Tomohisa Yamamoto

Circulating CD4+CD25+ regulatory T cells in patients with pancreatic cancer.

Objectives Regulatory T cells (Treg) can inhibit immune responses mediated by T cells. The aim of this study was to evaluate the prevalence of Treg in peripheral blood mononuclear cells from patients with pancreatic cancers in relation to their clinical outcomes. Methods Among a total of 100 patients with ductal adenocarcinoma of the pancreas, 40 underwent pancreatectomy and 60 had unresectable disease. Their peripheral blood mononuclear cells were evaluated to determine the proportion of CD4+CD25+ (FoxP3+) T cells, as a percentage of the total CD4+ cells, by flow cytometric analysis. Results The percentage of Treg in the patients with pancreatic cancer was significantly lower than that in the healthy volunteers (P = 0.048), and the patients who underwent surgical resection had lower Treg levels than those with unresectable disease (P = 0.040). Patients in the resected group with a higher percentage of Treg survived longer (P = 0.021). Treg in patients who remained disease free at postoperative 12 months significantly decreased compared to that of the postoperative period (P = 0.009). Conclusion A relative increase in Treg may be related to immunosuppression and tumor progression in patients with pancreatic cancer. The immunological monitoring of Treg may be useful to predict the prognosis for patients with pancreatic cancer.

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.

Selective use of staging laparoscopy based on carbohydrate antigen 19-9 level and tumor size in patients with radiographically defined potentially or borderline resectable pancreatic cancer.

Objective: The aims of this study were to verify whether the selective use of staging laparoscopy can prevent unnecessary laparotomy and to find a surrogate marker for surgical unresectability in patients with potentially or borderline resectable pancreatic cancer. Methods: Group A consisted of consecutive 33 patients evaluated between 2005 and 2006 and who directly underwent open laparotomy for planned surgical resection. Group B consisted of consecutive 61 patients evaluated between 2007 and 2009 and of whom 16 patients (26%) had a staging laparoscopy due to the presence of high-risk markers of unresectability defined as carbohydrate antigen 19-9 level 150 U/mL or greater and tumor size 30 mm or greater. Results: The frequency of unnecessary laparotomies for occult distant organ metastasis was significantly different between groups A and B (18% and 3%, respectively; P = 0.021). Of 16 patients who underwent staging laparoscopy in group B, 5 patients (31%) had occult metastases. The multivariate analysis showed that the presence of high-risk markers and extrapancreatic plexus invasion on multidetector-row computed tomography were significant independent risk factors for unresectability. Conclusions: The presence of high-risk markers was associated with surgical unresectability in patients with potentially or borderline resectable pancreatic cancer. The selective use of staging laparoscopy decreased the frequency of unnecessary laparotomy by detecting minute metastases.

A new guideline to reduce postoperative morbidity after pancreaticoduodenectomy.

Objectives: Pancreaticoduodenectomy (PD) is still associated with high morbidity. To reduce the frequency of postoperative complications, we have made revisions in perioperative managements of pancreaticoduodenectomy. Methods: Subjects were 128 consecutive patients who underwent PD between January 2000 and August 2006. In June 2004, the following new departmental guidelines were introduced: (1) modified Kakita method of pancreaticojejunostomy, (2) omental wrapping, (3) early removal of closed-suction drain, and (4) restrictive use of pancreatic and biliary duct stenting. Operative mortality and morbidity between 77 patients managed conventionally (group A) and 51 patients since 2004 (group B) were compared. Risk factors for postoperative complications were determined. Results: Postoperative morbidity in group B (39%) was significantly lower than in group A (64%; P = 0.019). Occurrence of grade B/C pancreatic fistula (PF) in group B (6%) was significantly lower than in group A (19%; P = 0.0376). Delayed gastric emptying was significantly reduced in group B relative to group A (23% vs 6%; P = 0.0133). Logistic regression analyses showed that the modified Kakita method was a negative independent factor for overall complications, PF, and delayed gastric emptying. Conclusions: The incidence of overall postoperative complications, grade B/C PF, and delayed gastric emptying after PD has been reduced because of the introduction of a new guideline.

Neo-adjuvant Chemoradiation Therapy Using S-1 Followed by Surgical Resection in Patients with Pancreatic Cancer

ObjectiveThe aim of this study was to compare short-term surgical results in pancreatic cancer patients who underwent surgical resection after neo-adjuvant chemoradiation therapy (NACRT) using S-1.MethodsThe study population comprised 77 patients with pancreatic cancer between 2006 and 2010. Out of 34 patients who underwent staging laparoscopy between 2008 and 2010, 31 patients without occult distant organ metastasis underwent chemoradiation and of whom 30 underwent pancreatectomy (NACRT group). Of the other 43 patients, 36 underwent surgical resection in 2006–2008, followed by adjuvant therapy (adjuvant group). The primary endpoint was frequency of pathological curative resection (R0).ResultsThe new regimen of NACRT was feasible and safe. Twenty-eight of 30 (93%) patients in the NACRT group had R0 resection, which was significantly higher than in the adjuvant group (21 of 36 patients, 58%, p = 0.005). The number and extent of metastatic lymph nodes in the NACRT group (1 (0–25), N0/1; 18 of 38) was significantly lower than in the adjuvant group (2 (0–19), N0/1; 23 of 30), p = 0.0363). The frequency of intractable ascites in the NACRT group (eight of 30) was significantly higher than in the adjuvant group (two of 36, p = 0.035).ConclusionNeo-adjuvant chemoradiation therapy using S-1 followed by pancreatectomy can improve the rate of pathologically curative resection and reduces the number and extent of lymph node metastasis.

