Masayuki Itakura

Implication of thymidylate synthase in the outcome of patients with invasive ductal carcinoma of the pancreas and efficacy of adjuvant chemotherapy using 5-fluorouracil or its derivatives.

Thymidine synthase (TS) is a key enzyme in the synthesis of pyrimidine in the de novo pathway of DNA synthesis and a major target of 5-fluorouracil (5-FU), but the implications of TS regarding human pancreatic cancer have not been reported. We assessed the expression of TS in invasive ductal carcinoma (IDC) of the pancreas by immunostaining and evaluated its clinicopathological significance, especially its implications regarding the efficacy of chemotherapy with 5-FU or its derivatives. The expression of TS in the nuclei of pancreatic cancer cells in 72 primary lesions of resectable IDC and 30 distant metastases of unresectable IDC was examined by immunostaining using anti-TS polyclonal antibody and immunoreactivity was classified into three categories: negative (−), low (+) and high (2+). High TS immunoreactivity was detected in 43% (31 of 72) of the primary lesions of the resectable IDCs and in 47% (18 of 38) of the metastatic lesions of the unresectable IDCs. The high TS in primary lesions showed a significantly inverse correlation with the level of nodal involvement. High TS immunoreactivity had a significant influence on the outcome of patients with resectable IDC and the rate of survival of the high TS immunoreactivity group was significantly higher than that of the negative or low reactivity groups, although high TS immunoreactivity did not have a significant influence on survival of the patients with unresectable IDC. The implications of TS immunoreactivity regarding the efficacy of 5-FU-based adjuvant chemotherapy (ACT) was also assessed. The high TS immunoreactivity group showed significantly better survival in both the patients who received ACT and those who were treated by surgery alone, in the resectable IDC among patients with resectable IDC. In cases of unresectable IDC, there were no differences in survival between the high and low TS groups among the patients who received ACT and those who were treated by surgery. In conclusion, high TS immunoreactivity was found to be cogent in predicting the prognosis of patients with pancreatic IDC, but its implications regarding the efficacy of 5-FU-based ACT are still unclear.

Antitumor effects of cytoplasmic delivery of an innate adjuvant receptor ligand, poly(I:C), on human breast cancer

Innate adjuvant receptors are expressed in immune cells and some types of cancers. If antitumor therapies targeting these receptors are established, it is likely that they will be therapeutically beneficial because antitumor effects and immune-cell activation can be induced simultaneously. In this study, we tested this possibility of using an innate adjuvant receptor ligand, polyinosinic–polycytidylic acid [poly(I:C)], to treat human breast cancer cell lines. Three breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549) were used in this study. Poly(I:C) was transfected into these cancer cells to stimulate melanoma differentiation–associated gene (MDA) 5, which is a cytoplasmic adjuvant receptor. Poly(I:C) transfection significantly reduced the viability of all cell lines in a manner partially dependent on MDA5. Flow cytometeric analyses and immunoblot assays revealed that the antitumor effect depended on both caspase-dependent apoptosis and c-Myc- and cyclinD1-dependent growth arrest. Interestingly, poly(I:C) transfection was accompanied by autophagy, which is thought to protect cancer cells from apoptosis after poly(I:C) transfection. In a xenograft mouse model, local transfection of poly(I:C) significantly inhibited the growth of xenografted MDA-MB-231 cells. Our findings indicate that cytoplasmic delivery of poly(I:C) can induce apoptosis and growth arrest of human breast cancer cells, and that therapy-associated autophagy prevents apoptosis. The results of this study suggest that the innate adjuvant receptors are promising targets and that their ligands could serve as antitumor reagents, which have the potential to simultaneously induce antitumor effects and activate immune cells.

Correlation between TGF-β1 and p21 (WAF1/CIP1) expression and prognosis in resectable invasive ductal carcinoma of the pancreas

Transforming growth factor-β1 (TGF-β1) inhibits the growth of a variety of epithelial cells; however, in many types of tumors it loses its inhibitory effect. p21(WAF1/CIP1), one of the cyclin-dependent kinase (Cdk) inhibitors induced by TGF-β1, is considered a downstream effector of the growth-inhibitory function of TGF-β1. We assessed the clinicopathologic significance of TGF-β1 and p21 expression in resectable invasive ductal carcinoma (IDC) of the pancreas. Immunohistochemical examination of the expression of TGF-β1 and p21 in 62 patients revealed positive expression of TGF-β1 in 28 (45%) and of p21 in 25 (40%) of the 62 patients, and a significant correlation between the two expressions. The survival curve of patients with TGF-β1(+) tumors was significantly higher than that of patients with TGF-β1(−) tumors; p21(+) patients showed a higher survival curve than did p21(−) patients, but the difference was not statistically significant. Simultaneous analysis of TGF-β1 and p21 expression showed that the patients with TGF-β1(+)/p21(+) tumors had a significantly better prognosis than the others. Multivariate analysis showed that TGF-β1 was a significantly low risk factor for death due to IDC. The concurrent evaluation of TGF-β1 and p21 expression would be an effective tool in the prediction of the prognosis of patients with pancreatic cancer.

Ileocecal Valve-Preserving Ileostomy after Total Proctocolectomy – A Novel Technique for Ileostomy

Background: Although ileoanal anastomosis has become popular for ulcerative colitis, in an emergency situation patients must undergo ileostomy. Aim: A novel ileocecal valve-preserving ileostomy procedure was devised to reduce high output liquid loss. Method: After total colectomy, the ascending colon was clamped and the terminal ileum and ileocecal valve were isolated from the cecum by dissection. The ileum was then brought out through a conventional ileostomy opening in the abdominal wall. Results: Two patients with ulcerative colitis underwent ileostomy in this fashion. The stool became solid within 1 week after the start of solid food and their body weight increased by more than 10% 1 year after surgery. Conclusion: This novel procedure may result in an improvement in the quality of life of patients who undergo total proctocolectomy.

Heterotopic autotransplantation of a pancreas segment with enteric drainage after total or subtotal pancreatectomy for chronic pancreatitis

SummaryFour patients with chronic alcoholic pancreatitis and one patient with idiopathic chronic pancreatitis, who had total or subtotal distal pancreatectomies for persistent pain, underwent simultaneous autotransplantation of a pancreas segment to preserve the pancreatic function. The segment was autotransplanted heterotopically to the iliac fossa with anastomosis of the splenic vessels to the iliac vessels to prevent reinnervation, and the pancreatic duct was anastomosed to the intestine to preserve exocrine function. Postoperatively, the patency of the graft vessels was confirmed by angiography in every patients. Complete pain relief has been obtained in all patients with a followup duration of 4–89 mo. Except for one patient who had been treated preoperatively with insulin injections for diabetes, the patients remained normoglycemic without exogenous insulin administration and demonstrated satisfactory insulin secretion during a 75-g oral glucose tolerance test. An exocrine pancreatic diagnostant test usingp-aminobenzoic acid yielded nearly similar levels to the preoperative value for all patients. Heterotopic autotransplantation of the pancreas segment appears to be effective for preserving pancreatic function, as well as providing permanent pain relief for patients with chronic pancreatitis who require extensive resection of the pancreas.

Oral UFT (uracil plus futrafur) for neoadjuvant chemotherapy of gastric cancer

Background. Neoadjuvant chemotherapy has become one of the topics of interest in chemotherapy of gastric cancer; the present study assessed the clinical benefits of neoadjuvant chemotherapy with oral uracil and futrafur (UFT) for gastric cancer. Methods. Between 1991 and 1997, 82 patients with gastric cancer (36 with early and 46 with advanced cancers) received UFT at 300–600 mg/day orally for 1–6 weeks before surgery. Objective responses, histological effects, and postsurgical survival rates were assessed. Results. In 69 of the 82 patients, the objective responses of the primary lesions were assessed by endoscopy or upper gastrointestinal series examination, and 2 complete responses (CR)s, 25 partial responses (PRs), and 42 no changes (NCs) were seen (39.1% response). Histological effects were evaluated in 82 patients, and 2 grade 3, 11 grade 2, 11 grade 1b, 27 grade 1a, and 31 grade 0 effects were seen. A longer period of UFT administration was associated with a CR or PR. However, the objective responses did not correlate with the histological effects. All the patients underwent gastrectomy, and during the median follow-up period of 41 months, 3-year survival rates were 97.1% for pTNM stage 1, 75% for stage 2, 86.7% for stage 3, and 41.6% for stage 4. The survival rates of stage 3 and stage 4 patients were higher than those of the historical controls in our department. However, CR or PR did not correlate with the improvement in survival. Side effects before surgery were not serious; they included slight myelotoxicity, liver dysfunction, and anorexia; however, 3 patients (3.7%) had suture insufficiency, 3 patients (3.7%) had methicillin-resistant Staphylococcus aureus (MRSA) enteritis, and 7 patients (8.5%) had liver dysfunction. Conclusions. Preoperative chemotherapy for gastric cancer with oral UFT was safe and resulted in a good local response (macro- and microscopically) which may indicate the possibility of improved survival with neoadjuvant chemotherapy with UFT. Furthermore, preoperative chemotherapy with oral UFT is easy and patients can receive this treatment on an outpatient basis.

