Long-term outcomes of extended radical resection combined with intraoperative radiation therapy for pancreatic cancer.

BACKGROUND/PURPOSE: Systemic and/or local recurrence often occurs even after curative resection for pancreatic cancer (PC). To prevent local relapse we adopted an extended radical resection combined with intraoperative radiation therapy in patients with PC, and all the patients were followed for more than 5 years. METHODS: We assessed the long-term outcomes of 41 patients who underwent this combined therapy. The cumulative survival curve in this series was depicted using the Kaplan-Meier method. Statistical analyses were performed using the log-rank test. RESULTS: The actual 5-year survival rate was 14.6%, with a median survival time of 17.6 months. Six patients have been 5-year survivors. Local recurrence occurred in only 2 patients (5.0%). Cancer-related death occurred in 32 patients, 18 of whom had liver metastases. The patients with liver metastases had a significantly shorter survival time than those with other cancer-related causes of death. Patients with n3 lymph node involvement, extrapancreatic nerve plexus invasion, and stage IV disease had significantly poorer prognoses than patients without these characteristics. CONCLUSIONS: Our combined therapy for patients with PC contributed to local control; however, it provided no survival benefit, because of liver metastases.

Complete remission of pancreatic cancer after multiple resections of locally pancreatic recurrent sites and liver metastasis: report of a case.

Pancreatic cancer has the most dismal prognosis of all gastrointestinal cancers. We herein report a case of complete remission from pancreatic cancer by multire-sections of locally pancreatic recurrent sites and liver metastasis over a 14-year period. A 60-year-old man was admitted to our hospital because of a neoplasm of the tail of the pancreas in April 1992. A distal pancreatectomy was curatively performed on this patient. At 1 year after surgery a solitary liver metastasis appeared, and we thus performed a partial hepatectomy. Thereafter, local recurrences appeared twice and we performed a pancreatectomy each time. Finally, we performed a total pancreatectomy. The histopathological findings of specimens of the pancreas showed papillary adenocarcinoma, although the original pancreatic tumor also demonstrated areas of tubular adenocarcinoma. Metastatic liver tumor showed tubular adenocarcinoma. The patient has survived for 14 years since the first operation. This is a rare case of a long survival of a patient with pancreatic cancer due to its histopathology and biologic characteristics.

Onset of liver metastasis after histologically curative resection of pancreatic cancer.

PURPOSE: We assessed the possibility of predicting the time of onset of liver metastases by measuring the postoperative changes in serum carbohydrate antigen (CA)19-9 after curative resection of pancreatic cancers. METHODS: Among 28 patients who underwent histologically defined curative resection of pancreatic cancer between 1984 and 1999, liver metastasis developed in 11 patients with elevated serum CA19-9 levels. We plotted the serum CA19-9 levels against time on a semilogarithmic graph. Over the linear part of the curve, the time when log[CA19-9] equaled zero was defined as the time of onset of liver metastases. The log[CA19-9] level doubling time was then calculated and evaluated in relation to the survival period. RESULTS: The serum CA19-9 levels increased linearly in 10 of the 11 patients. The predicted time of onset of liver metastasis ranged from preoperative day 163.0 to postoperative day 27.1, being preoperative in eight patients. The doubling time until death correlated strongly with survival in the eight patients with maintained log[CA19-9] linearity. CONCLUSION: The onset of liver metastases might be preoperative in patients with advanced pancreatic cancer. Therefore, neoadjuvant chemotherapy should be mandatory even if there is no sign of liver metastases.

Identification of prognostic factors associated with early mortality after surgical resection for pancreatic cancer--under-analysis of cumulative survival curve.

BACKGROUND: The 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. METHODS: Thirty-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. RESULTS: The 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. CONCLUSIONS: The 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.

5-fluorouracil intra-arterial infusion combined with systemic gemcitabine for unresectable pancreatic cancer.