Is a nonstented duct-to-mucosa anastomosis using the modified Kakita method a safe procedure?

Objectives: After standardization of the perioperative management of pancreaticoduodenectomy, we retrospectively compared results in nonstented pancreaticojejunostomy with external-stented pancreaticojejunostomy. Methods: The study population included 129 consecutive patients who underwent pancreaticoduodenectomy between 2004 and 2008. The postoperative mortality and morbidity were compared between 51 patients with restrictive use of external stenting (group A) and 78 patients without external stenting (group B). The patient with a pancreatic duct of less than 3 mm in diameter was 31% in group A and 46% in group B. Results: There were no differences in postoperative morbidity and mortality between the 2 groups. Although the frequency of overall postoperative pancreatic fistula development was significantly higher in group B than in group A (44% vs 27%, P = 0.0004), there was no difference in grade B/C postoperative pancreatic fistula rate (group A: 5.9% vs group B: 14.1%). The length of in-hospital stay in group B was significantly shorter than group A (13 vs 24 days, P < 0.0001). There were no differences in postoperative morbidity and mortality between subgroups that were consisted of patients with small pancreatic duct diameter. Conclusion: This retrospective single-center study showed that nonstented duct-to-mucosa anastomosis was a safe procedure and was associated with a shortened in-hospital stay.

Effects of pancrelipase on nonalcoholic fatty liver disease after pancreaticoduodenectomy

Postoperative nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD) has recently become recognized. However, the pathoetiology of postoperative NAFLD is largely unknown. Furthermore, the optimal treatment has not been established. The aim of this prospective study was to clarify whether pancrelipase, which contains digestive pancreatic enzymes, could reverse NAFLD.

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.

Reinforcement of pancreticojejunostomy using polyglycolic acid mesh and fibrin glue sealant.

Objectives: To examine whether pressure-tight reinforcement of pancreaticojejunostomy (PJ) using polyglycolic acid (PGA) mesh and fibrin glue sealant can reduce the incidence of postoperative pancreatic fistula (POPF). Methods: The study population included 128 consecutive patients who underwent pancreaticoduodenectomy between September 2006 and January 2010. Postoperative mortality and morbidity among 50 patients who underwent reinforcement of PJ anastomosis using PGA mesh and fibrin glue were compared with 78 patients (historical controls). Results: The 2 groups demonstrated no significant differences in frequencies of overall or septic complications, reoperation, or in-hospital death. No significant difference in the frequency of POPF, delayed gastric emptying, or intra-abdominal abscess was found between groups. There was no difference between the 2 groups in the number of necessary interventions, and no bleeding complications or POPF-related mortality occurred. The median length of postoperative in-hospital stay between the 2 groups was similar: 13 days (range, 8-101 days) versus 14 days (range, 8-61 days). Similar findings were observed in a subgroup analysis consisting of patients with a pancreatic duct diameter smaller than 3 mm. Conclusion: This retrospective single-center study showed that reinforcement of PJ anastomosis using PGA mesh and fibrin glue provided no significant benefit in reducing the frequency of POPF.

Multicenter Phase II Study of Intravenous and Intraperitoneal Paclitaxel With S-1 for Pancreatic Ductal Adenocarcinoma Patients With Peritoneal Metastasis.

Objective: To evaluate the clinical efficacy and tolerability of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel combined with S-1, “an oral fluoropyrimidine derivative containing tegafur, gimestat, and otastat potassium” in chemotherapy-naive pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis. Background: PDAC patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis. An effective treatment strategy remains elusive. Methods: Paclitaxel was administered i.v. at 50 mg/m2 and i.p. at 20 mg/m2 on days 1 and 8. S-1 was administered at 80 mg/m2/d for 14 consecutive days, followed by 7 days of rest. The primary endpoint was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect and safety (UMIN000009446). Results: Thirty-three patients who were pathologically diagnosed with the presence of peritoneal dissemination (n = 22) and/or positive peritoneal cytology (n = 11) without other organ metastasis were enrolled. The tumor was located at the pancreatic head in 7 patients and the body/tail in 26 patients. The median survival time was 16.3 (11.47–22.57) months, and the 1-year survival rate was 62%. The response rate and disease control rate in assessable patients were 36% and 82%, respectively. OS in 8 patients who underwent conversion surgery was significantly higher than that of nonsurgical patients (n = 25, P = 0.0062). Grade 3/4 hematologic toxicities occurred in 42% of the patients and nonhematologic adverse events in 18%. One patient died of thrombosis in the superior mesenteric artery. Conclusions: This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis.