therapeutic effects of a laparoscopic Heller myotomy and Dor fundoplication (LHD) on the chest pain associated with achalasia were investigated.MethodsSixty-six patients who were diagnosed to have achalasia underwent LHD. The degree of dilatation was assessed based on the maximum horizontal diameter of the esophagus (Grades I–III). The type of dilatation was assessed based on the shape of the distal esophagus, namely, spindle type (Sp), flask type (Fk), and sigmoid type (Sig). The degree of improvement was classified into three grades as follows: A (complete disappearance), B (partial response), and C (unchanged).ResultsChest pain improved (A or B) in 22 patients (92%). The statistical results revealed that the improvement of postoperative A or B was significantly better in patients with Sp than in those with Fk or Sig (P = 0.0213). In addition, the results revealed that the improvement of postoperative A or B was significantly better in patients with grade I and grade II than in those with grade III (P = 0.004).ConclusionLHD is an effective therapeutic technique for the treatment of chest pain associated with achalasia. These results suggest that both the morphological type and esophageal dilatation are useful predictors for the improvement of chest pain after surgical therapy.

Changes in gastric hormones associated with gastric outlet obstruction. An experimental study in rats.

To determine the effect of persistent narrowing of the gastric outlet on peptic ulcer disease, changes in gastric hormones induced by pyloric stenosis were studied in an experimental model in the rat. Pyloric stenosis was created by constricting the pylorus to a 4-mm channel. Changes in serum gastrin and plasma somatostatin concentrations, in the length of the lesser curvature, in the size of the fundic and pyloric regions, and in the G-cell and D-cell counts were determined after 4 and 8 weeks (PS4W and PS8W) and compared with those of control groups. The size of the stomach, the serum gastrin concentration, and the corrected G-cell count (indexed to stomach size) were greater in PS8W than in PS4W rats, and both were greater than in respective controls (p < 0.005). Serum somatostatin concentrations were not different, but the total D-cell count and the corrected D-cell count were higher in PS4W and PS8W rats than in controls. Moreover, the total D-cell count and the corrected D-cell count were greater in PS8W than in PS4W (p < 0.05, p < 0.005).

Laparoscopic Collis gastroplasty and Nissen fundoplication for reflux esophagitis with shortened esophagus in Japanese patients.

Background There is an extremely small number of surgical cases of laparoscopic Collis gastroplasty and Nissen fundoplication (LCN procedure) in Japan, and it is a fact that the surgical results are not thoroughly examined. Purpose To investigate the results of LCN procedure for shortened esophagus. Patients and Methods The subjects consisted of 11 patients who underwent LCN procedure for shortened esophagus and followed for at least 2 years after surgery. The group of subjects consisted of 3 men and 8 women with an average age of 65.0±11.6 years, and an average follow-up period of 40.7±14.4 months. Esophagography, pH monitoring, and endoscopy were performed to assess preoperative conditions. Symptoms were clarified into 5 grades between 0 and 4 points, whereas patient satisfaction was assessed in 4 grades. The use of postoperative acid-reducing medication and the recurrence of esophagitis were also investigated. Results None of the patients experienced intraoperative complications, received transfusions, required conversion to open surgery, or died postoperatively. The average preoperative heartburn, regurgitation, and dysphagia scores were 2.36±1.29, 2.27±1.19, and 1.82±1.78 points, respectively. These scores improved after surgery to 0.55±1.21 (P=0.0063), 0.55±1.21 (P=0.0094), and 1.0±1.18 (P=0.1236) points, respectively. All patients had esophagitis preoperatively, which recurred in 3 patients (27%). In these 3 patients, acid-secreting mucosa was confirmed on the oral side of the wrap, by positive Congo-red staining. Hiatal hernia recurred in one patient, who also experienced recurrent esophagitis. Five patients received acid-reducing medication postoperatively. The degree of satisfaction was excellent in 2, good in 6 patients, fair in 2, and poor in 1 patient(s). Conclusions Although the LCN procedure can be performed safely, the outcome was not necessarily satisfactory. The LCN procedure requires avoidance of residual acid-secreting mucosa on the oral side of the wrapped neoesophagus. If acid-secreting mucosa remains, continuous acid suppression therapy should be employed postoperatively.