Akiyuki Kanzaki

Correlation between radiographic classification and pathological grade of portal vein wall invasion in pancreatic head cancer.

ObjectivesA retrospective study was performed to clarify the correlation between radiographic type of portal vein (PV) invasion and pathological grade of PV wall invasion, and their correlation with postoperative prognosis. Background:In many patients with pancreatic cancer, PV resection is necessary to increase resectability and obtain cancer-free margins. Methods:We analyzed 671 patients who had undergone surgery for invasive adenocarcinoma of the pancreas between July 1981 and June 2010. Radiographic types of PV invasion of pancreatic head cancer were classified into A (normal), B (unilateral narrowing), C (bilateral narrowing), or D (complete obstruction with collateral veins), by portography or computed tomography. Pathological grades of PV wall invasion were classified as 0 (no invasion), 1 (tunica adventitia), 2 (tunica media), or 3 (tunica intima). Results:Four hundred and sixty-three patients underwent resection, and PV resection was performed in 297. Combined arterial vessel resection was performed in 16 cases. No significant difference in operative mortality was observed between PV preservation (0.6%) and PV-only resection (2.1%), and no operative deaths occurred after 1999. Radiographic classification of PV invasion correlated with incidence of pathological PV wall invasion. In pancreatic head carcinoma, no pathological PV wall invasion was observed in type A (n = 111). Pathological PV invasion was observed in 51% of type B (42/82), 74% of type C (72/97), and 93% of type D (63/68). Long-term survival (>5 years) was observed in types A and B, and grades 0 and 1 subgroups. Conclusions:Pancreatectomy with PV resection can be performed safely. Even in radiographic classification type B, pathological PV wall invasion was observed in 51% of patients. Long-term survival was observed in types A and B, and grades 0 and 1.

A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer

In 2005, we initiated a clinical trial that examined the efficacy of the oncolytic virus HF10 to treat pancreatic cancer. Pancreatic cancer continues to have a high mortality rate, despite multimodal treatments for patients, and new therapeutic methods are greatly needed. The current mainstream methods for cancer treatment include biological therapeutics such as trastuzumab (Herceptin) for breast cancer or erlotinib (Tarceva) for non-small cell lung cancer. Oncolytic virus therapy is a new and promising treatment strategy for cancer. Oncolytic viruses are novel biological therapeutics for advanced cancer that appear to have a wide spectrum of anticancer activity with minimal human toxicity. To examine the efficacy of oncolytic virus therapy for pancreatic cancer, we initiated pilot studies by injecting six patients with non-resectable pancreatic cancer with three doses of HF10. All patients were monitored for 30 days for local and systemic adverse effects and were not administered any other therapeutics during this period. There were no adverse side-effects, and we observed some therapeutic potential based on tumor marker levels, survival, pathological findings and diagnostic radiography. The tumors were classified as stable disease in three patients, partial response in one patient and progressive disease in two patients.

Prognostic impact of pancreatic margin status in the intraductal papillary mucinous neoplasms of the pancreas

BACKGROUND Intraductal papillary mucinous neoplasm (IPMN) of the pancreas often recurs after operative resection. The absolute risk and incidence of recurrence, however, especially in the remnant pancreas, is unknown. METHODS We reviewed our 18-year experience of 144 surgical cases of IPMNs and selected 103 cases of benign IPMN and carcinoma in situ (CIS) for analysis of the clinicopathologic features and long-term outcome of the recurrent disease, with particular emphasis on the status of the cut margins of the pancreas. RESULTS No patient with benign IPMN died within 5 years. Recurrences in the remnant pancreas were observed in 9 cases: 4 (4.9%) among the 81 cases of benign IPMNs and 5 (22.7%) among the 22 cases of CIS. All recurrences were considered as multicentric because none recurred at the true resection margin of the previous operative resection. The pancreatic transection margin was normal or hyperplastic in 64 patients, whereas adenoma was detected at the margin in 28 patients. The presence of adenoma had no influence on the outcome, and recurrence in the remnant pancreas was diagnosed in 5 (7.8%) of 64 adenoma-negative patients and 3 (10.7%) of 28 adenoma-positive patients. Furthermore, both overall survival and recurrence-free survival were similar between the 2 groups. CONCLUSION In benign IPMN and CIS, a favorable prognosis can be expected irrespective of the status of the pancreatic cut surface, although follow-up with adequate imaging studies is recommended for detection and resection of the recurrent disease.

