Motohira Yoshida

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.

Metastatic Osteosarcoma in the Jejunum with Intussusception: Report of a Case

We report a case of metastatic osteosarcoma in the jejunum causing intestinal intussusception. A 58-year-old woman underwent right femoral region amputation, lower lobectomy of the left lung and complete left pneumonectomy after four courses of chemotherapy for osteosarcoma of the right femur with left lung metastases. She was referred to our department 13 months later with progressive abdominal pain and vomiting. Abdominal radiography showed a small-bowel obstruction. She underwent emergency laparotomy, which revealed jejunal intussusception. The lead point was found to be an intraluminal tumor. We resected the jejunum containing the tumor and histological examination confirmed that the tumor was osteosarcoma metastasis.

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.

Development of a second-generation radiofrequency ablation using sintered MgFe2O4 needles and alternating magnetic field for human cancer therapy

Magnetic metal particles are known to induce heat energy under an alternating magnetic field (AMF). We developed a local tumor-heating device incorporating an MgFe(2)O(4) needle for the purpose of mild ablation for cancer treatment. A needle made from sintered MgFe(2)O(4) particles was embedded in the hepatic or breast tumors. Tumors were then heated by the energy dissipated from the needle exposed to an AMF. We sequentially evaluated histological changes, cellular activity of tumors, and the extent of thermal effect using nicotinamide adenine dinucleotide (NADH) diaphorase and terminal deoxynucleotidyl tranferase-mediated digoxigenin-DUTP nick-end labeling (TUNEL) staining. The mean temperature of the tumor tissue during heating was about 60 degrees C. Nuclei of the tumor cells became hyper-chromatin immediately after heating. The injured area spread progressively until 3 days after heating; when the area was surrounded by fibroblasts (meaning is not clear). Tumors disappeared after treatment without complications. This is the first time that the complete death of tumor cells has been realized by raising the tumor temperature above 60 degrees C using the heat generated by magnetic metal particles exposed to AMF. This device may be useful in the future for local hyperthemic treatment of human cancers.

Tumor local chemohyperthermia using docetaxel-embedded magnetoliposomes: Interaction of chemotherapy and hyperthermia.

Background and Aim:  We have studied and reported the usefulness of tumor local chemohyperthermia at a low‐grade temperature below 43°C with docetaxel‐embedded magnetoliposome (DML) and an applied alternating current magnetic field. However, the mechanisms of this treatment and the dynamics of the injected docetaxel were not investigated in our previous study. Thus, we investigated the interaction of chemotherapy and hyperthermia in the treated tumor.

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.

Carcinoma of the cystic duct associated with pancreaticobiliary maljunction.

We report a rare case of carcinoma of the cystic duct (CCD) associated with pancreaticobiliary maljunction (PBM). A 63-year-old man had presented with relapsing cholecystitis of 4 months, duration. Computed tomography showed a distended gallbladder: however, small mass in the cystic duct was overlooked. Endoscopic retrograde cholangiopancreatography demonstrated a long common channel (20-mm-long) and fusiform dilatation of the common bile duct, findings, which were consistent with PBM. At laparotomy, we found a papillary tumor, 20 mm in diameter, that obstructed the cystic duct. The patient underwent resection of the gallbladder and the common bile duct, lymph node dissection in the hepatoduodenal ligament, and hepaticojejunostomy. Histologic study revealed a papillary adenocarcinoma confined within the subserosal space. There was no lymphatic or perineural invasion of cancer cells. The surrounding cystic ductal mucosa showed dysplasia and hyperplasia, and the gallbladder and common bile duct showed severe inflammation. The patient has been doing well for 16 months after surgery, without tumor recurrence. This case suggests a relationship between CCD and chronic biliary inflammation caused by PBM, as in cases of gallbladder carcinoma.

Repeated inductive heating using a sintered MgFe2O4 needle for minimally invasive local control in breast cancer therapy.

