Incidence and treatment of metachronous gastric cancer after proximal gastrectomy.

BACKGROUND AND PURPOSE: Proximal gastrectomy (PG) is a widely accepted function-preserving surgical procedure; however, the incidence and treatment of metachronous gastric cancer (MGC) after PG have been the subject of a number of reports. METHODS: We collected data from 1576 consecutive patients who underwent gastrectomy for gastric cancer between January, 2003 and December, 2010, and analyzed the outcomes of 671 patients treated with PG or distal gastrectomy (DG) for cT1N0 disease. We also discuss the treatments for MGC. RESULTS: MGC was diagnosed within a median follow-up of 52.8 months after PG and DG in six (6.6%) and nine (1.8%) patients, respectively. The cumulative prevalence of MGC after PG was significantly higher than that after DG; P = 0.005. Univariate and multivariate analysis revealed male sex and PG as significant risk factors for MGC (P = 0.014 and P = 0.026, respectively). Five of the six patients who underwent PG were treated by endoscopic submucosal dissection. CONCLUSIONS: The incidence of MGC after PG was significantly higher than that after DG. However, most of the MGCs that developed after PG could be treated by endoscopic submucosal dissection.

Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients.

The recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively; p = 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively; p = 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine.

Neoadjuvant chemotherapy followed by surgery in gastric cancer patients with extensive lymph node metastasis.

Gastric cancer with extensive lymph node metastasis (ELM) is usually considered unresectable and is associated with poor outcomes. Cases with clinical enlargement of the para-aortic lymph nodes and/or bulky lymph node enlargement around the celiac artery and its branches are generally dealt with as ELM. A standard treatment for gastric cancer with ELM has yet to be determined. Two phase II studies of neoadjuvant chemotherapy followed by surgery showed that neoadjuvant chemotherapy with S-1 plus cisplatin followed by surgical resection with extended lymph node dissection could represent a treatment option for gastric cancer with ELM. However, many clinical questions remain unresolved, including the criteria for diagnosing ELM, optimal regime, number of courses and extent of lymph node dissection.

A Case of Gastric Cancer with Residual Tumor Only in the Para-Aortic Lymph Nodes after Systemic Chemotherapy followed by Conversion Surgery.

We report the case of a 60-year-old male who was diagnosed with gastric cancer. Upper gastrointestinal endoscopy indicated advanced cancer in the posterior wall of the gastric body. Biopsy revealed poorly differentiated adenocarcinoma. Abdominal computed tomography demonstrated thickening of the gastric wall and enlargement of the regional lymph nodes and of the para-aortic lymph nodes (PAN). The involvement of the PAN extended from the celiac axis to the caudal area of the inferior mesenteric artery [cT3N3aH0P0M1(LYM), stage IV]. Systemic chemotherapy was initiated. After 3 courses of S-1 plus cisplatin combination chemotherapy, the primary lesion and the enlarged lymph nodes revealed marked regression except for a minute residual lesion in the lymph nodes. Upon obtaining informed consent, open distal gastrectomy, D2 lymphadenectomy with PAN dissection, and Roux-en-Y reconstruction were performed. The patient was discharged from the hospital 35 days after the operation. Histopathological examination of the resected samples revealed malignant cells only in the PAN, not in the stomach or in the regional lymph nodes [ypT0N0M1(LYM), stage IV]. Currently, the patient is undergoing postoperative adjuvant chemotherapy with S-1 and has remained well without any recurrence after 6 months following surgery.

Recurrence patterns of esophagogastric junction adenocarcinoma according to Siewert's classification after radical resection.