Pattern of lymph node metastasis spread in pancreatic cancer.

Objectives: We aimed to clarify the detailed pattern of lymph node (LN) metastasis spread in patients with pancreatic cancer. Methods: This retrospective study enrolled 429 patients who underwent pancreatectomy with extended lymphadenectomy for pancreatic cancer. The prognostic implications of LN metastasis were evaluated, and the position, frequency, and association with other clinicopathologic factors were investigated. Results: Lymph node metastasis was confirmed pathologically in 289 patients (67.4%). The prognosis of patients with LN metastasis was significantly poorer than that of patients without LN metastasis (P < 0.001). Distant LN metastasis occurred frequently, regardless of the tumor site. Patients classified with T1 or T2 only had regional LN metastasis, whereas there was a high rate of distant LN metastasis, including the para-aortic LNs, in patients with T3 or higher-stage tumors. Para-aortic LN metastasis was significantly associated with arterial and perineural invasion (P = 0.006 and P < 0.001, respectively). Lymph node metastasis in the hepatic portal region was a strong predictor of para-aortic LN metastasis in pancreatic head cancer. Conclusions: Pancreatic cancer frequently metastasized to distant LNs via a complex pathway and developed into systemic disease. Aggressive multimodality therapy, including neoadjuvant therapy, is essential to improve the long-term survival of patients at substantial risk of distant LN metastasis.

Impact of operative blood loss on survival in invasive ductal adenocarcinoma of the pancreas.

Objectives: The aim of this study was to determine the prognostic factors and assess the impact of excessive operative blood loss (OBL) on survival after pancreatectomy for invasive ductal adenocarcinoma. Methods: From the retrospective analysis, 271 patients were eligible for evaluation. Overall survival was assessed to clarify the prognostic determinants, including patient characteristics, perioperative factors, and tumor characteristics. Results: The overall survival was significantly affected by the amount of OBL. The median survival times were 26.0, 15.3, and 8.7 months for OBL less than 1000, 1000 to 2000, and greater than 2000 mL, respectively (<1000 vs 1000-2000 mL, P = 0.019; 1000-2000 vs >2000 mL, P < 0.0001). Operative blood loss greater than 2000 mL remained an independent prognostic factor in multivariate analysis (P = 0.003; hazards ratio, 2.55). Operative blood loss of 2010 mL was found to be an appropriate cutoff level to predict early mortality within 6 months after resection (sensitivity, 0.660; specificity, 0.739). Male sex, year of resection, and plexus invasion were independently associated with OBL greater than 2000 mL. Conclusions: Excessive OBL was found to be a prognostic determinant of survival after surgery for pancreatic cancer. Operative blood loss can be used to stratify the risk for pancreatic cancer mortality. Successful curative resection with limited blood loss can contribute to improved survival.Abbreviations: OBL - operative blood loss, DGE - delayed gastric emptying, ROC - receiver operating characteristic, MST - median survival time, HR - hazards ratio

Invasion of the splenic artery is a crucial prognostic factor in carcinoma of the body and tail of the pancreas.

Objectives:A retrospective study was performed to determine the prognostic implications of invasion to the splenic vessels in pancreatic body and tail cancer. Summary Background Data:Involvement of the splenic artery (SA) and vein (SV) is frequently observed in carcinoma of the body and tail of the pancreas, but its correlation with various other clinicopathologic factors and prognosis has not been explored in detail. Methods:Fifty-one patients who had undergone distal pancreatectomy for invasive adenocarcinoma of the body and tail of the pancreas were discreetly selected from the prospective data base for analyses. Cases that required extended surgery due to invasion of the major vessels such as the portal vein, common hepatic artery, celiac artery, and superior mesenteric artery were excluded. Correlation between invasion of the splenic vessels and prognosis and other clinicopathologic factors were analyzed. Results:Seventeen patients with invasion of the SA had a significantly inferior prognosis compared with those without the invasion (P = 0.0067), whereas invasion of the SV, observed in 24 patients, did not affect prognosis. Additionally, invasion of the SA significantly correlated with tumor size ≧2 cm, anterior serosal infiltration, perineural invasion and SV invasion (P = 0.0440, P = 0.0406, P = 0.0460, and P = 0.0173, respectively). In univariate analysis, SA invasion, lymph node metastasis, and anterior serosal infiltration were identified as significant poor prognostic factors. In multivariable analysis, only SA invasion was an independent prognostic factor (odds ratio, 2.611, P = 0.0196). Conclusions:Our results indicated that the invasion of the SA, but not that of the SV, is a crucial prognostic factor in pancreatic body and tail cancer.

