Hiroki Sugishita

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.

L-Serine regulates the activities of microglial cells that express very low level of 3-phosphoglycerate dehydrogenase, an enzyme for L-Serine biosynthesis.

Microglia are well known to become activated during various kinds of neuropathological events. The factors that are responsible for the activation, however, are not fully determined. In the present study, L‐Ser was shown to enhance production of nitric oxide (NO), interleukin‐6 (IL‐6) and tumor necrosis factor α (TNF α) by lipopolysaccharide (LPS)‐stimulated cultured rat microglial cells. L‐Ser, however, did not enhance the expression of mRNAs encoding inducible NO synthase, IL‐6 and TNF α. On the other hand, astrocytes did not depend on L‐Ser for release of IL‐6 and TNF α. The expression of an enzyme 3‐phosphoglycerate dehydrogenase (3PGDH), which is essential for L‐Ser biosynthesis from a glycolytic intermediate 3‐phosphoglycerate, was investigated. As revealed by Western blotting and immunocytochemical staining, 3PGDH‐protein expression in vitro was the highest in astrocytes, intermediate in neurons and the lowest in microglial cells. Semiquantitative RT‐PCR showed that microglial cells expressed 3PGDH‐mRNA at a lower level than astrocytes. In frozen sections from rat forebrain, only astrocytes were immunoreactive for 3PGDH. The present study suggested that L‐Ser is able to modulate microglial function mainly at the translation level because microglial cells cannot synthesize sufficient amount of L‐Ser due to the scarce expression of 3PGDH. J. Neurosci. Res. 64:392–401, 2001.

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.

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.

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.

Laparoscopically Assisted Low Anterior Resection for Lower Rectal Endometriosis: Usefulness of Laparoscopic Surgery

A 34-year-old woman presented with pain during menstruation and was diagnosed with endometriosis of the lower rectum. Despite treatment with an LH-RH agonist, she was unable to become pregnant and surgical removal of her endometriosis was recommended. Preoperative magnetic resonance imaging revealed endometriosis localized between the neck of the uterus and rectum with indentation and scuffing. Laparoscopically assisted low anterior resection was performed. Exfoliation was started from the right side of the rectum to the presacral and retrorectal space, and the rectococcygeus ligament was transected. Exfoliation of the retrorectal space was continued to the levator ani muscle and mobilization of the right side of the rectum was performed. In front of the rectum, exfoliation was started posterior to the wall of the vagina, but layers became unclear near the tumor as the tissue was solid in this region. The left hypogastric nerve close to the tumor was inflamed and it was cut. The layer of the exfoliation was connected to the right side of the rectum, the tumor was isolated from the vagina, and the lower rectum was transected at a point 1 cm distal to the tumor with a 60-mm linear stapler. Reconstruction with a 31-mm circular stapler was performed using the double stapling technique. Operative time was 520 min with a blood loss of 320 ml. On the 9th post operative day, a rectovaginal fistula occurred, and ileostomy was performed. The patient was discharged from the hospital on the 25th postoperative day, and 4 months later, stoma closure was performed.

Acute respiratory distress syndrome after gastrointestinal surgery.

BACKGROUND/AIMS Acute respiratory distress syndrome (ARDS) occasionally occurs after gastrointestinal surgery involving severe inflammation such as diffuse peritonitis. Management of this condition has been difficult and effective therapies have not yet been established. In the present study the management for ARDS after gastrointestinal surgery was evaluated. METHODOLOGY A total of 15 patients developed ARDS after gastrointestinal operations performed in our institution. The mean patient age was 75.4±11.1 years. Onset of ARDS occurred ≤24 hours postoperatively in 12 patients and 3- 11 days postoperatively in 3 patients. Treatment for ARDS comprised continuous hemodiafiltration (CHDF), high-dose glucocorticoid therapy or administration of a neutrophil elastase inhibitor (sivelestat). RESULTS Four patients died 3-45 days after onset of ARDS (mortality rate, 26.6%). CHDF was performed in 12 patients, 8 patients received highdose glucocorticoid therapy and 11 patients received sivelestat. No differences in severity scores and clinical data were noted between survivors and non-survivors. PaO2/FiO2 ratio was significantly lower in non-survivors than in survivors from 5 days after starting treatment, whereas no difference was apparent at the onset of ARDS. CONCLUSIONS Multimodal therapies for ARDS were effective. Longitudinal fluctuation in PaO2/ FiO2 ratio after starting treatment appears to offer a prognostic factor for ARDS.

Metachronous intraductal papillary mucinous neoplasm with carcinoma in situ of the pancreas arising within a short interval: Report of a case

A 61-year-old man with an intraductal papillary mucinous neoplasm (IPMN) and carcinoma in situ (CIS) of the pancreatic body initially underwent a distal pancreatectomy. Postoperative follow-up included computed tomography (CT) and ultrasonography (US) every 6 months. Intraductal papillary mucinous neoplasm of the pancreatic head was diagnosed 17 months later using peroral pancreatoscopy (POPS) including a biopsy, revealing IPMN with highly dysplastic changes. A total pancreatectomy was therefore performed. The pathological examination revealed IPMN with CIS. The patient was discharged from the hospital and is doing well as of 1 year postoperatively. Although cautious surveillance seems mandatory, consensus has not yet been reached regarding postoperative surveillance. This report presents an unreported case of metachronously arising IPMN with CIS within a relatively early interval, thus suggesting that surveillance every 6 months is preferable to ≥1 year. In addition, endoscopic US, endoscopic retrograde cholangiopancreatography, intraductal US, or POPS should be included in pathological examinations to avoid missing opportunities to treat lesions such as noninvasive IPMN with a good prognosis. Surgically indicated patients with noninvasive recurrence should therefore be strongly considered to undergo a total pancreatectomy.