BACKGROUND: The treatment strategy for adenocarcinoma of the esophagogastric junction (AEG) remains controversial. In the present study, the recurrence pattern of AEGs according to Siewert's classification after radical resection was reviewed, and predictive factors of recurrence were examined. PATIENTS AND METHODS: We retrospectively analyzed the clinical data of 127 consecutive patients with Siewert type I, II, and III AEGs who underwent curative resection (R0) without perioperative chemotherapy at the National Cancer Center Hospital East between January 1993 and November 2006. RESULTS: The median follow-up period was 48.9 (range=1.5-179) months. The recurrence rates of type I, II, and III tumors were 57.1%, 44.4%, and 41.0%, respectively. The most frequent relapse site was lymphogenous in type I, hematogenous in type II, and disseminative in type III tumors. The median time-to-recurrence after surgery was 12.6 months in type I, 12.5 months in type II, and 12.7 months in type III disease, with no significant difference. Multivariate analysis revealed that mediastinal lymph node metastasis (p=0.005) (hazard ratio=2.954, 95% Confidence Interval=1.38-6.31) was a significant and independent prognostic indicator for poor recurrence-free survival. The recurrence rate in patients with mediastinal lymph node metastasis at the time of surgery was 100%. CONCLUSION: The recurrence pattern of AEGs differed according to Siewert's classification. Its tendency should be understood in order to determine the optimal surgical approach. Mediastinal lymph node dissection may be effective for local control, but may not significantly improve prognosis. When mediastinal lymph node metastasis is suspected, perioperative chemotherapy may be recommended.

Evaluation of Ki-67 index in EUS-FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors.

BACKGROUND AND STUDY AIM: Malignancy in pancreatic neuroendocrine tumors (PNETs) is graded by assessing the resected specimens according to the World Health Organization (WHO) 2010 criteria. The feasibility of such grading using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens remains unclear. The aim of this study was to ascertain the optimal method of measuring the Ki-67 index in EUS-FNA specimens, using resected specimens as the criterion standard. PATIENTS AND METHODS: A total of 58 consecutive patients diagnosed with PNETs between March 1998 and May 2011 were included. The study measured intratumoral Ki-67 index heterogeneity, concordance rates of PNET grading by EUS-FNA with grade of the resected tumor, optimal method of measuring the Ki-67 index in EUS-FNA specimens, and survival analysis based on EUS-FNA specimen grading. RESULTS: Intratumoral dispersion of Ki-67 index in resected specimens was 0.033 for Grade 1 and 0.782 for Grade 2 tumors (P<0.001). Concordance rates for WHO classification between EUS-FNA and resected specimens were 74.0% using the mean Ki-67 index in EUS-FNA specimens and 77.8% using the highest Ki-67 index. The concordance rate rose to 90% when EUS-FNA samples with less than 2000 tumor cells were excluded (26% of EUS-FNA cases). The Kaplan-Meier survival curves were significantly stratified by the EUS-FNA grading of PNETs with 5-year survival rates of 100%, 58.3%, and 0%, for Grade 1, Grade 2, and neuroendocrine carcinoma (NEC) tumors, respectively. CONCLUSIONS: Grading of PNETs by the highest Ki-67 index in EUS-FNA specimens with adequate cellularity has a high concordance with grading of resected specimens, and can predict long term patient survival with high accuracy.

Limited subtotal gastrectomy for early remnant gastric cancer.

BACKGROUND: Detection of early remnant gastric cancer (ERGC) is increasing as a result of the development of endoscopic technology and a surveillance program. The aim of this study was to evaluate the results of limited subtotal gastrectomy (SG) surgery for ERGC compared to total gastrectomy (TG). METHODS: We retrospectively reviewed a database of 72 consecutive patients with remnant gastric cancer who underwent laparotomy at the National Cancer Center Hospital East between January 1993 and December 2008. Thirty-five patients with a preoperative diagnosis of ERGC underwent curative resection: 13 SG and 22 conventional TG. Patients and tumor characteristics, operative results, and postoperative assessments 1 year after surgery were compared between the two groups. RESULTS: Operating time, blood transfusion, and hospital stay were similar in the two groups. In the SG group, blood loss and postoperative recovery of body weight tended to be better than in the TG group. There was no dumping syndrome in the SG group, while this occurred in three patients in the TG group. The levels of hemoglobin and total protein were higher 1 year after remnant gastrectomy in the SG group than in the TG group. No recurrence of gastric cancer was detected in the SG group during median follow-up of 99.2 months. CONCLUSION: In comparison to TG, limited SG surgery for ERGC improved the postoperative course, with no recurrence of cancer. Therefore, SG is a safe and effective treatment for ERGC.

Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population.