Classification of the celiac axis stenosis owing to median arcuate ligament compression, based on severity of the stenosis with subsequent proposals for management during pancreatoduodenectomy

BACKGROUND After pancreatoduodenectomy in patients with celiac axis stenosis or obstruction, it becomes problematic to maintain the upper abdominal organ blood flow, especially to the liver. The aim of this study was to investigate the celiac axis stenosis caused by median arcuate ligament (MAL) compression and to classify it according to preoperative image findings. METHODS From January 1989 to November 2010, 562 patients underwent operations for diseases of the pancreatic head region in our department. To diagnose celiac artery compression by the MAL, angiography was used in the early period and 3-dimensional image reconstruction of multidetector-row computed tomography was used from 2004. The morphologic characteristics of the celiac axis stenosis were analyzed during intraoperative treatment. RESULTS Twelve (2.1%) patients were diagnosed with MAL compression, and 8 of these patients only underwent MAL division to restore the celiac artery blood flow. One patient required conservation of the collateral circulation, and 2 patients needed arterial reconstruction. In the analysis of the level of origin of the celiac axis, there were no remarkable differences between nonstenotic and stenotic cases, or between mild and severe stenotic cases. Morphologic grades were defined based on the preoperative image findings and consequent intraoperative treatments. CONCLUSION Preoperative grading of celiac axis stenosis could make pancreatoduodenectomy safer with maintenance of the upper abdominal organ blood flow in patients with MAL compression.

Prognostic implications of lymph node metastases in carcinoma of the body and tail of the pancreas.

Objective: The current classification of pancreatic cancer is based only on anatomic location of metastatic lymph nodes (LNs). On the other hand, the number of metastatic LNs has been used in staging of colorectal, esophageal, and gastric cancers. The aim of this study was to assess the prognostic impact of the number or ratio of the metastatic LNs in pancreatic body and tail carcinoma. Methods: Eighty-five patients with pancreatic body and tail adenocarcinoma who underwent pancreatectomy were included. Location, number, ratio of metastatic LNs, and the survival of patients were analyzed. Results: Forty patients with LN metastasis had poor prognosis (P = 0.007). The prognoses of patients with 5 or more metastatic LNs were poorer than those with less than 5 metastatic LNs (P = 0.046), and patients with a metastatic LN ratio of 0.2 or more had the worst prognosis. Multivariate analysis revealed that 5 or more metastatic LNs and metastatic LN ratio of 0.2 or more were independent prognostic factors for survival (P = 0.0015 and P = 0.014, respectively). Conclusion: These results indicate that the number and the ratio of metastatic LNs can be used to predict poor patient survival and as a staging strategy.

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P=0.016). Angiogenesis was significantly higher in treatment group (P=0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P=0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

Comparison of pancreatic head resection with segmental duodenectomy and pylorus-preserving pancreatoduodenectomy for benign and low-grade malignant neoplasms of the pancreatic head.

Objective: The aim of this study was to investigate the clinical benefits of pancreatic head resection with segmental duodenectomy (PHRSD) with a particular emphasis on the long-term outcome. Methods: A retrospective analysis of PHRSD (77 patients) and pylorus-preserving pancreatoduodenectomy (PPPD; 55 patients) was performed for benign and low-grade malignant neoplasms of the pancreatic head. The zintraoperative and postoperative courses and long-term nutritional statuses were compared. Results: The mean operative time and blood loss were significantly less in the PHRSD group than in the PPPD group (351 vs 395 minutes, P = 0.005; and 474 vs 732 mL, P < 0.0001, respectively). Fewer overall postoperative complications occurred in the PHRSD group than in the PPPD group (33.8% vs 52.7%, respectively, P = 0.03). Postoperative weight loss and changes in the serum total protein and albumin levels were significantly milder in the PHRSD group than in the PPPD group (P = 0.04, P = 0.04, and P = 0.046, respectively). The overall recurrence-free survival rates in patients with noninvasive intraductal papillary mucinous neoplasms were equivalent in both groups. Conclusions: The present results suggest that PHRSD fulfills the operative safety, long-term nutritional status, and curative goals and could be the best option for patients with benign or low-grade malignant pancreatic lesions.