Hideyuki Kashiwagi

A novel magnetic crystal-lipid nanostructure for magnetically guided in vivo gene delivery.

Cancer gene therapy requires a safe and effective gene delivery system. Polymer- and lipid-coated magnetic nanocrystals have been used to deliver silencing RNA, but synthesizing these magnetic vectors is difficult. Here, we show that a new nanoparticle formulation can be magnetically guided to deliver and silence genes in cells and tumours in mice. This formulation, termed LipoMag, consists of an oleic acid-coated magnetic nanocrystal core and a cationic lipid shell. When compared with the commercially available PolyMag formulation, LipoMag displayed more efficient gene silencing in 9 of 13 cell lines, and better anti-tumour effects when systemically administered to mice bearing gastric tumours. By delivering an optimized sequence of a silencing RNA that targets the epidermal growth factor receptor of tumour vessels, the intended therapeutic benefit was achieved with no evident adverse immune reaction or untoward side effects.

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.

Validity of modified gastrectomy combined with sentinel node navigation surgery for early gastric cancer

BackgroundThe present study examined the clinical validity of modified gastrectomy for early gastric cancer, in terms of the results of sentinel node navigation surgery (SNNS), using infrared ray electronic endoscopy (IREE) plus indocyanine green (ICG) staining.MethodsOne-hundred and sixty-one patients with fT1N0 gastric cancer were enrolled in the study. ICG (0.5 ml, 5 mg/ml) was injected endoscopically into four quadrants of the submucosa surrounding the cancer. Twenty minutes after the injection, sentinel lymph nodes (SNs) stained with ICG were observed intraperitoneally around the serosa and surrounding fat tissue. IREE was used to illuminate regional lymph nodes from the serosal side.ResultsGroup 2 lymph nodes were judged as SNs in 52 patients (32%). The most common locations of the SNs were stations No. 7 in each of the upper-, middle-, and lower-thirds of the stomach. In two patients, lymph node metastasis was positive. One of these patients, with cancer in the middle one-third of the stomach, had SNs in stations No. 3, 4sb, 4d, 7, and No. 11p, and had metastatic lymph nodes in No. 3 and No. 7 (all SNs). The other patient, with cancer in the lower one-third of the stomach, had SNs in No. 1, 3, 4d, and 6, and had a metastatic lymph node in No. 4d (SN). Skip metastasis was not observed in this study, and metastatic lymph nodes were judged to have been dissected by the D1+a procedure.ConclusionFor T1N0 gastric cancer, modified gastrectomy (D1+a dissection) combined with SNNS is suitable; however, for those whose Group 2 lymph nodes are judged to be SNs, additional dissection of lymphatic basins detected by SNNS should be performed to confirm the absence of lymph node metastasis.

Laparoscopic Heller myotomy and Dor fundoplication for the treatment of achalasia. Assessment in relation to morphologic type

BackgroundThe significance of laparoscopic Heller myotomy and Dor fundoplication (LHD) for the treatment of achalasia in relation to the severity of the lesion has not been sufficiently assessed.MethodsOf patients who were diagnosed with achalasia from August 1994 to February 2004, 55 individuals who underwent LHD served as subjects. The therapeutic effects of LHD were assessed in terms of operation time, intraoperative complications, postoperative hospital stay, and symptom improvement in relation to morphologic type (spindle type, Sp; flask type, Fk; and sigmoid type, Sig). Degree of symptomatic improvement was classified into four grades: excellent, good, fair, and poor.ResultsBreakdown of morphologic type was as follows: Sp, n = 29; Fk, n = 18; and Sig, n = 8. Excluding one patient for whom conversion to open surgery was required, median average operation time for 54 patients was 160 min. As to intraoperative complications, esophageal mucosal perforation was seen in nine of the 55 patients (16%); however, conversion to open surgery could be avoided by suturing the affected area. Moreover, intraoperative bleeding of at least 100 g was seen in five of the 55 patients (9%), with one Fk patient requiring conversion to open surgery and transfusion. Median postoperative hospital stay was 8 days. Degree of dysphagia relief was excellent in 45 patients (83%), good in eight patients (15%), and fair in one patient (2%). Excellent improvement was obtained in 90%, 88%, and 50% in Sp, Fk, and Sig patients, respectively. Reflux esophagitis was seen in two patients, and was treated with a proton pump inhibitor.ConclusionsThe results of the present study suggest that classification of morphologic type is a useful parameter in predicting postoperative outcome in achalasia. In order to achieve excellent symptomatic relief, surgery for achalasia should be recommended for but not limited to Sp and Fk types.