BACKGROUND: The ToGA trial demonstrated the beneficial effect of trastuzumab in gastric cancer patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors. Therefore, evaluation of the relationship between HER2 expression and gastric cancer biology using a validated system has become an even more important task. Herein, we verified the correlation between HER2 overexpression in the tumor and the clinical course of gastric cancer patients. METHODS: A total of 1,006 consecutive patients with gastric cancer who underwent surgery at the National Cancer Center Hospital East between January 2003 and July 2007 were examined using the tissue microarrays approach. HER2 expression was determined based on an immunohistochemistry score of 3+, or an immunohistochemistry score of 2+ plus HER2 gene amplification as detected by double-color fluorescent in situ hybridization. A retrospective review of the medical records was conducted to determine the correlation between the presence of HER2 overexpression and clinicopathological factors. Then, in 948 patients who had undergone curative resection, HER2 status was compared with the survival. RESULTS: HER2 overexpression was detected in 118 (11.7 %) patients. HER2 overexpression was correlated with age, gender, grade of differentiation, expanding growth pattern, and nodal status. In the survival analysis, HER2 overexpression was not found to be correlated with either disease-specific survival or recurrence-free survival. CONCLUSIONS: HER2 overexpression in the tumor was not identified as a significant prognostic factor in patients with operable gastric cancer. The HER2-targeted therapy may be beneficial in a proportion of cases.

Assessing resectability in cholangiocarcinoma.

Assessment of surgical resectability in cholangiocarcinoma is more complicated than other gastrointestinal malignancies and remains unestablished. According to the primary origin and tumor extent, the applied surgical procedure varies from extrahepatic bile duct resection to right or left trisectionectomy concomitant with pancreatoduodenectomy. Portal vein resection and reconstruction during hepatectomy has been feasible. Thanks to the availability of new microscopic surgical techniques, hepatic arterial resection and reconstruction have also come to be applied for locally advanced cholangiocarcinoma cases. These vascular surgical techniques can expand surgical indications for advanced cholangiocarcinoma. On the other hand, determination of the tumor extent or staging still remains difficult and imprecise. The endoscopic approach has come to play significant roles both for preoperative biliary drainage and tumor staging. Estimation of the functional reserve of future remnant liver in cholestatic patients still remains unresolved. Hepatobiliary surgeons should carefully estimate the safety of the surgical procedure in each individual patient requiring extensive hepatobiliary resection. Early establishment of the measurement methods of the functional capacity of future remnant liver is an important and urgent issue for assessing safer surgical resectablity of cholangiocarcinoma.

Isolated caudate lobectomy with pancreatoduodenectomy for a bile duct cancer.

BACKGROUND: In patients with distal bile duct cancer involving the hepatic hilus, a major hepatectomy concomitant with pancreatoduodenectomy (HPD) is sometimes ideal to obtain a cancer-free resection margin. However, the surgical invasiveness of HPD is considerable. PATIENTS AND METHODS: We present our treatment option for patients with distal bile duct cancer showing mucosal spreading to the hepatic hilum associated with impaired liver function. To minimize resection volume of the liver, an isolated caudate lobectomy (CL) with pancreatoduodenectomy (PD) using an anterior liver splitting approach is presented. Liver transection lines and bile duct resection points correspond complete with our standard right and left hemihepatectomies with CL for perihilar cholangiocarcinoma. RESULTS: Total operation time was 765 min, and pedicle occlusion time was 124 min, respectively. Although the proximal mucosal cancer extension was identified at both the right and the left hepatic ducts, all resection margins were negative for cancer. CONCLUSIONS: Isolated CL with PD is an alternative radical treatment option for bile duct cancer patients with impaired liver function.