Purpose: This study investigated the efficacy of repeated thermotherapy for breast cancer utilising a novel sintered MgFe2O4 needle and alternating current (AC) magnetic field in xenograft animal models mimicking human breast cancer. Materials and methods: A sintered MgFe2O4 needle and an apparatus to apply an AC magnetic field were prepared for this study. Animals bearing BT-474 tumours (mean (±standard deviation) volume, 471 ± 153 mm3) were divided into four groups. A sintered MgFe2O4 needle (length, 5 mm) was placed in the centre of each tumour. An AC magnetic field (amplitude, 4 kA/m; 2 kW; 540 kHz) was applied for 10 min once, twice or three times for the first, second and third groups, respectively, and was not applied for the control group. Temperature during treatment and tumour volume 8 weeks after first treatment were assessed. Results: Maximum tumour temperature tended to increase in repeated-application groups: group 1, 59.2 ± 4°C; group 2, 58.9 ± 3.3°C and 61.2 ± 8.9°C for the first and second applications; and group 3, 60.4 ± 4.6°C, 62.1 ± 7.8°C and 71.1 ± 6.1°C for the first, second and third applications. Tumour volumes in control, groups 1, 2 and 3 at 8 weeks after treatment were 3633 ± 2478 mm3, 3240 ± 1031 mm3, 1252 ± 1289 mm3 and 0 mm3, respectively. Tumours were significantly smaller in group 3 than in the control and group 1 at 8 weeks. Conclusions: The efficacy of repeated inductive heating utilising a sintered MgFe2O4 needle was demonstrated. Thermotherapy using the present method may offer an effective non-surgical treatment for human breast cancer.

In vivo subcellular imaging of tumors in mouse models using a fluorophore‐conjugated anti‐carcinoembryonic antigen antibody in two‐photon excitation microscopy

Recently, there has been growing interest in applying fluorescence imaging techniques to the study of various disease processes and complex biological phenomena in vivo. To apply these methods to clinical settings, several groups have developed protocols for fluorescence imaging using antibodies against tumor markers conjugated to fluorescent substances. Although these probes have been useful in macroscopic imaging, the specificity and sensitivity of these methods must be improved to enable them to detect micro‐lesions in the early phases of cancer, resulting in better treatment outcomes. To establish a sensitive and highly specific imaging method, we used a fluorophore‐conjugated anti‐carcinoembryonic antigen (CEA) antibody to perform macroscopic and microscopic in vivo imaging of inoculated cancer cells expressing GFP with or without CEA. Macroscopic imaging by fluorescence zoom microscopy revealed that bio‐conjugation of Alexa Fluor 594 to the anti‐CEA antibody allowed visualization of tumor mass consisting of CEA‐expressing human cancer cells, but the background levels were unacceptably high. In contrast, microscopic imaging using a two‐photon excitation microscope and the same fluorescent antibody resulted in subcellular‐resolution imaging that was more specific and sensitive than conventional imaging using a fluorescence zoom microscope. These results suggest that two‐photon excitation microscopy in conjunction with fluorophore‐conjugated antibodies could be widely adapted to detection of cancer‐specific cell‐surface molecules, both in cancer research and in clinical applications.

Primary Pancreatic Lymphoma: The Role of Surgical Treatment

Primary pancreatic lymphoma (PPL) is a rare disease that is difficult to diagnose preoperatively. We describe the youngest case of PPL treated by surgical excision and chemotherapy. A 16-year-old male presented with abdominal pain and jaundice. Abdominal computed tomography showed a 3.0 × 4.5 cm homogeneously enhanced mass localized between the inferior vena cava and pancreatic head; the common pancreatic duct was dilated and the common bile duct was stenosed. Magnetic resonance imaging findings showed a 4.5 cm tumor localized between the inferior vena cava and pancreatic head with low signal intensity on T1W images and high intensity on T2W images, which enhanced inhomogeneously. Endoscopic retrograde cholangiopancreatography findings were compatible with smooth stenosis of the common bile duct. He was diagnosed as pancreatitis secondary to pancreatic tumor and pylorus-preserving pancreaticoduodenectomy was performed. Postoperative diagnosis was PPL and chemotherapy was performed. After 4 years of treatment he has no signs of recurrence.