OBJECTIVES: The aim of this study was to define assessment of response and adverse events of the combination chemotherapy of 5-fluorouracil (5-FU) pancreatic and hepatic arterial continuous infusion and systemic gemcitabine administration for unresectable pancreatic cancer. METHODS: We treated 24 chemotherapy-naive patients with unresectable pancreatic cancer. To prevent gastroduodenal injury from 5-FU infusion, the catheter was placed to allow the distribution of 5-FU to the pancreatic tumor and the liver after occlusion of the gastric and pancreaticoduodenal arteries. 5-FU was administered at a dose of 250 mg/d on days 1 to 5 every week as a continuous arterial infusion. Gemcitabine was infused intravenously at a dose of 1000 mg once weekly for 3 consecutive weeks of every 4 weeks. RESULTS: The partial response rate was 20.8% (5 of 24), although there was no case of complete response. Fourteen cases (58.3%) were stable disease, and 5 cases (20.8%) were progressive disease. The most common toxicities were hematological and gastrointestinal events. No patients died of adverse effects using this chemotherapy. Gastric and/or duodenal ulcers occurred because of 5-FU intra-arterial infusion. Catheter-related cholangitis occurred in patients with biliary drainage for obstructive jaundice. Median survival time was 14 months, with a 50.9% 1-year survival rate, although patients with performance status 2 and multiple organ metastases had a poor prognosis. CONCLUSIONS: This combination chemotherapy was well tolerated and seemed to be effective for patients with unresectable pancreatic cancer.

Pancreatic liver metastases after curative resection combined with intraoperative radiation for pancreatic cancer.

BACKGROUND/AIMS: A high proportion of patients even after curative resection for pancreatic cancer suffer from hepatic metastases. The aim of this study was to identify clinicopathological predictors of liver metastases after surgery, retrospectively. METHODOLOGY: Forty-one patients underwent extended radical pancreatectomy combined with intraoperative radiotherapy, which is one of the best local control methods for ductal cell carcinoma of the pancreas. Of the 41 patients, twenty-one patients regarded as being in a cancer free state after this combined therapy were studied to analyze clinicopathological predictors of hepatic metastases. Odds ratios and their 95% confidence intervals were calculated from data using logistic regression analysis. Statistical difference was considered significant at p<0.05. RESULTS: Liver metastases after curative resection occurred in 11 patients. Preoperative biliary drainage, jaundice, elevated preoperative serum tumor-associated carbohydrate antigens levels, microscopic distal bile duct invasion, duodenal wall invasion, extrapancreatic nerve plexuses invasion were factors influencing postoperative liver metastases. CONCLUSIONS: We found clinicopathological predictors of postoperative liver metastases. Patients with these factors require consideration in careful follow-up and perioperative adjuvant therapy for prevention of postoperative liver metastases.

Preoperative detection of liver metastases secondary to pancreatic cancer: utility of combined helical computed tomography during arterial portography with biphasic computed tomography-assisted hepatic arteriography.

OBJECTIVE: This study was designed to define the diagnostic advantage of computed tomography during arterial portography combined with computed tomography-assisted hepatic arteriography ( CTAP + CTHA) for preoperative detection of liver metastases secondary to pancreatic cancer compared with that of multidetector computed tomography (MDCT). METHODS: From January 2002 to February 2003, we retrospectively studied 19 consecutive patients with pancreatic cancer. MDCT was performed on all patients prior to preoperative visceral angiography. Fourteen patients underwent CTAP + CTHA at the time of preoperative angiography. RESULTS: Liver metastases were identified in 3 patients by means of MDCT. Of 14 patients who underwent CTAP + CTHA, 8 patients (57.1%) were diagnosed as having liver metastases, which could not be detected by MDCT. These tumors missed by MDCT ranged from 5 to 15 mm in size. On CTAP + CTHA, a single nodule in the liver was detected in 2 patients, 2 nodules in 2 patients, 3 lesions in 1 patient, and > or =4 lesions in 3 patients. The sensitivity and specificity of CTAP + CTHA versus MDCT were 75.0% versus 23.1% and 66.7% versus 100%, respectively. CONCLUSIONS: In conclusion, the combination of CTAP and CTHA is useful to confirm liver metastases before operation for resectable pancreatic cancer because it has higher sensitivity to detect of liver metastases compared with MDCT.