Infection control for prevention of pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND/AIMS: Effectiveness of infection control for prevention of pancreatic fistula (PF) after pancreaticoduodenectomy (PD) is not clear. We analyzed the impact of infection on the development of PF and examined the effect of enhanced infection control to prevent PF. METHODOLOGY: Amylase level (D-amylase) and bacterial culture (D-culture) of drainage fluid were evaluated on POD 1, 3, 5 and 7, in 90 consecutive patients with soft pancreas who underwent PD. The study period was divided into two periods. The relationship between D-amylase and D-culture was examined, and the clinicopathological factors predicting PF were analyzed in the first period. Then, anti-infection measures were introduced in the second period, and the effect of enhanced infection control was examined. RESULTS: Twenty-nine out of 58 patients (50.0%) developed PF in the first period. D-amylase were higher in patients with D-culture infection than in those without it (p<0.05). D-amylase above 10,000IU/L on POD1 and D-culture infection on POD3 were independent predictive factors for PF by multivariate analysis (p<0.01). After introduction of enhanced infection control in the second period, four out of 32 patients (12.5%) developed PF. The rates of PF and D-culture infection were significantly reduced (p<0.05). CONCLUSIONS: Infection of drainage fluid is related to an increased level of amylase, resulting in PF. Enhanced infection control can effectively prevent PF after PD in soft pancreas.

Role of adjuvant surgery for patients with initially unresectable pancreatic cancer with a long-term favorable response to non-surgical anti-cancer treatments: results of a project study for pancreatic surgery by the Japanese Society of Hepato-Biliary-Pancreatic Surgery.

PURPOSE: A multicenter survey was conducted to explore the role of adjuvant surgery for initially unresectable pancreatic cancer with a long-term favorable response to non-surgical cancer treatments. METHODS: Clinical data including overall survival were retrospectively compared between 58 initially unresectable pancreatic cancer patients who underwent adjuvant surgery with a favorable response to non-surgical cancer treatments over 6 months after the initial treatment and 101 patients who did not undergo adjuvant surgery because of either unchanged unresectability, a poor performance status, and/or the patients' or surgeons' wishes. RESULTS: Overall mortality and morbidity were 1.7 and 47 % in the adjuvant surgery group. The survival curve in the adjuvant surgery group was significantly better than in the control group (p < 0.0001). The propensity score analysis revealed that adjuvant surgery was a significant independent prognostic variable with an adjusted hazard ratio (95 % confidence interval) of 0.569 (0.36-0.89). Subgroup analysis according to the time from initial treatment to surgical resection showed a significant favorable difference in the overall survival in patients who underwent adjuvant surgery over 240 days after the initial treatment. CONCLUSION: Adjuvant surgery for initially unresectable pancreatic cancer patients can be a safe and effective treatment. The overall survival rate from the initial treatment is extremely high, especially in patients who received non-surgical anti-cancer treatment for more than 240 days.

NC-6300, an epirubicin-incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin.

Epirubicin is widely used to treat various human tumors. However, it is difficult to achieve a sufficient antitumor effect because of dosage limitation to prevent cardiotoxicity. We hypothesized that epirubicin-incorporating micelle would reduce cardiotoxicity and improve the antitumor effect. NC-6300 comprises epirubicin covalently bound to PEG polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure of 40-80 nm in diameter in an aqueous milieu. NC-6300 (10, 15 mg/kg) and epirubicin (10 mg/kg) were given i.v. three times to mice bearing s.c. or liver xenograft of human hepatocellular carcinoma Hep3B cells. Cardiotoxicity was evaluated by echocardiography in C57BL/6 mice that were given NC-6300 (10 mg/kg) or epirubicin (10 mg/kg) in nine doses over 12 weeks. NC-6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin. Moreover, NC-6300 also produced a significantly longer survival rate than epirubicin against the liver orthotopic tumor of Hep3B. With respect to cardiotoxicity, epirubicin-treated mice showed significant deteriorations in fractional shortening and ejection fraction. In contrast, cardiac functions of NC-6300 treated mice were no less well maintained than in control mice. This study warrants a clinical evaluation of NC-6300 in patients with hepatocellular carcinoma or other cancers.

Laparoscopic proximal gastrectomy with jejunal interposition for gastric cancer in the proximal third of the stomach: a retrospective comparison with open surgery.

