Tevfik Tolga Sahin

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.

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.

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.

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.

Neopterin, Catalase and Superoxide Dismutase in Females with Benign and Malignant Breast Tumors

Abstract The aim of the present study was to evaluate the relationship between the levels of neopterin among patients with benign and malignant breast disease and the relation with the stage of the malignant process. In this study, neopterin concentrations and enzyme activities of superoxide dismutase (SOD) and catalase (CAT) were determined in malign (n=30) and benign breast tumor patients (n=30) by high performance liquid chromatographic and spectrophotometric methods, respectively. Results were compared with a healthy control group (n=20). The correlations between neopterin, CAT and SOD were also evaluated in controls and patients. Urinary neopterin level of the control group was (mean value ± S.D.) 128.6 ± 64.6 μmol/mol creatinine. Neopterin concentrations in patients with breast malignancy were 153.6 ± 71.2 μmol/mol creatinine and 107.8 ± 32.1 μmol/mol creatinine in benign disorders patients. The mean neopterin level in the benign group was found to be statistically different from the malign tumor group (p = 0.039). SOD and CAT activities in controls were found as 3.57 ± 0.84 U/mg protein and 2.19 ± 0.20 U/mg protein, respectively. In patients with malignancy, the SOD activity was 3.84 ± 0.73 U/mg protein while CAT activity was 1.03 ± 0.13 U/mg protein. Patients with benign breast disorders, SOD activity was 4.09 ± 1.00 U/mg protein and CAT activity was 1.02 ± 0.18 U/mg protein. Whereas SOD activity did not differ between the groups of patients and controls, the mean catalase level in the control group was higher than in the benign and malign tumor groups (both p <0.001). Urinary neopterin concentration seems to be an important and useful biomarker in diagnosis of breast tumors in clinical practice.

Immune system modulation in patients with malignant and benign breast disorders: tryptophan degradation and serum neopterin

Tryptophan degradation metabolites are known to suppress T-cell function, which is a mechanism of resistance of tumor cells against immune surveillance. The aim of this study was to evaluate tryptophan degradation along with serum neopterin levels in benign and malignant breast disease. Serum tryptophan and kynurenine levels and neopterin concentrations of 30 patients with malignant and 27 patients with benign breast disease were determined by HPLC and ELISA, respectively. The slight increase in tryptophan degradation in a subgroup of cancer patients with higher grade tumors was not statistically significant, but the increased degradation was correlated with higher neopterin concentrations. Neopterin levels in patients with malignant breast disease were significantly higher than in the benign group (p<0.05). Tryptophan degradation positively correlates with the aggressiveness of the tumor because it changes with tumor grade rather than disease stage.