Naoyoshi Terakawa

Immunological evaluation of personalized peptide vaccination with gemcitabine for pancreatic cancer

The aim of the present study was to investigate the safety and immune responses of personalized peptide vaccination when administered with gemcitabine (GEM) in advanced pancreatic cancer (APC) patients. Thirteen patients with APC were enrolled. Pre‐vaccination with peripheral blood mononuclear cells and plasma was carried out to examine cellular and humoral responses to 25 or 23 peptides in human leukocyte antigen A24++ or A2+++ patients, respectively. Only the reactive peptides (maximum of four) were then administered weekly at three different dose settings: 1, 2 and 3 mg of peptide. GEM was administered at 1000 mg/m2 per week for 3 weeks, followed by 1 week of rest. The combination therapy was well tolerated. Grade 3 toxicities were: anemia (three patients), neutropenia (two patients) and thrombocytopenia (two patients). Of these 13 patients, 11 (85%) showed clinical responses, such as reduction in tumor size and/or level of tumor markers. Augmentation of peptide‐specific cytotoxic T lymphocyte activity against pancreatic cancer cells was observed at each dose level, whereas the increment of peptide‐specific IgG antibodies was dependent on peptide dose. GEM did not inhibit the immune responses induced by personalized peptide vaccinations, and this new type of immunochemotherapy combination is recommended for further clinical study in APC patients. (Cancer Sci 2007; 98: 605–611)

Neoadjuvant chemoradiation in patients with potentially resectable pancreatic cancer.

Objectives: To retrospectively evaluate the efficacy and tolerability of 5-fluorouracil and low-dose cisplatin (FP)-based preoperative concurrent chemoradiotherapy (PCRT) and gemcitabine (GEM)-based PCRT in patients with potentially resectable pancreatic cancer. Methods: Between December 2000 and December 2004, 32 patients with potentially resectable pancreatic cancer were treated with PCRT. All patients received external beam radiotherapy (total dose of 40 Gy) for 4 weeks. Concurrently, chemotherapy was performed intravenously with continuous 5-fluorouracil 200 mg/m2/d and intermittent cisplatin bolus 3 to 6 mg/m2/d for 4 weeks (Arm FP-PCRT, n = 14) or weekly GEM 400 mg/m2 for 3 weeks (Arm GEM-PCRT, n = 18). The patients were restaged 3 to 4 weeks after the end of PCRT and explored for resection in cases without distant metastases. Results: The 3-year survival rates and median survival were 29.4% and 20.5 months for the resected patients (n = 24) and 0% and 5.5 months for unresected patients (n = 8), respectively (P < 0.0001). The 1-, 2-, 3-year survival rates and median survival were 87.5%, 62.5%, 33.3%, and 26 months for the resected patients treated with FP-PCRT and 75%, 40%, 26.7%, and 19.9 months for the resected patients treated with GEM-PCRT (respectively; P = not significant). Most of the toxicities of both regimens were slight and were in grade1 to 2. Grade 1 to 3 leukopenia (43% vs 100%) and thrombocytopenia (0% vs 39%) were significantly different between the FP-PCRT and GEM-PCRT patients. Conclusions: The PCRT regimens in this article enabled selection of 24 of 32 patients for surgery and resulted in encouraging survival results and acceptable toxicities.

Immunological effect of active hexose correlated compound (AHCC) in healthy volunteers: a double-blind, placebo-controlled trial.

The aim of this study was to evaluate the effects of active hexose correlated compound (AHCC) intake on immune responses by investigating the number and function of circulating dendritic cells (DCs) in healthy volunteers. Twenty-one healthy volunteers were randomized to receive placebo or AHCC at 3.0 g/day for 4 wk. The number of circulating cluster of differentiation (CD)11c+ DCs (DC1) and CD11c− DCs (DC2) were measured. Allogeneic mixed-leukocyte reaction (MLR) was performed. Natural killer (NK) cell activity and the proliferative response of T lymphocytes toward mitogen (phytohemagglutinin [PHA]) were measured. We also measured cytokine production stimulated by lipopolysaccharide [interleukin (IL)-2, IL-4, IL-6, IL-10, interferon gamma-γ, tumor necrosis factor-α). The AHCC group (n = 10) after AHCC intake had a significantly higher number of total DCs compared to that at baseline and values from control subjects (n = 11). The number of DC1s in the AHCC group after intake was significantly higher than at baseline. DC2s in the AHCC group were significantly increased in comparison with controls. The MLR in the AHCC group was significantly increased compared to controls. No significant differences in PHA, NK cell activity, and cytokine production were found between groups. AHCC intake resulted in the increased number of DCs and function of DC1s, which have a role in specific immunity.

Less morbidity after pancreaticoduodenectomy of patients with pancreatic cancer.

