Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study.

We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1-year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide-specific immune responses. All enrolled patients received therapy without the HLA-A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1-year survival rates between the HLA-A*2402-matched and -unmatched groups were not significantly different. In the HLA-A*2402 matched group, patients showing peptide-specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA-A*2402-matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study).

BACKGROUND: We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy. METHODS: The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups. RESULTS: Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p=0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p=0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of <3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p=0.289) but showed a delayed response. CONCLUSIONS: Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of <3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination. TRIAL REGISTRATION: Trial registration: UMIN000001791.

[A case of long-term survival of small intestinal adenocarcinoma treated by resection and chemotherapy].

A 60-year-old man had visited our hospital a few times due to vomiting since July 2008. In January 2009, because he was no longer able to eat, he was hospitalized to receive close examination. Single balloon enteroscopy revealed jejunal adenocarcinoma. After examination of the whole body, as there was no distant metastasis, jejunum partial resection was performed in February 2009. One dissemination nodule was recognized on the serosa near the main tumor. We obtained the final pathological diagnosis as Stage IV. From April 2009, adjuvant chemotherapy with combination of oxaliplatin, 5-fluorouracil and Leucovorin (mFOLFOX6) was performed 8 times. In April 2009, a small metastatic lesion appeared in the upper lobe of the right lung. We started administering combination of irinotecan, 5-fluorouracil and Leucovorin (FOLFIRI) from January 2010, but stopped because of side effects after the second cycle. Administration of capecitabine was started in March 2010. The metastatic lesion had diminished for a time but was found to be enlarged in March 2011. Thus, a partial right lung resection was performed in April 2012. After lung resection, systemic chemotherapy was not performed. The patient remains alive without a recurrence 3 years after lung resection and over 5 years after detection of the small intestinal adenocarcinoma.

[A case of combined resection of multiple adjacent organs in a patient with locally advanced residual gastric cancer].

A 69-year-old man with a history of distal gastrectomy for early gastric cancer consulted our department concerning a possible diagnosis of sigmoid colon cancer. After detailed examination, he was diagnosed with type 3 advanced sigmoid colon cancer with colonic stenosis and large type 3 gastric cancer in the residual stomach with gross infiltration of the adjacent organs. The patient first underwent sigmoidectomy and then received a regimen of neoadjuvant combination chemotherapy with S-1, cisplatin( CDDP), and Lentinan( LNT)( S-1 80 mg/m2, CDDP 60 mg/m2, and LNT 2 mg/body twice weekly for 2 weeks) for gastric cancer( cT4b[ SI, liver, pancreas], N2M0H0, Stage IIIC). After 2 courses of treatment, the gastric tumor had reduced in size but had penetrated the transverse colon. We performed total resection of the gastric remnant, D2 lymph node dissection, and en bloc resection of the transverse colon, partial liver, pancreas body and tail, partial diaphragm, and pericardium. S-1/CDDP (a total of 11 courses) followed by single-agent S-1 therapy was continued as adjuvant chemotherapy. With a follow-up time of 3 years and 10 months, no recurrence was noted following total resection of the gastric remnant.

[A case of locally advanced residual gastric cancer treated with combined resection of multiple adjacent organs].

A 60-year-old man was diagnosed as having type 3 advanced gastric cancer in the gastric antrum and multiple liver metastases( S2, S3, S4, and S7)( cT3[ SS] N0M0H1, Stage IV). The patient received combined neoadjuvant chemotherapy with S-1 and cisplatin( CDDP). S-1( 80 mg/body/day) was administered orally for 3 weeks followed by 2 drug-free weeks as a course, and CDDP (60 mg/m2) was administered by intravenous infusion on day 8. The gastric tumor reduced in size and the liver metastases improved after 5 courses of treatment. Distal gastrectomy, D2 lymph node dissection, and partial liver resection( 4 sites) were performed. S-1 alone was continued as adjuvant chemotherapy; no recurrence was detected in 2 years and 2 months after surgery. Although there is insufficient evidence to support the benefit of surgical resection in patients with advanced gastric cancer with liver metastases, chemotherapy combined with surgical resection would improve the survival time without deterioration of quality of life of these patients. This case suggests that neoadjuvant chemotherapy is effective against advanced gastric cancer even with multiple liver metastases.

