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.

Comparison of inflammation-based prognostic scores as predictors of tumor recurrence in patients with hepatocellular carcinoma after curative resection.

BACKGROUND: Various inflammation-based prognostic scores, including the Glasgow prognostic score (GPS), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI), have been associated with survival in patients with several types of cancer. This study compared the ability of these scores to predict recurrence-free survival (RFS) in patients with hepatocellular carcinoma (HCC) after curative hepatectomy. METHODS: Data were collected prospectively from 113 patients who underwent curative resection for HCC from January 2003 to December 2012. Clinicopathological variables including preoperative inflammation-based prognostic scores were analyzed. Univariate and multivariate analyses were performed to identify factors predictive of RFS. RESULTS: Univariate analysis showed that NLR (P < 0.0001) and PI (P = 0.0194) were significantly associated with RFS. Multivariate analysis showed that NLR (hazard ratio [HR]; 2.58, P = 0.0020), tumor differentiation (HR; 9.55, P < 0.0001), serosal invasion (HR; 2.24, P = 0.0112), and vascular invasion (HR; 2.18, P = 0.0106) were independently correlated with RFS. CONCLUSIONS: Preoperative NLR is an independent predictor of RFS in patients with HCC after curative hepatectomy, and is superior to the other inflammation-based prognostic scores.

Preservation of the pyloric ring confers little benefit in patients undergoing total pancreatectomy.

BACKGROUND: The clinical significance of preservation of the pyloric ring in total pancreatectomy (TP) has not been elucidated. METHODS: A total of 48 consecutive patients underwent TP and were categorized into two groups based on the absence or presence of pylorus resection: the TP (N = 33) and pylorus-preserving TP (PPTP) (N = 15) groups. Preoperative patient background, intraoperative conditions, postoperative complications, and long-term nutritional status were retrospectively compared between the two groups. RESULTS: Patient background was similar between the groups, with the exception of the prevalence of preoperative diabetes mellitus (55 and 20 %, respectively; p = 0.021). There were no differences between groups with respect to operative times, blood loss, or blood transfusion. The PPTP group was more likely to have postoperative delayed gastric emptying than was the TP group (53 and 21 %, respectively; p = 0.029), and it tended to become increasingly severe. The length of the postoperative fasting period was significantly longer in the PPTP group than in the TP group (mean 15 ± standard deviation [SD] 10.8 and 9 ± 9.7 days, respectively; p = 0.023). The body weights in the TP group started to recover by 1 year postoperatively, whereas those in the PPTP group continued to decrease. Serum hemoglobin levels tended to be higher in the TP group than in the PPTP group at 1 year postoperatively. CONCLUSIONS: Preservation of the pyloric ring provided little or no benefit to short-term outcome or long-term nutritional status among patients who underwent TP.

Combination treatment of human pancreatic cancer xenograft models with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib and oncolytic herpes simplex virus HF10.

BACKGROUND: There is the potential to use replication-competent oncolytic viruses to treat cancer. We evaluated the efficacy of HF10, a herpes simplex virus type 1 (HSV-1) mutant, in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in human pancreatic cancer xenograft models. METHODS: The viability of human pancreatic cancer cell lines (BxPC-3 and PANC-1) treated with HF10 and erlotinib, on their own or in combination, was determined. Effects of erlotinib on HF10 entry into tumor cells were also investigated. BxPC-3 subcutaneous tumor-bearing mice were treated with HF10 and erlotinib, on their own or in combination, with effects on tumor volume determined. Immunohistochemical examination of HSV-1 and CD31 was conducted to assess virus distribution and angiogenesis within tumors. A peritoneally disseminated BxPC-3 xenograft model was evaluated for survival. RESULTS: HF10 combined with erlotinib demonstrated the highest cytotoxicity against BxPC-3. A combination effect was not observed in PANC-1 cells, and erlotinib did not affect virus entry into tumor cells. In the peritoneally disseminated model, HF10 combined with erlotinib had no beneficial effect on survival. In the subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth to a greater extent than using each agent on its own. Immunohistochemistry revealed that virus distribution within the tumor persisted in the combination therapy group. CONCLUSIONS: Combination therapy with HF10 and erlotinib warrants further investigation to establish a new treatment strategy against human pancreatic cancers.

Phase I Dose-escalation Clinical Trial of HF10 Oncolytic Herpes Virus in 17 Japanese Patients with Advanced Cancer.

Oncolytic virus therapy is a promising new therapeutic method, one of an eagerly anticipated class of biological therapies against cancer. There are many different classes of oncolytic virus. One of these, herpes oncolytic virus, is strongly oncolytic and has a large DNA genome as 150k bp. HF10 is a spontaneous mutant of herpes simplex virus -1 (HSV-1) that replicates within tumors and destroys cancers without damaging normal tissue and organs. Clinical trials of HF10 are underway in Japan and the United States. The first pilot study of HF10 was initiated in Japan in 2003. This study examined the safety and efficacy of HF10 in the treatment of breast cancer and head and neck cancers; the trial also included careful dose escalation studies. In 2005, a clinical trial using HF10 to treat pancreatic cancer was initiated. screened In this Japanese study, 17 patients received HF10 in their tumor sites. A clinical trial in the United States is also ongoing to evaluate safety, tolerability and evidence of antitumor activity in patients with refractory superficial solid tumors. Here, we report the evaluation of the 17 patients treated in Japan. Among the patients, 6 had recurrent breast cancer, 3 had recurrent head and neck cancer, and 8 had non-resectable pancreatic cancer. No severe adverse side effects have been observed, and some therapeutic potential has been reported based on pathological findings, tumor markers, and diagnostic radiography. Those results should encourage further clinical trials of HF10 around the world.