Objectives: The pancreaticoduodenectomy with extended resection has been frequently performed in patients with pancreatic cancer in Japan. One result of this additional surgical stress may be that postoperative complications in patients with pancreatic cancer are more frequent than in patients with periampullary cancer. Methods: The 198 patients with pancreatic and periampullary cancer underwent pancreaticoduodenectomy. The operative mortality and morbidity between patients with pancreatic and periampullary cancer were compared, and the risk factors of postoperative complications and in-hospital death were determined. Results: Patients with pancreatic and periampullary cancer made up 52% and 48% of total patients. The duration of surgery and volume of intraoperative blood loss were significantly higher in patients with pancreatic cancer than in patients with periampullary cancer. Additional organ resections were frequently performed in patients with pancreatic cancer. However, significantly lower morbidity rates were observed in patients with pancreatic cancer. Among all complications evaluated, pancreatic fistula and abdominal abscess were found less frequently in patients with pancreatic cancer. Logistic regression analyses showed a positive correlation between periampullary cancer and an increased risk of complications, pancreatic fistula, and abdominal abscess. The in-hospital mortality rate has significantly reduced since 2000. When pancreatic fistula was clinically diagnosed, we immediately started a closed lavage using continuous administration of natural saline at 1000 to 4000 mL/d, after exchange of a nasogastric tube drain. Conclusion: Pancreaticoduodenectomy for patients with pancreatic cancer can be a safe procedure in spite of surgical stress. Further surgical strategies will be needed to reduce postoperative complications, especially in patients with periampullary cancer.

Circulating Myeloid Dendritic Cells as Prognostic Factors in Patients with Pancreatic Cancer Who Have Undergone Surgical Resection

OBJECTIVE Pancreatic cancer is a malignant neoplasm with poor prognosis that might be associated with defective immune function. We aimed to determine the influence on survival of circulating myeloid dendritic cells (c-m-DCs), circulating lymphoid DCs (c-l-DCs), and DCs within the tumor tissue in patients with pancreatic cancer. PATIENTS AND METHODS Between December 2001 and June 2006, of a total of 110 patients with ductal adenocarcinoma of the pancreas, 42 underwent pancreatectomy, and 68 had unresectable disease. Numbers of c-m-DCs and c-l-DCs were assessed by flow cytometry, and DCs in the tumor tissue by immunohistochemical staining with anti-fascin mAb. RESULTS The percentage of the c-m-DCs subset in pancreatic cancer patients was significantly lower than in healthy volunteers, and the similar finding was observed between patients who underwent surgical resection and non-resection. Patients with a high percentage of c-m-DCs or with many DCs accumulated in the cancer tissue survived longer than patients with a low percentage or low number in peripheral blood or the tumor, respectively. Moreover, there was a positive correlation between c-m-DCs within peripheral blood mononuclear cells and the number of DCs per field in the cancer tissue. CONCLUSIONS Preoperative c-m-DCs levels in the PBMC of patients with pancreatic cancer and DCs counts in the cancer tissue can be a prognostic factor after surgical resection. Modulating the distribution of DCs may be an effective therapy in pancreatic cancer patients with a dismal prognosis.

Clinical monitoring of innate cellular immunity of monocytes/macrophages by tumor necrosis factor alpha productivity in whole blood stimulated by lipopolysaccharide in patients with pancreatic cancer.

Objective: The aim of this study was to evaluate the tumor necrosis factor alpha (TNF-&agr;) releasing capacity in whole blood stimulated by lipopolysaccharide (LPS) in patients with pancreatic cancer during the perioperative period, and before and after chemotherapy. Methods: The current study involved a total of 39 patients with pancreatic cancer (PC), who were further divided into a PC-Op group (n = 16, underwent pancreatectomy) and a PC-chemo group (n = 23, received chemotherapy). The control groups consisted of patients with hepatocellular carcinoma (n = 27, HCC group) and with benign diseases (n = 15, control group). Serial changes in TNF-&agr; in whole blood stimulated by LPS were compared in various clinical settings. Results: Preoperative TNF-&agr; levels in the PC-Op group were significantly lower than those in the HCC and control groups (P = 0.034). The TNF-&agr; variable surgical index (s-index) was defined as the ratio of the preoperative TNF-&agr; level to postoperative level in the PC-Op and HCC groups. Although the TNF-&agr; s-index in the PC-Op group was significantly decreased on postoperative day 1 and recovered on postoperative day 3 (P < 0.002), there were no significant changes in the TNF-&agr; s-index in the HCC group. The TNF-&agr; variable chemotherapeutic index (c-index) was defined as the ratio of the TNF-&agr; level before to that after chemotherapy in the PC-chemo group. The TNF-&agr; c-index in all 7 patients was reduced to less than 0.3 until leukopenia appeared. Patients who had an increase in TNF-&agr; production (TNF-&agr; c-index >1.0) on day 3 or 7 after chemotherapy had significantly better cumulative survival than those with no increase (P < 0.033). Conclusions: TNF-&agr; production stimulated by LPS in the whole blood of patients with pancreatic cancer was low. Surgical stress and depressed immunocompetence might induce such profound decreases. A method of assessing the capability of leukocytes, particularly macrophages, to produce TNF-&agr; could be useful for prognostis and for monitoring immunocompetence in patients with pancreatic cancer who have undergone chemotherapy.