Hiromichi Nakagawa

Feasibility of chemohyperthermia with docetaxel-embedded magnetoliposomes as minimally invasive local treatment for cancer

Hyperthermia is a minimally invasive approach to cancer treatment, but it is difficult to heat only the tumor without damaging surrounding tissue. To solve this problem, we studied the effectiveness of chemohyperthermia with docetaxel‐embedded magnetoliposomes (DMLs) and an applied alternating current (AC) magnetic field. Human MKN45 gastric cancer cells were implanted in the hind limb of Balb‐c/nu/nu mice. Various concentrations of docetaxel‐embedded DMLs were injected into the tumors and exposed to an AC magnetic field (n = 6, each). For comparison with hyperthermia alone, magnetite‐loaded liposome (ML)‐injected tumors were exposed to an AC magnetic field. Furthermore, the results of DML without AC treatment and docetaxel diluted into PBS with AC treatment were also compared (n = 10, each). Tumor surface temperature was maintained between 42 and 43°C. Tumor volume was reduced in the DML group with a docetaxel concentration > 56.8 μg/ml, while a docetaxel concentration > 568.5 μg/ml was required for tumor reduction without hyperthermia. Statistically significant differences in tumor volume and survival rate were observed between the DML group exposed to the magnetic field and the other groups. The tumor disappeared in 3 mice in the DML group exposed to the magnetic field; 2 mice survived over 6 months after treatment, whereas all mice of the other groups died by 15 weeks. Histologically, hyperthermia with DML damaged tumor cells and DML diffused homogeneously. To the best of our knowledge, this is the first report to show that hyperthermia using chemotherapeutic agent‐embedded magnetoliposomes has an anticancer effect.

Intestinal ischemia/reperfusion-induced bacterial translocation and lung injury in atherosclerotic rats with hypoadiponectinemia.

BACKGROUND Intestinal ischemia/reperfusion causes intestinal mucosal injury, which may result in bacterial translocation (BT) and multiple organ failure. Lung injury is a common complication after intestinal ischemia/reperfusion. Adiponectin is an antiinflammatory adipokine, and it plays an important role in the development of metabolic syndrome in hypoadiponectinemia. In atherosclerosis with hypoadiponectinemia, BT also may aggravate injuries induced by intestinal ischemia/reperfusion. METHODS Wistar rats were divided into 3 groups: Normal group (normal diet), Chol group (2% high cholesterol diet), and Chol+1400W group (Chol group plus 1400W, an inducible nitric oxide [iNOS] inhibitor, at 1 mg/kg intraperitoneally 30 minutes preoperatively). The serum concentrations of lipids and adiponectin and vascular responses were measured. After midline laparotomy (time, T0), the superior mesenteric artery was occluded with a microvascular clamp for 30 minutes, followed by 360 minutes of reperfusion (T1). Intestinal injury was assessed from microcirculatory flow, histology, serum diamine oxidase activity, and permeability. Lung injury was assessed by histology, pulmonary permeability index (PPI), and wet-to-dry lung weight (W/D) ratio. Intestinal and lung nitric oxide (NO) concentrations were also measured. BT was assessed by serum peptidoglycan (PG) concentration. RESULTS The Chol and Chol+1400W groups developed hyperlipidemia and hypoadiponectinemia; the 2 groups also had vascular endothelial dysfunction without histological changes, indicating early atherosclerosis. These groups also showed poor recovery of intestinal microcirculatory flow at T1. The serum diamine oxidase activity, histological intestinal damage, and permeability were elevated at T1 in the Chol group; however, these findings were not significant in the Normal and Chol+1400W groups. Histological lung damage and lung PPI and W/D ratio were increased only in the Chol group. Intestinal and lung NO concentrations were significantly elevated at T1 in the Chol group. The serum PG concentration was elevated significantly in the Chol group. CONCLUSION In atherosclerotic rats with hypoadiponectinemia, intestinal microcirculatory flow does not recover adequately after intestinal ischemia/reperfusion because of endothelial dysfunction. Atherosclerosis with hypoadiponectinemia increased the incidence of BT further by aggravating intestinal mucosal injury and, moreover, it aggravated lung injury. Although inhibition of iNOS does not lead to adequate recovery of intestinal microcirculatory flow, it reduces injury by decreasing the amount of NO derived from high enzymatic iNOS activity in the intestine.