BACKGROUND: The incidence of cancer in the proximal third of the stomach is increasing. Laparoscopic proximal gastrectomy (LPG) seems an attractive option for the treatment of early-stage proximal gastric cancer but has not gained wide acceptance because of technical difficulties, including the prevention of severe reflux. In this study, we describe our technique for LPG with jejunal interposition (LPG-IP) and evaluate its safety and feasibility. METHODS: In this retrospective analysis, we reviewed the data of patients with proximal gastric cancer who underwent LPG-IP (n = 22) or the same procedure with open surgery (OPG-IP; n = 68) between January 2008 and September 2011. Short-term surgical variables and outcomes were compared between the groups. The reconstruction method was the same in both groups, with creation of a 15 cm, single-loop, jejunal interposition for anastomosis. RESULTS: There were no differences in patient or tumor characteristics between the groups. Operation time was longer in the LGP-IP group (233 vs. 201 min, p = 0.0002) and estimated blood loss was significantly less (20 vs. 242 g, p < 0.0001). The average number of harvested lymph nodes did not differ between the two groups (17 vs. 20). There also were no differences in the incidence of leakage at the esophagojejunostomy anastomosis (9.1 vs. 7.4%) or other postoperative complications (27 vs. 32%). The number of times additional postoperative analgesia was required was significantly less in the LPG-IP group compared with the OPG-IP group (2 vs. 4, p < 0.0001). CONCLUSIONS: LPG-IP has equivalent safety and curability compared with OPG-IP. Our results imply that LPG-IP may lead to faster recovery, better cosmesis, and improved quality of life in the short-term compared with OPG-IP. Because of the limitations of retrospective analysis, a further study should be conducted to obtain definitive conclusions.

Impaired mental health among the bereaved spouses of cancer patients.

OBJECTIVE: Few cancer physicians routinely provide bereavement follow-up in clinical practice. The purpose of this study was to identify the prevalence of impaired mental health among the bereaved spouses over several years and explore the indicators for early detection of high-risk spouses during end-of life (EOL) care. METHODS: A cross-sectional mail survey was conducted for the bereaved spouses of patients who had died at the National Cancer Center Hospital of Japan. Bereaved spouses with potential psychiatric disorders were identified by the cut-off score of the 28-item General Health Questionnaire. Associated factors of potential psychiatric disorders were explored by logistic regression analysis. RESULTS: A total of 821 spouses experiencing bereavement from 7 months to 7 years returned the questionnaires. Overall mean prevalence of potential psychiatric disorders was 44% (360/821). Bereaved spouses 'under 55 years' (71%) or '2 years after bereavement' (59%) revealed a significantly higher prevalence (p < 0.01). Associated factors during EOL care were several characteristics such as 'spouses' history of psychiatric disorder (odds ratio (OR) = 3.19), 'patients' with stomach cancer (OR = 1.87), and 'patients' using psychiatric consultation services (OR = 1.52) as well as spouses' dissatisfaction with EOL care such as 'physicians' treatment of physical symptoms' (OR = 3.44) and 'time spent communicating with patients' (OR = 1.55). CONCLUSIONS: Nearly half the bereaved spouses showed potential psychiatric disorders even 7 years after bereavement. Patients' psychological distress, spouses' history of psychiatric disorder, and dissatisfaction with EOL care were indicators of high-risk spouses.

Treatment outcome for systemic chemotherapy for recurrent pancreatic cancer after postoperative adjuvant chemotherapy.

OBJECTIVES: A global consensus on how to treat recurrent pancreatic cancer after adjuvant chemotherapy with gemcitabine (ADJ-GEM) does not exist. METHODS: We retrospectively reviewed the clinical data of 41 patients with recurrences who were subsequently treated with chemotherapy. RESULTS: The patients were divided into two groups according to the time until recurrence after the completion of ADJ-GEM (ADJ-Rec): patients with an ADJ-Rec < 6 months (n = 25) and those with an ADJ-Rec ≥ 6 months (n = 16). The disease control rate, the progression-free survival after treatment for recurrence and the overall survival after recurrence for these two groups were 68 and 94% (P = 0.066), 5.5 and 8.2 months (P = 0.186), and 13.7 and 19.8 months (P = 0.009), respectively. Furthermore, we divided the patients with an ADJ-Rec < 6 months into two groups: patients treated with gemcitabine (n = 6) and those treated with alternative regimens including fluoropyrimidine-containing regimens (n = 19) for recurrent disease. Patients treated with the alternative regimens had a better outcome than those treated with gemcitabine. CONCLUSIONS: Fluoropyrimidine-containing regimens may be a reasonable strategy for recurrent disease after ADJ-GEM and an ADJ-Rec < 6 months.