[A case of transverse colon cancer mimicking urachal cancer].

A 55-year-old man was admitted to our hospital because of abdominal distension. Computed tomography revealed an abscess in the anterior abdominal wall and invasion of the large intestine. Biopsy of the large intestine revealed adenocarcinoma. Immunohistochemically, the antigen expression profile of the tumor was positive for cytokeratin 7, cytokeratin 903 (34ßE12), and cytokeratin 20. We diagnosed the tumor as urachal cancer and performed surgery. Examination of the resected specimen showed that the tumor was located in the transverse colon. Finally, the patient was diagnosed as having transverse colon cancer with urachal abscess.

[A case report of complete response by weekly paclitaxel and 5'-DFUR combination chemotherapy for recurrenced gastric cancer with peritoneal dissemination].

A 77-year-old man complained chiefly of chest pain and heartburn. He had type 3 gastric cancer on the posterior wall of vestibular part. Distal partial gastrectomy and D2 lymph node dissection were performed. The pathological findings were as follows: partially poor tub2, pT2 (SS), ly2, v0, pN1, H0, P0, CY0, M0, pStage II,and Cur A. S-1 was administered orally as an adjuvant therapy. Carbohydrate antigen(CA) 19-9 levels were elevated 16 months after the operation. Computed tomography revealed a small amount of ascitic fluid with no other significant findings. Endoscopy revealed an erythrogenic protruding lesion 20 cm from the anal verge. In the biopsy, the lesion was classified as Group V, indicating metastasis of gastric cancer. It was judged that the S-1 therapy had led to the recurrence of peritoneal dissemination. Weekly paclitaxel (PTX; 3-week administration followed by 1-week withdrawal) was used together with doxifluridine(5'-DFUR; daily oral administration). CA19-9 levels decreased gradually, becoming normal in 3 months. Most of the ascitic fluid disappeared in 4 months. In the endoscopy performed after 9 months, the lesion was classified as Group I, revealing a histological complete response (CR). No serious side effects were observed, although epilation occurred as an adverse event. Currently, 21 months after the start of treatment, the CR has persisted. These results suggest that despite a few side effects, concomitant therapy with weekly PTX and 5'-DFUR can be continued as ambulatory care, and it may be effective in patients treated previously with S-1 who exhibit recurrence of peritoneal dissemination of gastric cancer.

Initial Report: A Novel Intraoperative Navigation System for Laparoscopic Liver Resection Using Real-Time Virtual Sonography.

Recent progress in navigation has revealed problems involving non-rigid registration for hepatic surgery. With the increasing popularity of laparoscopic liver surgery, a new laparoscopic navigation system is necessary. This study involved an in-vitro demonstration of a 3-dimensional printer model and in vivo demonstration in four patients. For the in vitro examination, a position detecting unit attached at 33 cm and 13 cm distance conditions from the tip of the electrocautery was examined eight times at the marked points on the liver surface eight times respectively. The differences between the simulation and the authentic dissecting plane were conventionally investigated in vivo. In vitro, the errors of the 33 cm and 13 cm distance model were7.8 ± 3.5 mm (mean ± SD), and 3.3 ± 1.0 mm, respectively. The mean differences of the dissection plane were within 10 mm. The potentiality and safety of the novel navigation system was confirmed, although further investigation is recommended.

Extremely rare case of H-type gallbladder duplication coexistent with carcinoma: a case report and review of the literature.

INTRODUCTION: Multiple gallbladders represent a rare congenital disorder, and coexistence with carcinoma is extremely rare, leading to a high possibility of misdiagnosis and surgical complications. In this study, a case was reported and the literature was reviewed. CASE PRESENTATION: An 80-year-old woman was diagnosed with acute cholecystitis via ultrasonography and was successfully treated with antibiotics. After the patient's biliary colic relapsed, she was referred to our hospital. Multiple imaging modalities revealed duplication of her gallbladder (H-type) and suggested coexistence with carcinoma. According to preoperative evaluations, we assumed the patient had stage IIIA disease, and cholecystectomy, cholangiography using a near-infrared ray vision system, and sectionectomy of segments 4a and 5 were performed. Contrary to the high standardized uptake values obtained by 18F-fluoro-2-deoxy-D-glucose positron emission tomography, gallbladder carcinoma was pathologically diagnosed as stage 0 mucosal cancer. Seven days after the operation, portal thrombosis of the posterior branch was revealed, and conservative therapy was indicated; satisfactory results were achieved. The patient was discharged 65 days after surgery. No recurrence was observed for 1 year after surgery. CONCLUSIONS: An extremely rare case of malignancy in a duplicated gallbladder was reported, and the literature was reviewed. Accurate estimations are feasible for diagnoses of multiple gallbladders, where correct evaluations are vital, especially in malignant cases. Because of the possibility of malignancy, resected accessory gallbladders should be scrutinized pathologically.

[Local resection and jejunal patch duodeno-plasty for the duodenal gastrointestinal stromal tumor--a case report].

Many gastrointestinal stromal tumors( GISTs) were treated according to the guidelines in Japan. In this paper, our procedure of the local resection, minimal invasive surgery, the jejunal graft patching and an attractive new method of treating duodenal GISTs was reported. A 50-year-old woman with duodenal submucosal tumor was referred to our hospital. The gastrointestinal endoscopic examination, the computed-tomographic images, and the magnetic resonance images showed a 3.5 cm hyper vascular tumor at the posterior superior aspect of the pancreatic head. PET-CT images revealed accumulations only in the duodenal tumor. The endoscopic ultra-sonographic images and biopsy revealed that the tumor was positive for c-kit, as a periampullary GIST of the duodenum presumed pancreatic invasion. The authors showed a" conventional and safe" local resection and duodenoplastic surgical technique for duodenal GISTs, although some reports declared the efficacy of the Roux-en Y duodeno-jejunostomy in Japan.

[Skeletal muscle metastasis of rectal carcinoma--a case report].

Skeletal muscle metastasis of carcinoma is comparatively rare. We report a case of metastasis to the quadriceps femoris muscle after the operation for rectal carcinoma. A 70-year-old man underwent rectal amputation in May 2007 due to rectal carcinoma. In May 2008, he noticed a painful tumor in the right femoral region. We obtained the diagnosis of recurrent rectal carcinoma by open biopsy. Simultaneously, lung metastasis was revealed by a close examination. Metastatic tumor resection was performed before chemotherapy, because it was important to preserve his performance status. From June 2008, chemotherapy was started. A year after the second operation, lung metastatic lesions were gradually progressed. At present, new skeletal muscle metastasis is not found. He is receiving chemotherapy in outpatient care. The resection of skeletal muscle metastasis made a contribution to his quality of life.

[Ovarian metastasis after complete response of colon cancer].

We report a case of ovarian metastasis after complete response of colon cancer. A 55-year-old woman underwent a sigmoidectomy for sigmoid colon cancer with hepatic metastasis and para-aorta lymph node metastasis. After the operation, the patient was given chemotherapy with bevacizumab+mFOLFOX6. Nine months after the operation, the patient was judged to have achieved complete response. Thirteen months after the operation, right ovarian tumor was found and bilateral oophrectomy, hysterectomy and omentectomy were performed. Histopathologically the ovarian tumor was metastasized from colonic cancer. After the second operation, the patient was given chemotherapy with bevacizumab+FOLFIRI. At present, the patient remains disease-free for 6 months after the ovarian operation.

A case report: Feasibility of a near infrared ray vision system (Photo dynamic eye®) for the postoperative ischemic complication of gallbladder carcinoma.

INTRODUCTION: Radical resection with or without preserving extra-hepatic bile duct has shown similar prognoses for gallbladder carcinoma (GB ca), although aggressive resection is essential. In preserving bile duct, ischemic complications are serious, life-threatening serious problems. Correct evaluation of the blood flow to the biliary tract is crucial. CASE PRESENTATION: A case of gallbladder ca in a 62-year-old man was reported. The patient was diagnosed with stage Ⅱ GB ca (T2, N0, M0) by ultrasonography, computed tomography, magnetic resonance imaging, and endoscopic ultrasonography. Cholecystectomy and intraoperative frozen section examination were planned. After recognition of invasion to subserosa and negative cystic duct margin, radical dissection of the lymph nodes in the hepatoduodenal ligament with preserving biliary tract was performed. Three days after the operation, biliary peritonitis was revealed. Emergency laparotomy showed ischemic bile leakage. Proper blood flow of the biliary system was realized by a near-infrared ray vision system (Photo Dynamic Eye®: HAMAMATSU Photonics) using indocyanine green. Primary suture of the extra-hepatic biliary duct and T-tube drainage were selected. No stricture of the bile system nor recurrence was recognized for two years after surgery. DISCUSSION: In the case of ischemic biliary complications, whether to preserve the extrahepatic bile duct is a critical issue for the surgeons. In this case study, the feasibility of authentic indocyanine green near-infrared imaging was shown for postoperative ischemic biliary situations. CONCLUSIONS: Authentic indocyanine green near-infrared imaging was feasible for the estimation of the blood flow to the postoperative ischemic biliary complication.

Case: Authentic multimodal therapy and liver resection for an initially unresectable intrahepatic cholangiocarcinoma.

INTRODUCTION: Although curative resection is an outstanding prognostic factor of intrahepatic cholangiocarcinoma (ICC), certain segments remain unresectable. The standard therapy for initially unresectable ICC is uncertain. In this case report, we reported the feasibility of multimodal chemotherapy and curative resection. CASE: A 59-year-old Asian woman with back pain was referred to the hospital by her family physician regarding liver mass visible on ultrasonography. At admission, the carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were high, and images showed characteristic signs of ICC with intrahepatic metastases and invasions to on the right Glisson's sheath. Multimodal therapy was applied to the ICC, which could not be resected at first. The therapy comprised hepatic arterial chemoembolization with drug-eluting beads (DEB-TACE), angiographic subsegmentectomy (AS), and systemic chemotherapy. Downstaging of the ICC, which results in curative resection, was planned due to non-normalization of the tumor markers, and pathological analysis revealed complete remission. At 34 months after the surgery, the patient was alive without relapse. DISCUSSION: Recently, chemotherapy and/or an interventional approach were reported to be feasible, although unresectable advanced ICC has a poor prognosis. Some studies have reported that multimodal chemotherapy and R0 resection of initially unresectable ICC can prolong survival time. However, some reports have shown high morbidity and mortality associated with initially unresectable ICC treated with multimodal chemotherapy and R0 resection. Our study resulted in complete remission without complications. CONCLUSION: Multimodal chemotherapy and hepatic curative resection on locally advanced ICC are feasible treatment approaches for initially unresectable ICC.

A new prognostic model for hepatocellular carcinoma recurrence after curative hepatectomy.

We previously reported the effectiveness of the product of tumor number and size (NxS factor) for the prognosis of hepatocellular carcinoma (HCC) in patients following hepatectomy. The present study aimed to propose a new score based on the NxS factor to predict HCC recurrence following hepatectomy. A total of 406 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine were retrospectively analyzed to develop the new score. Among clinicopathological factors, including the NxS factor, the marker subset that achieved the best performance for prediction of early recurrence was assessed, and a prognostic model for HCC recurrence after curative hepatectomy (REACH) was developed. As the validation set, 425 patients who underwent hepatectomy for HCC at Yamaguchi University Graduate School of Medicine and Shimonoseki Medical Center were analyzed, and the prognostic ability of the REACH score was compared with that of well-known staging systems. Following analysis, the REACH score was constructed using six covariates (NxS factor, microscopic hepatic vein invasion, differentiation, serum albumin, platelet count and indocyanine green retention rate at 15 min). In the validation set, the REACH score predicted early recurrence in 73 of 81 samples, with a sensitivity of 89% and a specificity of 58%. The area under the curve (AUC) of the receiver operating characteristic curve of the REACH score was 0.78 and 0.74, respectively, for 1- and 2-year recurrence after hepatectomy; each AUC was higher than that of any of the other staging systems. Survival analysis indicated the REACH score had the best predictive value in disease-free and overall survival. The present findings demonstrated that the REACH score may be used to classify patients with HCC into high- and low-risk of recurrence, and to predict subsequent survival following hepatic resection.

Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701).