Pancreatic Cancer Registry in Japan: 20 years of experience.

The prognosis of pancreatic cancer is defined by the histology and extent of disease. Preoperative histologic diagnosis and diagnostic imaging are fundamentals in managing the disease, but it is not rare to find unexpected peritoneal dissemination or liver metastasis at the time of operation. The overall resectability rate of pancreatic cancer is 40% in Japan. Resecting the portal vein and peripancreatic plexus were performed on 40% of the patients who underwent pancreatectomy for invasive cancer in the head of the pancreas. Long-term survival was only found in patients who underwent pancreatectomy. Radical lymph node dissection, or combined resection of the large vessels, did not seem to improve survival further than the standard resection. Multidisciplinary treatments combined with surgery were performed, and various effects of postoperative chemotherapy after pancreatectomy, intraoperative- and postoperative-radiation therapy, or postoperative chemotherapy for unresectable tumor, were shown. Development of unconventional therapies and refinement of the conventional therapy should be promoted on a randomized prospective trial basis. To promote this effort, which requires the international comparisons and cooperation, JPS developed a computerized JPS registration system downloadable from the JPS website (http://www.kojin.or.jp/suizou/index.html).

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.

WARTS tumor suppressor is phosphorylated by Cdc2/cyclin B at spindle poles during mitosis.

Identification of physiological substrates for Cdc2/cyclin B is crucial for understanding the functional link between mitotic events and Cdc2/cyclin B activation. A human homologue of the Drosophila warts tumor suppressor, termed WARTS, is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that Cdc2/cyclin B forms a complex with a fraction of WARTS in the centrosome and phosphorylates the Ser613 site of WARTS during mitosis. Immunocytochemical analysis has shown that the S613-phosphorylated WARTS appears in the spindle poles at prometaphase and disappears at telophase. Our findings suggest that Cdc/cyclin B regulates functions of WARTS on the mitotic apparatus.

Production, characterization, and interspecies reactivities of monoclonal antibodies against human class A macrophage scavenger receptors.

Class A macrophage scavenger receptor (SR-A) is one of the major receptors of macrophages and plays important roles in atherogenesis and host defense mechanisms. To assess the role of SR-A, monoclonal antibodies were generated by immunizing SR-A-deficient mice with a recombinant protein of human type I SR-A as immunogen. Four antibodies (SRA-C6, SRA-D10, SRA-E5, and SRA-F8) were confirmed to be specific for SR-A by Western blot analysis. In early atherosclerotic lesions, these antibodies recognized scattered macrophages in intima and foamy macrophages in the periphery of atheromatous cores. Interestingly, foamy macrophages in the core lesion were only weakly stained. In other organs, the antibodies recognized tissue macrophages such as alveolar macrophages, Kupffer cells in the liver, red pulp macrophages in the spleen, sinus macrophages in lymph nodes, and interstitial macrophages in various organs. Perivascular macrophages in the brain (Mato cells) were also positive for these antibodies. Freshly isolated blood monocytes were negative; however, they became positive for these antibodies after 1 day in culture. At 3-5 days in culture, the reaction intensity became stronger along their differentiation towards macrophages. Dendritic cells such as interdigitating cells of lymphoid tissues and epidermal Langerhans cells were invariably negative. In the reaction with animal tissues, each antibody showed a unique reaction pattern. Among four antibodies, SRA-E5 recognized SR-A molecules in all animal species examined, including rats and mice. These antibodies will be useful tools for the study of SR-A in atherogenesis and various other pathological conditions in humans and animal species.