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.

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.

Early postoperative enteral nutrition is useful for recovering gastrointestinal motility and maintaining the nutritional status

PurposeThe efficacy of enteral nutrition in postoperative nutritional management is known, but the effects on gastrointestinal motility and nutrition have not yet been elucidated. The purpose of this study was to compare the effects of enteral and parenteral nutrition soon after open abdominal surgery on gastrointestinal motility and nutritional status.MethodsA partial resection of rectum models was prepared to compare two types of nutrient administration: enteral nutrition and total parenteral nutrition. The differences between the effects of nutrition types in terms of gastrointestinal motility and nutritional status were investigated.ResultsEnteral nutrition contributed to recovery of gastrointestinal motility and maintenance of nutritional status.ConclusionEnteral nutrition should therefore be initiated soon after surgery if the gastrointestinal tract is available.

The possibility of performing a limited resection and a lymphadenectomy for proximal gastric carcinoma based on sentinel node navigation

PurposeThis study examined the possibility of performing a limited resection and a lymphadenectomy with sentinel node navigation surgery (SNNS) for the treatment of proximal gastric carcinoma.MethodsThirty patients with cT1N0 (n = 23) and cT2N0 (n = 7) proximal gastric carcinoma that was located primarily in the U area (the upper third of the stomach) were enrolled. indocyanine green (ICG; 0.5 ml) was injected endoscopically into the submucosa of the four quadrants encompassing the cancer. Twenty minutes after injection, infrared ray electronic endoscopy (IREE) was used to identify the lymph nodes that were stained with ICG (sentinel nodes, SNs) around the serosa and surrounding fat tissue.ResultsOne hundred percent of the SNs were identified with our SNNS method. The most common location of SNs was No. 3 (T1: 78%, T2: 100%). The main route of lymphatic drainage was from No. 1 or No. 3 to No. 7 (T1: 95%, T2: 100%). In T1 cancer, Indocyanine green was not distributed to the right gastric area, and no patients had SNs in No. 5 or No. 8a. Four cT2 cancer patients had lymph node metastases, all of which were SNs. There were no cases of postoperative metastasis or recurrence.ConclusionsFor the cT1 proximal gastric carcinoma patients, limited dissection of the ICG tracer-positive lymphatic areas alone by SNNS using IREE may be acceptable. The main lymphatic drainage route of proximal gastric carcinoma is the left gastric artery area (Nos. 1, 3, and No. 7) and dissection of this area is important.

Immunohistochemical study of the muscularis externa of the esophagus in achalasia patients.

The etiology of achalasia is believed to be the neuropathy associated with chronic inflammation of the nerve plexus, but the cause of plexus inflammation is unknown. The purpose of this study was to evaluate the pathophysiology of achalasia by examining the muscularis externa of the esophagus. We used the muscularis externa of the esophagus of 62 patients with achalasia (median 44 years, male : female 32:30) who underwent surgical treatment (achalasia group) and of 10 patients (median 65.5 years, male : female 9:1) who underwent esophagectomy for thoracic esophageal cancer (control group) to perform immunohistochemical staining with S-100, CD43, c-kit (CD117), n-NOS, vasoactive intestinal polypeptide (VIP), and ubiquitin. The cell counts that were positive for S-100, n-NOS, VIP, and ubiquitin were significantly lower in the achalasia group compared with the control group (P < 0.001, P= 0.001, P < 0.001, and P= 0.001, respectively). There were no statistically significant differences with respect to CD43 and c-kit staining (P= 0.586 and P= 0.209, respectively). In conclusion, the pathophysiology of achalasia is therefore considered to be an impaired production of NO and VIP, which both affect interstitial cell of Cajal and smooth muscles, and this impairment is therefore considered to play a role in the pathophysiology of achalasia.