BACKGROUND: Lentinan (LNT) is a purified ß-1, 3-glucan that augments immune responses. The present study was conducted to assess the efficacy of LNT in combination with S-1 as a first-line treatment for unresectable or recurrent gastric cancer. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive S-1 alone or S-1 plus LNT. The primary end-point was overall survival (OS). Secondary end-points were time-to-treatment failure (TTF), overall response rate (ORR), safety, quality of life (QOL), and biomarker. The percentages of LNT-binding monocytes in peripheral blood prior to treatment were analysed for the biomarker assessment. RESULTS: One hundred and fifty-four and 155 patients were randomly assigned to receive S-1 alone or S-1 plus LNT, respectively. The median OS was 13.8 and 9.9 months (P = 0.208), the median TTF was 4.3 and 2.6 months (P < 0.001), the ORR was 22.3% and 18.7% for the S-1 and S-1 plus LNT groups, respectively. The incidences of haematologic and non-haematologic adverse events were similar, and no significant changes in QOL scores were observed during the treatment in both groups. In a subpopulation of patients with LNT-binding monocytes ≥2%, patients who received more than two cycles of chemotherapy showed a longer survival time in the S-1 plus LNT group. CONCLUSIONS: OS did not improve and TTF was significantly worse in the S-1 plus LNT group as compared with the S-1-only group. This study showed no efficacy of LNT when combined with S-1 treatment in patients with unresectable or recurrent gastric cancer. CLINICAL TRIAL REGISTRATION ID NUMBER: UMIN 000000574.

Efficient detection of hepatocellular carcinoma by a hybrid blood test of epigenetic and classical protein markers.

BACKGROUND: There are few blood tests for an efficient detection of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection. METHODS: The abilities of quantitative analyses of 7 genes hypermethylation in serum DNA, α-fetoprotein (AFP) and prothrombin-induced vitamin K absence II (PIVKA-II), and various combinations to detect HCC were evaluated in a training cohort of 164 HCV-infected patients (108 HCCs; 56 non-HCCs). An optimal hybrid detector, built using data for 2 methylated genes (SPINT2 and SRD5A2), AFP, and PIVKA-II, achieved the most satisfactory ability to detect HCC in the training cohort. We evaluated the ability of the optimal hybrid detector to detect HCC in an independent validation cohort of 258 consecutive HCV-infected patients (112 HCCs; 146 non-HCCs) who were newly enrolled in 4 distinct institutes. RESULTS: In the validation cohort of 258 patients, accuracy, sensitivity, and specificity of the hybrid detector for detection of HCC were 81.4%, 73.2%, and 87.7%, respectively. Notably, even when detecting HCC ≤ 2 cm in diameter, the hybrid detector maintained markedly high abilities (84.6% accuracy, 72.2% sensitivity, 87.7% specificity). Youden's index (sensitivity+specificity - 1) for HCC ≤ 2cm was 0.60, vastly much superior to the 0.39 for AFP at a cut-off value of 20 ng/ml and the 0.28 for PIVKA-II at a cut-off value of 40 mAU/ml. CONCLUSIONS: These results show that the optimal hybrid blood detector can detect HCV-related HCC more accurately.

A serous oligocystic adenoma of the head of the pancreas successfully treated by dome resection and chemocautery: a new approach to serous oligocystic adenoma.

Serous oligocystic adenoma (SOA) is an extremely rare benign tumor and ill-demarcated large cyst. We report a case of pancreatic SOA. During abdominal ultrasonography (US) for a routine health examination and computed tomography (CT), a 69-year-old woman was found to have a 9-cm unilocular cyst located in the head of her pancreas. After a 2-year follow up, the cyst was seen to increase in size. The results of US, CT, magnetic resonance imaging, endoscopic retrograde cholangiopancreatography (ERCP), and angiography led to suspicion of a benign or low grade malignancy cystadenoma of the pancreas adjacent to the peripheral organs. Fluid analysis and frozen section pathological studies revealed a serous oligocystic adenoma with no malignancy. Dome resection, chemocautery, and omental filling were performed, and the postoperative course was uneventful. SOAs are difficult to diagnose without surgery. When the cyst exists in the head of the pancreas, adjacent to the biliary tract, portal system, or visceral vessels, it is also difficult to perform complete resection without the threat of morbidity or mortality. We have developed a new approach to SOA diagnosis and treatment that involves minimally invasive procedures.