Kei Kimizuka

Physiologic Studies on Nitric Oxide in Rat Small Bowel Isografts

The enteric nervous system (ENS), especially the nonadrenergic noncholinergic (NANC) inhibitory nerves, is an important factor in intestinal peristalsis. Recently, it was established that nitric oxide (NO) is released after stimulation of NANC inhibitory nerves. Inhibitory nerves such as NANC inhibitory nerves in the ENS are more easily damaged than excitatory nerves by reperfusion or ischemic injuries during small bowel transplantation (SBT). To evaluate the effects of reperfusion and ischemic injuries to the ENS in the transplanted small bowel, we examined the ENS responses, including the effects of NO in the isografted rat jejunum, using the nontransplanted jejunum as a control. To avoid potentially confounding immune phenomena, we used syngeneic Lewis (LEW) rats. Orthotopic entire SBT with portocaval drainage was performed from LEW rats to LEW rats. Isografted muscle strips were obtained from 8 LEW rats 130 days after SBT (n = 24). As controls, normal muscle strips of the jejunum were obtained from 20 nontransplanted LEW rats (n = 60). A mechanograph was used to evaluate in vitro jejunal responses to electrical field stimulation of the adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers, Ng-nitro-l-arginine (L-NNA), and l-arginine. The results indicated that excitatory nerves, especially NANC excitatory nerves, were more dominant in the isografted jejunum than in the normal jejunum (p < 0.01). NANC inhibitory nerves were found to act on the normal jejunum and to a lesser extent on the isografted jejunum (p < 0.05). NO mediates the relaxation reaction of NANC inhibitory nerves in the normal jejunum and to a lesser extent in the isografted jejunum. These results indicated that the intrinsic intestinal innervation contains excitatory and inhibitory nerves and that the former, especially NANC excitatory nerves, are more dominant in the isografted jejunum than in the normal jejunum. In addition, reduction of the action of NANC inhibitory nerves such as that by NO may be largely related to impaired motility in the isografted jejunum. Thus over a long period of time (more than 130 days after SBT) transplanted small bowel dysmotility may be influenced by reperfusion or ischemic injury to the ENS (especially NANC inhibitory nerves) via NO in the transplanted jejunum after syngeneic SBT.

Feasibility study of TS-1 additional therapy for the triple-negative breast cancer received neoadjuvant or adjuvant chemotherapy (SBCCSG14).

162 Background: Prospective randomized clinical trials have demonstrated a significant advantage from postoperative adjuvant chemotherapy for patients with breast cancer. However, triple-negative breast cancer is high rate of early recurrence. Therefore, patients who do not achieve pathological complete response (pCR) for neoadjuvant chemotherapy have worse long-term survival than patients who achieve pCR. Treatment after adjuvant chemotherapy and neoadjuvant chemotherapy is not established yet. We notice that TS-1 improve early recurrent rate of breast cancer. TS-1 proved good response for advanced breast cancer and long-term therapy is possible. We planned the study for the purpose of inspecting it about the safety, completion and efficacy of giving TS-1 after standard therapy of triple negative breast cancer for one year. METHODS The patients with stage ±/II/ III triple negative breast cancer received neoadjuvant or adjuvant chemotherapy and surgery and/or radiotherapy. Furthermore, the cases of neoadjuvant chemotherapy did not achieved pCR. After that, dose of TS-1 is 80mg/m² administered orally daily for 2 weeks followed by a 1-week rest period given as 3-week cycles. RESULTS 63 patients were enrolled, including 44 patients received neoadjuvant chemotherapy and 19 patients received adjuvant chemotherapy. The average age is 50 years (28-68 years). 38 cases (60.3%) brought oral administration for one year to completion. The reasons of discontinuance were 15 cases of toxicity and 10 cases of recurrence. Average relative dose intensity was 80%. The compliance of TS-1 was 70.1% (222.4 days). Overall survival of 3 years was 86.47%, progression-free survival 50.8%. The overall incidence of toxicity was 54 cases (85.7%), and grade 3 toxicity occurred in 21 cases (33.3%). CONCLUSIONS The compliance of TS-1 was approximately equal to the compliance for gastric cancer in spite of receiving treatments of anthracycline and/or taxane. The toxicity was approximately equal to the results for metastatic breast cancer. TS-1 administered orally for one year was feasible for triple negative breast cancer received standard therapy. CLINICAL TRIAL INFORMATION UMIN000001414.