Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft.

Breast cancer is one of the most common and feared cancers faced by women. The prognosis of patients with advanced or recurrent breast cancer remains poor despite refinements in multimodality therapies involving chemotherapeutic and hormonal agents. Multimodal therapy with more specific and effective strategy is urgently needed. The oncolytic herpes simplex virus (HSV) has potential to become a new effective treatment option because of its broad host range and tumor selective viral distribution. Bevacizumab is a monoclonal antibody against VEGFA, which inhibits angiogenesis and therefore tumor growth. Our approach to enhance the antitumor effect of the oncolytic HSV is to combine oncolytic HSV HF10 and bevacizumab in the treatment of breast cancer. Our results showed that bevacizumab enhanced viral distribution as well as tumor hypoxia and expanded the population of apoptotic cells and therefore induced a synergistic antitumor effect. HF10 is expected to be a promising agent in combination with bevacizumab in the anticancer treatment.

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

OBJECTIVES: A 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.

Preservation of the pyloric ring has little value in surgery for pancreatic head cancer: a comparative study comparing three surgical procedures.

BACKGROUND: Pylorus-preserving pancreatoduodenectomy (PPPD) has replaced conventional pancreatoduodenectomy with a distal gastrectomy (cPD) as the most commonly performed procedure. However, there has been no evidence from prospective studies to indicate the overwhelming superiority of PPPD over cPD. A recent report revealed that resection of the pyloric ring reduced the incidence of delayed gastric emptying (DGE) in a randomized controlled trial. METHODS: In 158 patients with pancreatic head cancer, the perioperative outcomes and long-term nutritional consequences were retrospectively compared among three types of pancreatoduodenectomy: cPD; PPPD; and subtotal stomach-preserving pancreatoduodenectomy (SSPPD), in which the pyloric ring and duodenum were removed and more than 90% of the stomach was preserved. RESULTS: The incidence of DGE was significantly higher in the PPPD group than in the cPD and SSPPD groups (27.3 vs. 5.8 and 5.4%, respectively; P = 0.0012). The serum albumin concentration and total lymphocyte count at 1 year postoperatively were significantly higher in the SSPPD group than in the PPPD group (P = 0.0303 and P = 0.0203, respectively). The patients in the SSPPD group showed longer survival times than the patients in the cPD and PPPD groups (median survival times, 21.3, 17.1, and 17.7 months, respectively), although the differences did not reach statistical significance. CONCLUSIONS: Our results suggest that preservation of the pyloric ring without vagal innervation has little significance, and that SSPPD with better perioperative and long-term outcomes is more suitable as a standard procedure for patients with pancreatic head cancer.

Combination of the tumor angiogenesis inhibitor bevacizumab and intratumoral oncolytic herpes virus injections as a treatment strategy for human gastric cancers.

BACKGROUND/AIMS: Advanced gastric cancer is difficult to treat due to the frequency of liver metastases and peritoneal dissemination. A combination of two new strategies, including the anti-angiogenesis inhibitor bevacizumab and an oncolytic herpes virus is a promising treatment for advanced cancer. METHODOLOGY: The effects of bevacizumab on oncolytic herpes virus replication and viral cytotoxicity were examined at varying bevacizumab concentrations and viral titers. In addition, the ability of these two new promising anticancer agents to inhibit tumor growth was studied. Histological examinations of CD31 and LacZ were used to assess angiogenesis and virus distribution within the tumor, respectively. RESULTS: Bevacizumab did not affect viral replication or viral cytotoxicity in vitro. The combination of bevacizumab and the oncolytic herpes virus hrR3 significantly reduced tumor growth in vivo in an experimental gastric cancer model. Bevacizumab inhibited angiogenesis caused by local injection of hrR3 and induced virus spread. Bevacizumab increased the distribution of the intratumorally injected oncolytic herpes virus within the tumor. CONCLUSIONS: Combination therapy consisting of bevacizumab and an oncolytic herpes virus is a promising new treatment strategy for gastric cancer.

Recurrence pattern and prognosis of pancreatic cancer after pancreatic fistula.

BACKGROUND: The negative impact of anastomotic leakage on cancer-specific survival and recurrence patterns has been recognized in colorectal cancer. In pancreatic cancer, pancreatic fistula (PF) is a serious morbidity, but its negative effect on long-term outcome remains to be elucidated. The aim of this study was to determine the impact of PF on pancreatic cancer recurrence. METHODS: The medical records of 184 patients with curative pancreatectomy for pancreatic cancer were reviewed. PF was scored on the basis of the International Study Group of Pancreatic Fistula classification. Overall and disease-free survivals and recurrence patterns were analyzed. Grade A PF was excluded because the negative effects can be negligible. RESULTS: PF occurred in 51 of the 184 patients (27.7%). The mortality related to PF was 0.5% (1 of 184). PF was an independent risk factor for peritoneal recurrence (hazard ratio 3.974; 95% confidence interval 1.345-11.737; P = 0.013). According to the analysis of disease-free survival in patients with peritoneal recurrence, time to recurrence was shorter and the survival rate was worse in patients with PF than in those without PF (5.6 vs. 8.2 months; 6-month survival, 40 vs. 71%; 1-year survival, 7 vs. 19%; P = 0.053). PF was an independent prognostic factor after multivariate analysis (hazard ratio 3.257; 95% confidence interval 1.201-8.828; P = 0.020). CONCLUSIONS: PF was statistically significantly related to peritoneal recurrence, and patients with PF developed peritoneal recurrence earlier than those without PF. With regard to the development of peritoneal recurrence, PF may be considered to be a negative prognostic factor.