Pitavastatin prevents intestinal ischemia/reperfusion-induced bacterial translocation and lung injury in atherosclerotic rats with hypoadiponectinemia

BACKGROUND Atherosclerosis with hypoadiponectinemia can be further aggravated by intestinal ischemia/reperfusion (II/R)-induced injuries, such as bacterial translocation and lung injury. We investigated the effect of statin administration on the risk of II/R-induced injury in atherosclerotic rats with hypoadiponectinemia. METHODS Wistar rats were divided into 4 groups: (1) the Normal group (normal diet), (2) the Chol group (2% high cholesterol diet), (3) the St-1w group, and (4) the St-2w group (Chol group plus pitavastatin administration for 1 or 2 weeks, respectively). The serum concentrations of lipids and adiponectin were measured preoperatively. After midline laparotomy (time, T0), the superior mesenteric artery was occluded with a microvascular clamp for 30 min, followed by 360 min of reperfusion (T1). Intestinal and lung nitric oxide (NO) concentrations were measured. Intestinal injury was assessed by microcirculatory flow, histology, and permeability. Bacterial translocation was assessed by analysis of serum peptidoglycan concentration. Lung injury was assessed by histologic examination, pulmonary permeability index, and wet/dry lung weight ratio. RESULTS The 2-week administration of statins with high-cholesterol feeding (St-2w group) improved hypoadiponectinemia to levels similar to those of the Normal group. Intestinal and lung NO concentrations were significantly lower at T1 in the Normal and St-2w groups than in the Chol group. Statin administration improved poor recovery of intestinal microcirculatory flow in the Chol group. At T1, intestinal and lung injuries were significantly aggravated and serum peptidoglycan concentration was significantly elevated in the Chol group compared with the Normal and St-2w groups. The 1-week administration of statins had no significant influence on serum adiponectin levels, tissue NO concentration, or tissue injury. CONCLUSION Administration of pitavastatin reduces the risk of II/R-induced injury in atherosclerotic rats with hypoadiponectinemia by improving hypoadiponectinemia and inhibiting inducible NO synthase-produced NO. Furthermore, preoperative improvement of hypoadiponectinemia may be important as an index of the protective effect of pitavastatin for II/R-induced injury in atherosclerotic rats with hypoadiponectinemia.

Simultaneous off-pump coronary artery bypass grafting and in vivo heterogenous renal transplantation. Considering results and indications.

Complications of arterial sclerosis lesions are found in patients in dialysis for end-stage chronic renal failure. We present a case of simultaneous coronary artery bypass grafting (CABG) and renal transplantation. A 64-year-old man was to undergo in vivo heterogenous renal transplantation for chronic renal failure. Angiography was undertaken for preoperative abnormal electrocardiography, which showed severe long segmental stenosis of the left anterior descending coronary artery. We discussed the possibility of simultaneous surgery, conducting off-pump CABG and renal transplantation at the same time. Postoperative management of the implanted kidney was easy despite high infusion. His postoperative course went well, without cardiac events. Simultaneous off-pump CABG and in vivo heterogenous thus provide a viable option for patients with comorbid disease.

