Masaru Suda

Factor Xa-inhibitor (DX-9065a) modulates the leukocyte-endothelial cell interaction in endotoxemic rat.

Abnormalities of vascular endothelial function and coagulation play important roles in the development of septic organ dysfunction. DX-9065a is a novel Factor Xa inhibitor that is expected to modulate both coagulation and endothelial function. The purpose of this study is to examine the effect of DX-9065a on leukocyte-endothelial interaction. Rats were injected with 1.0 mg/kg of endotoxin simultaneously with saline, (placebo group), 0.3 mg/kg DX-9065a (low-dose group), or 3.0 mg/kg DX-9065a (high-dose group;n = 6 in each group). At 1 and 3 h after injection, the mesenteric microcirculation was observed under intravital microscopy. In addition, TNF, IL-6, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and lactate levels were measured. The number of leukocytes adhering to the endothelium was significantly reduced in both the high-dose and low-dose groups (P < 0.05 for both, compared to the control group). A comparison of the cytokine levels showed that the peak levels in the treatment groups tended to be lower. Markers of organ damage also showed less increase in the treatment groups (P < 0.05 for both treatment groups compared to the control group). In summary, the Factor Xa inhibitor DX-9065a showed a protective effect on the microcirculation of endotoxemic rats by attenuating leukocyte-endothelial interaction. Although the mechanism for this effect could not be fully elucidated, suppression of both excessive coagulation and cytokine production appear to play a role.

Laparoscopy-Assisted Low Anterior Resection with a Prolapsing Technique for Low Rectal Cancer

Laparoscopy-assisted low anterior resection (LAR) for low rectal cancer is a difficult procedure, presenting problems with rectal washout, selecting the appropriate distal transection line, and achieving safe anastomosis. To resolve these problems, we used a prolapsing technique to perform laparoscopy-assisted LAR. Total mesorectal excision (TME) is performed laparoscopically. The proximal colon is transected laparoscopically with the aid of an endoscopic stapler, and the distal rectum, including the lesion, are everted and pulled transanally to outside the body. Only washout of and wiping off the distal rectum and intestinal resection are performed extracorporeally. The distal rectum is pushed back through the anus into the pelvis, and intracorporeal anastomosis is completed laparoscopically with a double-stapling technique. Our limited experience suggests that the prolapsing technique helps to prevent problems with laparoscopy-assisted LAR in selected patients with low rectal cancer.

Kinetics of cytokines and PMN-E in thoracoscopic esophagectomy

BACKGROUND Perioperative increases in the levels of cytokines and polymorphonuclear leukocyte elastase (PMN-E) have been shown to be related to degree of surgical trauma. METHODS We measured the changes in levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and PMN-E in the perioperative period in patients undergoing thoracoscopic esophagectomy (n = 15) and conventional transthoracic esophagectomy (n = 15) for thoracic esophageal cancer. RESULTS Both IL-6 and IL-8 increased markedly immediately after transthoracic esophagectomy and thereafter, but only a slight increase was observed after the thoracoscopic procedure (IL-6: p = 0.047; IL-8: p = 0.03). A difference was also seen in the pattern of changes in PMN-E. Levels of PMN-E increased immediately after transthoracic esophagectomy and continued to be high up to the 3rd postoperative day, but they remained low after the thoracoscopic procedure and showed no increase (p <lt; 0.01). CONCLUSION These results suggest that, compared with transthoracic esophagectomy, thoracoscopic esophagectomy results in less production of cytokines and PMN-E and thus causes less surgical trauma.

Antithrombin modulates the leukocyte-endothelial cell interaction in the staphylococcal enterotoxin B-challenged mouse.

BACKGROUND The beneficial effects of antithrombin on endotoxemia are well known. The purpose of this study was to examine the effects of antithrombin in a supertoxin-induced sepsis. METHODS Mice were injected with staphylococcal enterotoxin B simultaneously with antithrombin. At 1 hour after injection, the mesenteric microcirculation was observed under intravital microscopy. In addition, humoral mediators were measured at the same time. RESULTS The number of rolling leukocytes on the endothelium was significantly reduced in the treated mice (p < 0.01). The decrease of white blood cell and platelet counts was significantly inhibited in the treated animals (p < 0.01 for both). A comparison of the intercellular adhesion molecule-1 (p < 0.05), soluble tumor necrosis factor-alpha receptor (p < 0.05), and interleukin-6 (p < 0.01) levels showed less increase in the treated mice. CONCLUSION Antithrombin showed a protective effects on the microcirculation of staphylococcal enterotoxin B-challenged mice by attenuating leukocyte-endothelial cell interaction. Suppression of adhesive molecule expression and cytokine production appears to play roles in this effect.

Microinvasive neuroendocrine carcinoma arising from a central papilloma of the breast

Breast central papilloma is a benign papillary neoplasm usually arising in the subareolar region.1 Cancerous change in a central papilloma is exceptionally rare, and, to our knowledge, there are only a few reports describing this unique condition.2–4 In the WHO Classification of tumours of the breast published in 2003, neuroendocrine carcinoma (NEC) is classified as a special tumour entity representing only about 2–5% of invasive breast carcinomas.5 Herein, we describe the first case of an NEC arising from a central papilloma of the breast. The patient was a premenopausal Japanese woman, 43 years of age, with a clinical symptom of bloody nipple discharge from the left breast. Ultrasonography revealed a well-defined, localised solid mass in a dilated large duct immediately beneath her left nipple, suggesting an intraductal papilloma (figure 1). Figure 1 Ultrasonographic finding. A sharply elevated hypoechoic homogeneous mass in the dilated duct beneath the left nipple. On the cut surface of the lumpectomy specimen from the left breast, a circumscribed grey-whitish tumour was found in a prominently dilated lactiferous duct. Histopathologically, this intracystic tumour was supported by arborised and/or intricate fibrovascular cores lined with myoepithelial cells within a proliferation of two different types of epithelial cells: benign ductal cells and bland-appearing carcinoma cells (figure 2A,B). Benign ductal cells closely lining the myoepithelial cells were cuboidal to columnar in shape with a relatively high nuclear/cytoplasmic ratio and somewhat densely stained nuclei (figure 2B). By contrast, …

The efficacy of long-term oral chemotherapy with 5′-deoxy-5-fluorouridine and cyclophosphamide for recurrent breast cancer

Background5′-Deoxy-5-fluorouridine (5′-DFUR) is a prodrug of 5-fluorouracil (5-FU), which is known to be converted by thymidine phosphorylase (dThdPase). A recent preclinical study revealed that cyclophosphamide (CPA) upregulated dThdPase activity, specifically in tumor cells. The purpose of the present study was to examine the efficacy of long-term administration of 5′-DFUR/CPA for patients with recurrent breast cancer.MethodsFifteen breast cancer patients with recurrent tumors entered this study. Ten patients had bone metastasis, five had lung metastasis, and two had liver metastasis. Three patients had multiorgan metastases. All patients had had previous exposure to standard chemotherapy such as CAF (CPA, doxorubicin, and 5-FU) and CMF (CPA, methotrexate, and 5-FU). The patients were orally administered with daily doses of 5′-DFUR at 800–1200 mg and CPA at 200 mg for 2 weeks as induction therapy, followed by 2 weeks’ rest (one to two cycles). Daily doses of 800 mg of 5′-DFUR and 100 mg of CPA (as maintenance therapy) were continuously administered thereafter. Ten of the 15 patients received the maintenance therapy alone. The treatment was continued for at least 24 months (average, 35.2 months).ResultsThe main findings included a significant decrease in pain in nine patients with bone metastasis, and this effect continued for more than 2 years. As the pain decreased, the patients’ quality of life (QOL) was improved. Liver metastasis was diminished in two out of two patients. Hematological toxicity of more than grade 3 was recognized in three patients, but only during the induction therapy.ConclusionOral administration of 5′-DFUR/CPA is well tolerated and useful for patients with recurrent breast cancer.