Laparoscopic transhiatal resection for Siewert type II adenocarcinoma of the esophagogastric junction: operative technique and initial results.

Laparoscopic distal gastrectomy has gained wide acceptance, and laparoscopic total gastrectomy (LTG) and laparoscopic proximal gastrectomy (LPG) are now also performed for gastric cancer. We extended these techniques to treat Siewert type II adenocarcinoma of the esophagogastric junction (AEG). Ten patients with clinical T1 AEG type II underwent laparoscopic transhiatal (LTH) resection combined with LTG reconstructed by Roux-en-Y (LTH+LTG: n=2) or LPG reconstructed by jejunal interposition (LTH+LPG: n=8). Intracorporeal esophagojejunostomy was performed using a circular stapler, of which the anvil head was introduced transabdominally or transorally. The median operation time was 243 minutes, and blood loss was 25.5 g. There were no intraoperative complications or conversion to open surgery. No anastomotic leak was observed, but 1 diaphragmatic herniation to the left thoracic cavity occurred postoperatively. The median length of the proximal margin was 14.5 mm. This operation is technically feasible and can be safely performed after adequate experience of LTG or LPG, though esophagojejunostomy in the mediastinum is technically demanding.

Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head.

Tumor-associated macrophages (TAMs) are candidate histological factors in invasive ductal carcinoma (IDC) of the pancreas. Tumor-associated macrophages can be affected by cancer-related inflammation and pancreatitis and interact with important invasive behavior in a recurrent manner in pancreatic IDC. These features may help elucidate the aggressiveness of pancreatic IDC. The aim of this study was to characterize TAMs in pancreatic IDC in comparison with chronic pancreatitis (CP) and to reveal TAM-related factors and the clinical impact of TAMs. CD68 (a pan-macrophage marker) and CD204 (an M2 macrophage marker) immunohistochemistry was carried out in pancreas head specimens from 107 IDC cases and 11 CP cases. Immunopositive cell areas were calculated at the periphery and center of the tumor. The distributions of macrophages in IDC and CP and the relationship between TAMs and histological tumor factors, survival, and recurrence were evaluated. Macrophages were more frequently observed in the lesion periphery than the center in IDC and CP. The density of macrophages was elevated in IDC compared to CP. Dense M2 macrophages at the tumor periphery were frequently seen in large tumors and showed an independent impact on overall survival and disease-free time. Early recurrence in the liver or the local manipulated area was associated with high accumulation of peripheral M2 macrophages. More M2 macrophages were seen in IDC than in CP in both the periphery and the center. High numbers of peripheral M2 macrophages were associated with large tumor size, early recurrence in the liver, local recurrence, and shortened survival time in patients with pancreatic IDC.

Intraductal oncocytic papillary neoplasm of the extrahepatic bile duct: report of a case.

We report a rare case of an intraductal oncocytic papillary neoplasm (IOPN) of the extrahepatic bile duct. A 66-year-old man was admitted to our hospital for investigation of right-sided back pain. Ultrasonography, computed tomography and magnetic resonance imaging showed a papillary lesion, 3 cm in diameter, in the middle bile duct, invaginating into the cystic duct. We made a provisional diagnosis of middle bile duct cancer and performed substomach-preserving pancreatoduodenectomy. Macroscopically, the middle bile duct contained a two-humped papillary tumor, one tip of which invaginated into the cystic duct. Microscopically, the tumor consisted of cuboidal cells with abundant eosinophilic cytoplasm resembling that of oncocytes and a fine fibrovascular core. The tumor cells were stained strongly with antimitochondria antibody. Based on these findings, the tumor was diagnosed histologically as IOPN of the extrahepatic bile duct. The patient died of prostate cancer 51 months after surgery, but without evidence of recurrence of the IOPN.

Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival.

PURPOSE: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC. EXPERIMENTAL DESIGN: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-γ ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS). RESULTS: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers α-fetoprotein and/or des-γ-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N = 15) than in those with low frequencies (N = 18; P = 0.033). CONCLUSIONS: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination.