Keiichiro Kanemitsu

Combination of intraoperative radiation with resection of Cancer of the pancreas

SummaryThe utility of intraoperative radiation therapy (IORT) as an adjuvant to the surgical resection of pancreatic cancer was studied. In 1976, as our first trial with this combined therapy, we applied IORT with 30 Gy of electron beam with 8 MeV to 15 patients to prevent local recurrence around the celiac axis and superior mesenteric artery after standard pancreatectomy. However, the combined therapy did not show an improvement in survival rate as compared to that of 19 patients with standard operation alone. Autopsies of three patients with the combined therapy did not show involved lymph nodes in the radiation field, but did show local recurrence around the aorta outside the radiation field.By comparison, we performed extended operation without IORT on nine patients, with almost complete dissection of the lymph nodes around the aorta, from the diaphragm to the level of the inferior mesenteric artery. This extended surgery did not improve survival time, and autopsy showed local recurrence in spite of the dissection of lymph nodes.Therefore, since 1984, we have performed IORT with a dose of 30 Gy, 9 MeV, and an extended radiation field from the diaphragm above to the inferior mesenteric artery below, following extended operation on 14 patients. The five-year cumulative survival rate of these cases was 33.3%. Four autopsies showed improvement of local control rate. No radiation-related complications were noticed postoperatively in patients who underwent extended IORT following pancreatectomy. We were encouraged to continue this approach for the cure of pancreatic cancer.

Applicability of disseminated intravascular coagulation parameters in the assessment of the severity of acute pancreatitis.

Objectives: To evaluate the clinical applicability of the determination of disseminated intravascular coagulation (DIC) parameters in acute pancreatitis. Methods: The subjects for this study were 139 consecutive patients with acute pancreatitis. DIC parameters were assessed at the initial observation of these patients. Results: The levels of the DIC parameters at admission were significantly associated with the severity and the prognosis of acute pancreatitis. Antithrombin III (AT-III), fibrin/fibrinogen degradation products-E, platelet count, D-dimer, and thrombin-AT-III complex at admission showed better area under the receiver operating characteristics curve values compared with C-reactive protein. An AT-III value of 69% at admission was the best cut-off value to predict fatal outcome (sensitivity, 81%; specificity, 86%). Conclusions: The aggravated coagulation parameters predict a fatal outcome in patients with acute pancreatitis. AT-III level (<69%) was the most accurate marker for poor outcome of acute pancreatitis at admission.

Vascular encasement by pancreatic cancer : Correlation of CT findings with Surgical and pathologic results

Purpose The purpose of this study was to correlate thin-slice high-resolution helical CT findings of arterial and venous involvement in pancreatic cancers with surgical and histopathologic results. Method Forty-eight patients with pancreatic cancer underwent preoperative thin-slice high-resolution helical CT, followed by surgical dissection of the pancreatic vessels during curative or palliative surgery. Major vessels running within 1 cm from the tumor margin were evaluated. CT appearance was graded on a 0–4 scale (0: none, 1: <24%, 2: 25–49%, 3: 50–74%, 4: 75–100%) by circumferential contiguity of tumor to vessels. Resected specimens were available from 26 patients. Results Surgical correlation of CT findings was available in 89 veins and 83 arteries, and both surgical and histologic correlation was available for 42 veins and 29 arteries. At surgical observation, 29 of 35 veins (82.9%) evaluated as CT grade 3 or 4 were found to be involved, whereas only 18 of 30 arteries (60%) evaluated as CT grade 3 or 4 were proved to be involved. On microscopic observation, tumor invasion to the portal venous systems was confirmed in 15 of 42 (35.7%) vessels, and this invasion was depicted as from CT grades 1 to 4. In arteries, tumor invasion was seen in 3 of 29 vessels (10.3%), all of which were graded as 3 or 4 by CT. Conclusion The grading system of vascular invasion should differ between arteries and veins. Involvement of the venous system exceeding one-half circumference of the vessels (grade 3 or 4) was suggestive of vascular invasion; however, this criterion was not always satisfactory for the evaluation of tumor invasion in the arterial system.

Pancreatoduodenectomy using a no-touch isolation technique.

BACKGROUND Pancreatoduodenectomy is the only effective treatment for cancers of the periampullary region. Because surgeons usually grasp tumors during pancreatoduodenectomy, this procedure may increase the risk of squeezing and shedding the cancer cells into the portal vein, retroperitoneum, and/or peritoneal cavity. In an effort to overcome these problems, we have developed a surgical technique for no-touch pancreatoduodenectomy. METHODS From March 2005 through May 2008, 42 patients have been operated on following this technique. Resected margins were microscopically analyzed. RESULTS We describe a technique for pancreatoduodenectomy using a no-touch isolation technique. We resect cancers with wrapping them within Gerotas fascia and transect the retroperitoneal margin along the right surface of the superior mesenteric artery and abdominal aorta without grasping tumors. CONCLUSIONS No-touch pancreatoduodenectomy has many potential advantages that merit further investigation in future randomized controlled trials.

Carcinogenesis of Intraductal Papillary Mucinous Neoplasm of the Pancreas: Loss of MicroRNA-101 Promotes Overexpression of Histone Methyltransferase EZH2

BackgroundThe mechanisms of IPMN carcinogenesis are as yet unclear. This study aimed to determine whether expression of EZH2 promotes neoplastic progression of IPMN and PDCA, and to elucidate regulation of EZH2 expression by miR-101.MethodsEZH2 mRNA and protein expression were investigated in 8 human pancreatic cancer cell lines by PCR and western blotting. Pre-miR-101 and anti-miR-101 were transfected into pancreatic cancer cells to elucidate EZH2 regulation by miR-101. To evaluate whether EZH2 modulates malignant progression of IPMN, EZH2 expression in IPMN was examined by immunohistochemistry. Next, we collected malignant and benign cells from FFPE samples of IPMNs using laser capture microdissection and extracted the RNA. miR-101 expression in IPMN was assessed using real-time PCR.ResultsAll pancreatic cancer cell lines expressed EZH2 mRNA and protein. The induction of miR-101 by transfection of pre-miR-101 in MIA PaCa-2 was closely related to a reduction in EZH2 protein production compared with control, whereas there was little difference in the expression of EZH2 mRNA. Anti-miR-101 transfected pancreatic cancer cells showed an increase in EZH2 protein, while the level of EZH2 mRNA was not elevated. Immunohistochemistry revealed that the expression of EZH2 was significantly higher in malignant than benign IPMN. Expression of miR-101 was significantly lower in malignant IPMN than benign IPMN.ConclusionsMiR-101 targets EZH2 at the posttranscriptional level, and loss of miR-101 could be a trigger for the adenomacarcinoma sequence of IPMN by upregulation of EZH2. This study suggests miR-101–EZH2 blockade as a potential therapeutic target in IPMN carcinogenesis.

Predictive factors for platelet increase after partial splenic embolization in liver cirrhosis patients

Background and Aim:  Partial splenic embolization (PSE) is often performed for improving thrombocytopenia in cirrhotic patients. We investigated the largely unclear predictive factors for platelet increase at both 1 month and 1 year after PSE.

A method for safe pancreaticojejunostomy

We devised a new technique to increase the safety of pancreaticojejunostomy in patients with an extended operation for pancreatic cancer. This new pancreaticojejunostomy was created by end-to-side anastomosis with four layers about 7 cm distal to the jejunal stump. The cut surface of the pancreas was placed on the seromuscular coat of the ventral aspect of the jejunum to cover the posterior surface of the anastomosis, and the anastomosis between the pancreas and the jejunum was created using fibrin glue. The pancreatic duct was intubated with a silicone tube, and its stenting tube was brought out through a opening in the jejunum. The anterior surface of the pancreaticojejunostomy was covered by the proximal jejunum as a serosal patch. We used this technique in seven patients. No patient developed an anastomotic leak or any other complication. The anastomosis is covered by the jejunum and is not open to the peritoneum. This new technique of pancreaticojejunostomy may reduce the risk of pancreatic leak, especially when an extended operation is performed.