True Carcinosarcoma of the Esophagus: Report of a Case

Carcinosarcoma of the esophagus is a malignant neoplasm involving both carcinomatous and sarcomatous components. We report a patient with true esophageal carcinosarcoma who underwent laparoscopy-assisted surgery. An upper gastrointestinal barium study revealed a lobulated intraluminal filling defect in the lower intrathoracic esophagus. The patient underwent esophagectomy and regional lymphadenectomy with gastric tube reconstruction by laparoscopy-assisted surgery and thoracotomy. The esophageal hiatus was entered and the mediastinal esophagus was dissected using a laparoscopic approach. Microscopically, the tumor comprised poorly differentiated squamous cell carcinoma and spindle-shaped cells resembling leiomyosarcoma. Immunohistochemically, spindle-shaped sarcomatous cells displayed strongly positive reaction to vimentin and negative reaction to cytokeratin AE1/AE3 and CD68. No transitional zone was seen between sarcomatous and carcinomatous elements. The patient was finally diagnosed with true esophageal carcinosarcoma. Laparoscopic transhiatal esophagectomy seems to be a rational and safe procedure for lower esophageal neoplasms, even for patients with impaired respiratory function.

Pitavastatin Prevents Bacterial Translocation after Nonpulsatile/Low-Pressure Blood Flow in Early Atherosclerotic Rat: Inhibition of Small Intestine Inducible Nitric Oxide Synthase

Background: Cardiopulmonary bypass decreases intestinal mucosal blood flow because of nonpulsatile and low-pressure blood flow resulting in bacterial translocation (BT) and atherosclerosis also has peripheral blood flow deficiency. The risk of nonpulsatile and low-pressure blood flow for atherosclerotic animals and the effect of statin administration, which has pleiotropic effects, were studied. Methods: Wistar rats were divided into four groups: group N (normal diet), group C (high-cholesterol diet), group S (group C plus pitavastatin therapy), and group I [group C plus inducible nitric oxide (iNOS) inhibitor therapy]. First of all, vascular responses were measured. Then the rats underwent nonpulsatile/low-pressure blood flow in the intestine, and the serum peptidoglycan concentration as a parameter of BT, the small intestinal PO2 ratio (intestinal PO2/PaO2) as a parameter of mucosal blood flow, and NO concentrations were measured before surgery (T0), at the end of 90 min of stenosis (T1), and 90 min after the release of stenosis (T2). Immunostaining for nitrotyrosine was also performed at T2. Results: Group C had vascular endothelial dysfunction without histological changes, which indicated early atherosclerosis. The serum peptidoglycan concentration increased significantly at T2 only in group C. The intestinal PO2 ratio was decreased at T1 in all the groups, and retuned to baseline at T2 in group N and group S, but not in group C or group I. Jejunal NO only in group C was significantly higher at all time points and ileal NO production at T1 and T2. There tended to be a positive stain for nitrotyrosine along the mucosal epithelium in group C. Conclusion: In the setting of early atherosclerosis, intestinal blood flow does not only improve after nonpulsatile/low-pressure blood flow but causes BT because of a large amount of NO from high enzymatic intestinal iNOS activity, and pitavastatin treatment can prevent BT by improving both issues.

A Case of Cystic Formed Aberrant Pancreas Arising from the Gastric Antrum and Prolapsing into the Duodenum

症例は51歳の男性で, 人間ドックにおける上部消化管造影検査で異常を指摘されたため近医を受診し, 上部消化管内視鏡検査にて粘膜下腫瘍を認めたため当院を紹介され受診した. 胃十二指腸造影検査, 胃内視鏡検査では胃前庭部から発生し, 十二指腸球部に嵌入した球形の腫瘍を認め, また, 同時に行った生検では正常粘膜のみであった. X 線造影CTでは内部に嚢胞を形成し, 周囲が軽度造影される3cm大の球形の腫瘍を認めた. 変性したGISTなどを疑ったが確定診断は得られず, また内視鏡下の切除は困難であると考えられたため, 腹腔鏡補助下胃内手術にて腫瘍を摘出し, 術後病理診断にて最終的に迷入膵と診断した. 迷入膵は胃粘膜下腫瘍の鑑別の際に疑うべき疾患であり, まれであるが本症例のような形態を呈することも念頭におくべきであると考えられた.