[A Case of Hepatic Undifferentiated Embryonal Sarcoma in an Adult].

A 20-year-old woman was admitted with abdominal pain and a cystic liver tumor. A hemorrhagic cyst was suspected. Contrast-enhanced computed tomography(CT)and magnetic resonance imaging(MRI)revealed a space-occupying solid mass in the right lobule. Positron emission tomography(PET)-CT revealed 18F-fluorodeoxyglucose uptake in the tumor. We performed a right hepatic lobectomy. Histopathological evaluation of the resected tumor revealed an undifferentiated embryonal sarcoma of the liver(UESL). The patient refused adjuvant chemotherapy but showed no recurrence 30 months postoperatively. UESL is a rare malignant mesenchymal tumor that occurs in infants and children. It is extremely rare and is associated with poor prognosis in adults. In this report, we described a case of adult UESL.

[Two Cases of Laparoscopic Partial Resection of Stomach Using a Trans-Gastric Wall Approach for Submucosal Tumors].

We performed laparoscopic partial resection of the stomach with a trans-gastric wall approach for submucosal tumors. Case 1: A 67-year-old woman was referred to our hospital because of tarry stool. Upper gastrointestinal endoscopy revealed a well demarcated, round, 45mm intraluminal-type submucosal tumor with delle on the anterior wall of the gastric upper body. Case 2: An 86-year-old woman was referred to our hospital because of anemia. Upper gastrointestinal endoscopy revealed a well demarcated, round, 25mm intraluminal-type submucosal tumor on the posterior wall of the gastric upper body. Laparoscopic partial resection of the stomach with a trans-gastric wall approach was performed. The operation times were 58 minutes and 73 minutes, respectively, and blood loss was low in both cases. This operative procedure is safe and easy and allows for resection resected with a direct view for surgeons without endoscopists.

Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: results from a prospective multi-institutional phase 2 trial.

BACKGROUND: Surgical resection is the only curative strategy for pancreatic ductal adenocarcinoma (PDAC), but recurrence rates are high even after purported curative resection. First-line treatment with gemcitabine and S-1 (GS) is associated with promising antitumor activity with a high response rate. The aim of this study was to assess the feasibility and efficacy of GS in the neoadjuvant setting. METHODS: In a multi-institutional single-arm phase 2 study, neoadjuvant chemotherapy (NAC) with gemcitabine and S-1, repeated every 21 days, was administered for two cycles (NAC-GS) to patients with resectable and borderline PDAC. The primary end point was the 2-year survival rate. Secondary end points were feasibility, resection rate, pathological effect, recurrence-free survival, and tumor marker status. RESULTS: Of 36 patients enrolled, 35 were eligible for this clinical trial conducted between 2008 and 2010. The most common toxicity was neutropenia in response to 90% of the relative dose intensity. Responses to NAC included radiological tumor shrinkage (69%) and decreases in CA19-9 levels (89%). R0 resection was performed for 87% in resection, and the morbidity rate (40%) was acceptable. The 2-year survival rate of the total cohort was 45.7%. Patients who underwent resection without metastases after NAC-GS (n = 27) had an increased median overall survival (34.7 months) compared with those who did not undergo resection (P = 0.0017). CONCLUSIONS: NAC-GS was well tolerated and safe when used in a multi-institutional setting. The R0 resection rate and the 2-year survival rate analysis are encouraging for patients with resectable and borderline PDAC.

[A 5-year survival case of locally advanced cancer of the pancreatic body treated by distal pancreatectomy with en bloc celiac axis resection after neoadjuvant chemoradiation therapy].

A 59-year-old man was diagnosed with locally advanced cancer of the pancreatic body, involving the nerve plexus around the celiac axis, the common hepatic artery, and the splenic artery. He was treated with a combination of irradiation (2 Gy/day, total 24 Gy) and 600 mg/m2 of gemcitabine(GEM)biweekly. The tumor size and the involved plexus area were not diminished, but CA19-9 was reduced by half. Distal pancreatectomy with en bloc celiac axis resection(DP-CAR)was performed. The histological findings indicated extensive invasion into the nerve plexus, including that adjacent to the stump of the pancreas, and thus the R classification was R1. After surgery, 1,000 mg/m2 of GEM was administered biweekly. The chemotherapy has been performed for 5 years to prevent local and systemic recurrence. No recurrence has been found 5 years after surgery. Multidisciplinary treatment, combined with neoadjuvant chemoradiation therapy, curative-intent resection, and postoperative chemotherapy is important for effective treatment of locally advanced pancreatic cancer.

Clinicopathological characteristics and molecular analyses of multifocal intraductal papillary mucinous neoplasms of the pancreas.

OBJECTIVE: To examine the clinicopathologic features and clonal relationship of multifocal intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. BACKGROUND: Intraductal papillary mucinous neoplasms are increasingly diagnosed cystic precursor lesions of pancreatic cancer. Intraductal papillary mucinous neoplasms can be multifocal and a potential cause of recurrence after partial pancreatectomy. METHODS: Thirty four patients with histologically documented multifocal IPMNs were collected and their clinicopathologic features catalogued. In addition, thirty multifocal IPMNs arising in 13 patients from 3 hospitals were subjected to laser microdissection followed by KRAS pyrosequencing and loss of heterozygosity (LOH) analysis on chromosomes 6q and 17p. Finally, we sought to assess the clonal relationships among multifocal IPMNs. RESULTS: We identified 34 patients with histologically documented multifocal IPMNs. Synchronous IPMNs were present in 29 patients (85%), whereas 5 (15%) developed clinically significant metachronous IPMNs. Six patients (18%) had a history of familial pancreatic cancer. A majority of multifocal IPMNs (86% synchronous, 100% metachronous) were composed of branch duct lesions, and typically demonstrated a gastric-foveolar subtype epithelium with low or intermediate grades of dysplasia. Three synchronous IPMNs (10%) had an associated invasive cancer. Molecular analysis of multiple IPMNs from 13 patients demonstrated nonoverlapping KRAS gene mutations in 8 patients (62%) and discordant LOH profiles in 7 patients (54%); independent genetic alterations were established in 9 of the 13 patients (69%). CONCLUSIONS: The majority of multifocal IPMNs arise independently and exhibit a gastric-foveolar subtype, with low to intermediate dysplasia. These findings underscore the importance of life-long follow-up after resection for an IPMN.

[A case of distal cholangiocarcinoma with high sensitivity to neoadjuvant chemoradiation therapy].

We hypothesized that neoadjuvant chemoradiation therapy for cholangiocarcinoma (NACRAC) using gemcitabine would improve the prognosis of resected cases. Phase II trial of NACRAC is ongoing. We report a very effective case to NACRAC for distal cholangiocarcinoma, which markedly reduced the size and levels of the tumor markers. The patient was a 50- year-old man who presented jaundice. Serum tumor markers were clearly elevated, and abdominal CT scan revealed an enhanced mass in the lower bile duct, a dilatation of the intrahepatic to the middle bile duct and a swollen regional lymph node. After NACRAC, the tumor markers were decreased within a normal range. Also on CT scan, the main tumor was slightly detectable and the swollen node was reduced more than 30% in short diameter. Therefore, the effect of NACRAC was considered PR in RECIST guidelines (ver.1 .1). Pancreaticoduodenectomy was performed 2 weeks after NACRAC. No perioperative complications occurred. Pathological examination showed a good response, Grade 2b on Oboshi-Shimosato's classification. In this case, NACRAC had a good effect in imaging and pathological findings as well as in the tumor markers. Therefore, the neoadjuvant chemoradiation therapy has a potential to improve the prognosis for cholangiocarcinoma.

Severe cholestatic liver failure associated with gemcitabine adjuvant monotherapy for pancreatic cancer.

We report a case of severe hepatic failure caused by gemcitabine hydrochloride (GEM) monotherapy after pancreaticoduodenectomy for advanced pancreatic cancer. A 73-year-old woman received GEM as an adjuvant chemotherapy. She suffered from progressive edema, fatigue, and jaundice after the third GEM administration. Severe liver dysfunction and elevation of bilirubin was observed. A computed tomography scan and magnetic resonance imaging showed diffuse liver swelling suggesting severe hepatic edema with fat accumulation. Needle biopsy of the liver revealed remarkable cholestasis and fat deposition with mild damage of hepatocytes. Drug-induced liver failure was suspected. GEM-stimulated lymphocyte test was negative, but antinuclear antibody was elevated with a marked inflammatory response. She improved to an almost normal condition by steroid and liver protective therapies within a week. Although the frequency of liver failure induced by GEM monotherapy is very rare, it could be fatal. It is important to distinguish it from other causes of liver dysfunction following pancreaticoduodenectomy. Early detection and appropriate drug therapy can improve the prognosis.

Computed tomography reflected endocrine function of the pancreas.

UNLABELLED: BACKGROUNS/AIMS: There are few studies about the assessment of pancreatic function using computed tomography (CT) volumetry. In this study, we examined the correlation between CT volumetry and endocrine parameters (blood glucose and HbA1c) of the pancreas. METHODS: A total of 68 patients underwent enhanced CT for pancreatic disease from January to December in 2008. In particular, we analyzed the correlation of diabetic status and pancreatic CT parameters at 1 year after pancreatoduodenectomy in 32 patients. CT parameters including volume, volume/body weight, arterial phase density, the arterial phase to portal phase density ratio (A/P ratio) of the pancreas, and size of pancreatic duct were also analyzed. Correlation between CT parameters and diabetic status was analyzed preoperatively and postoperatively by ANOVA test. RESULTS: The preoperative diabetic status and parameters correlated well with arterial phase density (p = 0.004), A/P ratio, and pancreatic duct size (p < 0.0001). In the patients who underwent pancreatectomy, two out of 25 patients without preoperative diabetes mellitus (DM) had DM, and two out of seven patients with preoperative DM recovered from DM. Postoperative CT parameters correlated with the DM status 1 year after pancreatectomy. CONCLUSION: CT is a useful modality for evaluation of the pancreatic endocrine function and could be used for the prediction of postoperative diabetic outcome.