Oxysterol binding protein-related protein-5 is related to invasion and poor prognosis in pancreatic cancer

In previous studies, the gene expression profiles of two hamster pancreatic cancer cells with different potentials for invasion and metastasis were analyzed. In the present study, we identified that one of the genes expressed strongly in the highly metastatic cell line is hamster oxysterol binding protein‐related protein (ORP)‐5. The aim of the present study was to clarify the relationship between ORP5 and invasion and poor prognosis of human pancreatic cancer. Invasion assays were carried out in both hamster and human pancreatic cancer cells by suppressing the ORP5 gene with short interfering RNA or inducing its expression by introducing an expression vector. To evaluate the relationship between ORP5 and the characteristics of human pancreatic cancer, 56 pancreatic cancer tissue specimens were analyzed and the ORP5 expression in each pancreatic cancer tissue specimen was analyzed by immunohistochemistry. In both the hamster and human pancreatic cancer cells, suppression of ORP5 significantly reduced the invasion rate of the cells and induction of ORP5 significantly enhanced the invasion rate of the cells. In the clinical sample, the median survival times of the patients with ORP5‐positive (n = 33) and ORP5‐negative (n = 23) cancer were 8.3 and 17.2 months, respectively (P = 0.02). Also, the 1‐year survival rates of patients with ORP5‐positive and ORP5‐negative cancer were 36.4 and 73.9%, respectively (P = 0.005). The ORP5 expression level was related to both invasion and poor prognosis in human pancreatic cancer. These findings suggest that the expression of ORP5 may induce cancer cell invasion, resulting in the poor prognosis of pancreatic cancer. (Cancer Sci 2008; 99: 2387–2394)

Implication of Micrometastases of Lymph Nodes in Patients With Extended Operation for Pancreatic Cancer

Introduction Accurate evaluation of lymph node metastases is very important in planning treatment for pancreatic cancer. Aim To detect micrometastases in lymph nodes dissected from patients with pancreatic cancer. Methodology We used cytokeratin staining of negative lymph nodes in routine hematoxylin–eosin (HE) staining. We examined by cytokeratin staining 239 HE-negative nodes from 7 patients with no pathologic evidence of lymph node metastasis (n0 cases) and 718 HE-negative group 2 nodes from 23 patients with metastasis in group 1 lymph nodes (n1 cases) who underwent extended operation combined with intraoperative radiation therapy (IORT). Results Cytokeratin staining identified 15 positive nodes among the 239 HE-negative nodes from the 7 n0 cases and 8 positive nodes among the 718 HE-negative nodes from the 23 n1 cases. Among the 7 n0 cases, 5 (71.4%) had positive n1 nodes and 2 (28.3%) also had positive n2 nodes. Among the 23 n1 cases, 4 (17.4%) had positive n2 nodes. Patients with micrometastases in n2 nodes died within 25 months. Conclusion Cytokeratin staining is very useful to evaluate the involvement of lymph nodes in pancreatic cancer. Prognosis of pancreatic cancer should be determined in conjunction with evaluation of nodal status by cytokeratin staining. Extended operation was not useful for pancreatic cancer patients with micrometastases of group 2 nodes.

Identification of Prognostic Factors Associated with Early Mortality after Surgical Resection for Pancreatic Cancer—Under-analysis of Cumulative Survival Curve

BackgroundThe cumulative survival curve after surgery for advanced pancreatic cancer is characterized by a steep downward slope in the early postoperative period. The aim of this investigation was to identify the characteristics associated with early mortality in patients undergoing pancreatic resection for pancreatic cancer.MethodsThirty-seven patients with extended radical pancreatectomy combined with intraoperative radiation therapy were studied. The cumulative survival curve in this series was depicted using the Kaplan-Meier method. Assuming that there were two distinct survival curves, below and above the breakpoint, each part of the curve was modeled as an exponential distribution. Three parameters, the breakpoint, the high hazard rate below the breakpoint, and the low hazard rate above the breakpoint were estimated by the maximum likelihood method. Prognostic factors associated with early mortality after surgery were evaluated using univariate and multivariate Cox proportional hazards regression analyses.ResultsThe breakpoint of the survival curve was estimated at 41 months. The short-survival group (SSG) was defined as deceased earlier than 41 months after surgery, and included 31 patients (83.8 %). The long-survival patient group (LSG) consisted of 6 patients who were alive more than 41 months after surgery. Eighteen SSG patients (58.1 %) died of hepatic metastases, whereas no LSG patients died of hepatic metastases. Abdominal pain and/or back pain during clinical course was identified by multivariate analysis as a prognostic factor for patients undergoing pancreatic resection.ConclusionsThe high hazard rate in the early postoperative period was closely linked with death due to liver metastases. The preoperative presence of local pain was a prognostic factor associated with early mortality.