Clinicopathologic study of intrapancreatic cancer spread in carcinoma of the body and tail of the pancreas.

OBJECTIVE: The aims of this study were to clarify the type of intrapancreatic spread of cancer of the pancreatic body and tail and to assess whether a 2-cm transection margin is adequate to ensure negative margins. METHODS: We selected 66 patients who underwent distal pancreatectomy for cancer of the pancreatic body and tail. We investigated intrapancreatic cancer spread in these patients histopathologically and analyzed the relationship between 2-cm-margin positivity and other clinicopathological characteristics. RESULTS: Two-centimeter-margin positivity was observed in 17 cases. In these, tumors had a tendency to spread toward the pancreatic head along the main pancreatic duct. As a result of statistical analysis, we considered venous invasion (odds ratio [OR], 15.48; 95% confidence interval [CI], 1.61-148.94; P = 0.0177), 2-cm-margin fibrosis (OR, 173.88; 95% CI, 8.96-3375.03; P = 0.0007), and 2-cm-margin hardness (OR, 5.97; 95% CI, 1.07-33.46; P = 0.0420) as being independently related to 2-cm-margin positivity. CONCLUSIONS: The results suggest that 2 cm is not a safe length to ensure a negative margin. In the future, preoperative and intraoperative evaluation of the degree of fibrosis of pancreatic parenchyma could lead to cancer-free pancreatic cut-end margins.

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.

Primary malignant melanoma of the stomach: report of a case.

We report a case of primary malignant melanoma (MM) of the stomach. The patient, a 73-year-old man, was referred to our hospital for investigation of an elevated lesion in the stomach, detected by gastroscopy. On admission, physical examinations and laboratory data were unremarkable. Gastroscopy revealed a pigmented, elevated tumor, approximately 2 cm in diameter, in the posterior wall of the stomach. A biopsy was taken, which resulted in a diagnosis of MM, based on the presence of melanin in tumor cells. F-18 fluorodeoxyglucose positron emission tomography showed no accumulation of tracer except for the tumor in the stomach, indicating that it was a primary MM of the stomach. The patient underwent distal gastrectomy, but died of recurrence 1 year later. Very few cases of primary MM of the stomach have been reported. Thus, we report this case, followed by a review of the literature.

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.

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.

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.

[Analysis of hypertension in advanced, recurrent colorectal cancer patients treated with first-line bevacizumab].

PURPOSE: The aim of this study was to retrospectively assess if arterial hypertension induced during treatment with bevacizumab was associated with the clinical outcome in advanced, recurrent colorectal cancer patients treated with first-line bevacizumab. SUBJECTS: 13 patients( 7 men and 6 women) with advanced, recurrent colorectal cancer were treated by mFOLFOX6 regimen with first-line bevacizumab from August 2008 to July 2009. The median age was 64. 4 years (51 to 79 years old) with 10 and 3 patients having a PS score of 0 and 1. All patients received bevacizumab at a dose of 5 mg/kg every 2 weeks in association with oxaliplatin, 5-fluorouracil and folinic acid according to the mFOLFOX6 regimen. RESULTS: 9 patients (69. 0%) had hypertension, while 5 patients developed grades 2-3 hypertension on bevacizumab. Patients with hypertension tended to have a better response rate and disease control rate than patients without hypertension. CONCLUSION: Bevacizumab-induced hypertension may represent a prognostic factor for clinical outcome in advanced, recurrent colorectal cancer patients treated with first-line bevacizumab.

[A phase I study of TS-1 and weekly cisplatin in patients with advanced gastric cancer].

This is a phase I study to determine the maximum tolerated dose (MTD) and toxicity of a combination of TS-1 and weekly cisplatin (CDDP) in advanced gastric cancer patients. TS-1 was administered orally twice daily after meals, at a standard dose of 80 mg/m2. One course consisted of 21 days' consecutive administration followed by 14 days' rest. Cisplatin (CDDP) was injected intravenously on days 8, 15 and 22 using the following dose levels: dose level 1 20 mg/m2, dose level 2 25 mg/m2, and dose level 3 30 mg/m2. Twelve patients were entered in this trial. One of the 6 patients at dose level 3 had neutropenia NCI-CTC grade 3, while another patient at dose level 3 suffered from DLT (liver function grade 3. The maximal tolerable dose (MTD) was not reached using dose level 3. Partial responses were seen in 5 (62.5%) of 8 patients with evaluable lesions. At level 2 (25 mg/m2), the response rate was 100%. We recommended dose level 2 for phase II trials from the standpoint of toxicity and response rate.

[A case of recurrent advanced gastric cancer with lung metastasis effectively treated by combined chemotherapy of TS-1 and weekly CDDP].

We report a case of a patient with recurrent gastric cancer and lung metastasis, who responded remarkably to combination chemotherapy using TS-1 and weekly CDDP. The patient was administered 2 courses of TS-1 (80 mg/m2/day, on day 1-21) and CDDP (25 mg/m2/day, on day 8, 15, 22) every 5 weeks. The regimen was done on an outpatient basis. The treatment resulted in the metastatic tumors in the lung disappearing after 1 course. No severe side effects were observed. This combination therapy proved useful for treating lung metastasis from gastric cancer in this patient.