Prognostic implications of intraoperative radiotherapy for unresectable pancreatic cancer.

BACKGROUND/AIMS: To assess the prognostic effect of intraoperative radiotherapy (IORT) in unresectable pancreatic cancer. METHODS: We reviewed 198 patients with unresectable pancreatic cancer, which was found during experimental laparotomy. Liver metastasis was observed in 70 patients, peritoneal metastasis in 44, liver and peritoneal metastasis in 23 and locally advanced tumor in 61. Treatment consisted of IORT with or without postoperative chemotherapy. Overall survival (OS) and prognostic factors were evaluated for each pattern of disease spread. RESULTS: IORT was performed in 120 patients, and chemotherapy was administered in 80. Sixty patients did not receive either treatment. OS in the untreated group was significantly inferior to that for IORT alone and IORT plus gemcitabine (GEM)-based chemotherapy. IORT and GEM-based chemotherapy were identified as independent prognostic factors [hazard ratio (HR) = 0.51, p < 0.001; HR = 0.43, p < 0.001]. IORT was an independent prognostic determinant for patients with peritoneal metastasis (HR = 0.24, p = 0.011) but not for those with liver metastasis (HR = 0.78, p = 0.381). CONCLUSION: IORT followed by GEM-based chemotherapy is the recommended treatment strategy in unresectable pancreatic cancer. and IAP.

Oncolytic herpes virus induces effective anti-cancer immunity against murine colon cancer.

UNLABELLED: BACK GROUND/AIMS: Oncolytic virus therapy is becoming a promising anti-cancer therapy and oncolytic viruses have been shown to elicit anti-cancer immunity. We evaluated the anti-tumor immune responses elicited by the herpes oncolytic virus R3616 compared to a representative chemotherapy drug, 5-FU. METHODOLOGY: R3616 or 5-FU was directly injected into subcutaneous tumors of non-immunized mice. Additionally, complete adjuvant, R3616-infected MC26 cells or 5-FU plus MC26 cells were frozen, thawed and used to immunize mice. After 21 days of immunization, the adaptive immune response suppressed implanted tumor growth and prolonged survival rate. We monitored differences in the number of infiltrating CD8- and CD4-positive lymphocytes in implanted tumors by immunofluorescence. RESULTS: R3616 induced a statistically greater number of infiltrating T cells (Thy1.2), macrophages (CD68) and dendritic cells (CD83) in injected tumors than 5-FU. The group immunized with R3616-infected MC26 cells had greater tumor suppression and longer survival rate than non-immunized mice and mice treated with 5-FU plus MC26 cells with statistically significant differences between these groups. The mice immunized with R3616-infected MC26 cells had a statistically greater number of infiltrating T cells in the implanted tumor than non-immunized and mice treated with 5-FU plus MC26 cells. CONCLUSIONS: These results indicate that oncolytic herpes virus R3616 can elicit more effective host anti-tumor immune responses than 5-FU against murine colon cancer model.

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 > or = 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.

Clinicopathologic assessment of pancreatic ductal carcinoma located at the head of the pancreas, in relation to embryonic development.

OBJECTIVES: Pancreaticoduodenectomy is performed for pancreatic head cancer that originated from the dorsal or ventral primordium. Although the extent of lymph node (LN) dissection is the same irrespective of the origin, the lymphatic continuities may differ between the 2 primordia. METHODS: Between March 2003 and September 2010, 152 patients underwent pancreaticoduodenectomy for pancreatic cancer. One hundred six patients were assigned into 2 groups according to tumor location on preoperative computed tomography, and their clinical and pathological features were retrospectively analyzed in view of the embryonic development of the pancreas. RESULTS: Sixty of 106 patients were classified with tumors that were derived from the dorsal pancreas (D group) and 46 from the ventral pancreas (V group). The frequency of LN involvement around the middle colic artery (LN 15) in the D group was higher than in the V group (P = 0.008). The rate of additional resection of the pancreas tended to be higher in the D group (P = 0.067). CONCLUSIONS: The present study showed the detailed pattern of spread of pancreatic ductal carcinoma to the LNs and provided important information for determining the optimal surgical strategy.

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.

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.

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.

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.

High therapeutic potential for systemic delivery of a liposome-conjugated herpes simplex virus.

PURPOSE: Oncolytic viral therapy is a newly developed modality to treat tumors. Many clinical trials worldwide have examined the efficacy of locally injected oncolytic viruses. However, systemic intravascular injections are limited by the humoral immune response, which dramatically decreases the level of infection. To overcome this limitation, we encapsulated the oncolytic virus in liposomes. METHODS: The infectious properties of the herpes simplex virus type 1 (HSV-1) mutant, hrR3, with or without liposomes in the presence of neutralizing antibodies were evaluated using replication and cytotoxicity assays in vitro. To evaluate the efficacy of intravascular virus therapy with liposomes in the presence of neutralizing antibodies, immunized mice bearing multiple liver metastases were intraportally or peritoneally administered hrR3 or hrR3 complexed with liposomes. RESULTS: Anti-HSV antibodies attenuated the infectiousness and cytotoxicity of hrR3, whereas hrR3/liposome complexes were not attenuated by these anti-HSV antibodies. Although the survival rate of non-immunized mice treated with hrR3 alone was similar to that of mice treated with the hrR3/liposome complexes, the survival rates of immunized mice treated with hrR3 alone were significantly reduced compared to mice treated with the hrR3/liposome complexes. CONCLUSIONS: This systemic intravascular delivery of hrR3/liposome complexes in the presence of pre-existing neutralizing antibodies is effective to treat multiple liver metastases.

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.