Heterotopic autotransplantation of the pancreas segment after pylorus-preserving total pancreatectomy: A case report of successful surgical treatment for chronic pancreatitis

A 38-year-old man who had suffered for 5 years from persistent abdominal pain caused by alcoholic chronic pancreatitis, presented with diffuse calcification of the entire pancreas with cystic formation of the pancreatic head. After a pylorus-preserving total pancreatectomy, the pancreatic head, including the cyst, was removed extracorporeally by bench surgery, and the remaining segment of the body and tail autotransplanted heterotopically to the iliac vessels with a pancreaticojejunostomy. Total resolution of the pain was achieved postoperatively, and dietary intake has been satisfactory. Both endocrine and exocrine pancreatic functions have been well preserved, and no insulin has been needed. Three months after his operation, the patient has returned to leading a normal life.

Neoadjuvant Chemotherapy of Gastric Cancer with UFT

Gastric cancer is the most common cancer in Japan. The treatment results for gastric cancer in Japan have been improving over the last two decades, and the 5-year survival rates after surgery have reached more than 90% for stage 1 and 70%–80% for stage 2. The prognosis of patients with stage 3 or 4 gastric cancer is still poor, and 5-year survival rates are about 40% for stage 3 and 5%–10% for stage 4. To improve the treatment results for gastric cancer, a variety of therapies have been applied, with chemotherapy playing the most important role. It is still unclear whether postoperative adjuvant chemotherapy improves survival, although gastric cancer is now considered to be relatively sensitive to chemotherapy compared to that of other digestive organ cancers.

SURVIVAL RATE OF GASTRIC CANCER ACCORDING TO THE NEW AND FORMER “THE GENERAL RULES FOR GASTRIC CANCER”

“The General Rules for the Gastric cancer”were newly revised in July, 1993. In order to know the differences from the former Rules, 989 patients with gastric cancer, who underwent gastric resection in the department in the past 11 years, were statistically reanalized and corrected survival rates were calculated in this study. In the former stage classification, stage I and II cases accounted for 50.9% and 11.5%, respectively. The disproportion of the percentage in both stages resulted from the imbalance of the percentages of ps(-) and ssγ cases, which were 65.3% and 4.3%, respectively. Five-years survival rates in stage I, II, III and IV cases were 97.8, 89.3, 51.8% and 13.9%, respectively, and the there were significant differences among stage II, III and IV (p<0.01). In the new stage classification, percentage of each stage appeared to be distributed more appropriately, and the distribution was corrected. Five-year survival rates in stage Ia, Ib, II, IIIa, IIIb, IVa, and IVb cases was 98.2, 97.1, 78.1, 64.5, 23.0, 20.5, and 7.3%, respectively. In these values, stage Ia and IIIb almost equal to Ib and IVa, respectively, and significant differences were recognized between stage Ib and II, IIIa and IIIb (p<0.01), and IVa and IVb (p<0.05).

A Case Report of Extracorporeal Hepatectomy of the Medial and Anterior Segments for Liver Tumor.

中肝静脈を巻き込み, 左右肝静脈と大きな肝内門脈枝にはさまれた内側区域から前区域にまたがる腫瘍に対し, 比較的出血の少なくてすむ右3区域切除を行い, 摘出した右3区域を冷却臓器保存液中に浸漬して体外手術により内側および前区域を切除し, 後区域を同所性に自家移植した.本法は前・後区域間の広範囲な肝実質切離を無血下に行うので通常の中央2区域切除より出血は少なく, 無肝期はないので安全に行える術式である.本症例では術中術後の総輸血量3,600mlであった.自家移植肝の血流再開直後より動脈血中ケトン体比は危険域を脱し術翌日からは安全域に入った.肝細胞障害は術後4日目に正常化したがそれ以後も高ビリルビン血症は数日間遷延した.移植肝の胆管ドレナージの胆汁排出や胆汁中直接型ビリルビン濃度はその生着機能の確認に有用であった.術後3か月の現在, 肝機能のすべての指標は正常値を保っている.