[Long-term survival case after liver resection and postoperative hepatic arterial infusion for multiple liver metastases from rectal cancer].

A 45-year-old man underwent a low anterior resection for rectal cancer [T3, N1, M0, Stage IIa: UICC]. He received a postoperative systemic chemotherapy with 5-FU and LV. Five months after the operation, multiple liver metastases were detected in the right hepatic lobe (S5, 6, 8). Right hepatectomy was performed. Seventeen courses of postoperative hepatic arterial infusion (HAI) chemotherapy (weekly high-dose 5-FU regimen) were performed without severe adverse events. He was still alive with no sign of recurrence for 69 months after hepatectomy. After liver resection for metastases of colorectal cancer, although a systemic chemotherapy has been mainly performed, HAI chemotherapy is one of the important options for prevention of local recurrence.

Assessment of Frey procedures: Japanese experience.

BACKGROUND/PURPOSE: The Frey procedure, the coring out of the pancreatic head and longitudinal pancreaticojejunostomy, is a safe, easy, and reliable method to solve most of the problems associated with chronic pancreatitis. During long-term follow up, unexpected relapse in the pancreatic tail was encountered. The pattern of failure and the rationale for a new procedure to treat or prevent such relapse were investigated. METHODS: From 1992 to 2008, 71 patients with chronic pancreatitis underwent the Frey procedure at Tohoku University Hospital. The etiology was alcoholic in 92.6% of them, followed in incidence by idiopathic and hereditary chronic pancreatitis. In the primary operation, besides the Frey procedure, combined resection of the pancreatic tail was performed in three patients, and choledochoduodenostomy was performed in one patient. The follow-up rate was 92.9%, with a median period of 46 months. RESULTS: The incidence of early postoperative complications was 18.4%, with one reoperation for gastrointestinal bleeding from the splenic artery. Pain control was achieved in all patients and there was no operative mortality. During the long-term follow up of 62 patients with the Frey procedure, eight patients had relapse of inflammation and required reoperation. Five of these eight patients had a pseudocyst in the pancreatic tail and underwent distal pancreatectomy (DP). CONCLUSIONS: Relapse occurred in alcoholic middle-aged male patients, and in the patients with hereditary and idiopathic pancreatitis. Frey-DP and Frey-spleen-preserving DP (SPDP) procedures can be performed safely and effectively to treat the relapse and to prevent relapse in the pancreatic tail.

Institutional indications for islet transplantation after total pancreatectomy.

BACKGROUND/PURPOSE: This study was designed to establish institutional indications for pancreatic islet transplantation by examining patients with total pancreatectomy as candidates for islet allotransplantation. METHODS: In 12 patients who underwent total pancreatectomy, we compared pre-and postoperative plasma glucose level, body mass index, HbA1c, and daily insulin use; we examined candidacy for islet allotransplantation based on the guidelines of Japan's islet transplantation registry. RESULTS: Eight of the 12 patients with total pancreatectomy were operated for intraductal papillary mucinous neoplasm. At our institution, the 5-year survival of patients with intraductal papillary mucinous neoplasm was far better (76.3%) than that of patients with pancreatic cancer. Postoperatively, plasma glucose level, HbA1c, and daily insulin use were increased in all patients with total pancreatectomy. Of the 12 patients treated with total pancreatectomy, 4 (intraductal papillary mucinous neoplasm, n = 2; islet cell tumor, n = 1; and acute pancreatitis due to arteriovenous malformation, n = 1) showed deteriorated diabetic control and therefore were considered to be candidates for islet allotransplantation according to the guidelines. CONCLUSIONS: Islet allotransplantation could be indicated for patients with favorable postoperative survival who have had a total pancreatectomy for either benign or neoplastic disease.

Oncolytic virotherapy as a novel strategy for pancreatic cancer.

We have developed a novel gene therapy that targets genetic alterations in pancreatic cancer using oncolytic replication-selective adenoviruses in tumor cells. E1B-55kDa-deleted adenovirus (AxE1AdB) can selectively replicate in TP53-deficient human cancer cells but not cells with functional TP53. Consecutive injection with AxE1AdB markedly inhibited the growth of human pancreatic tumors in severe combined immunodeficiency disease mice. Furthermore, AxE1AdB displayed the ability to enhance gene expression as a virus vector. It is reported that uracil phosphoribosyl transferase (UPRT) overcomes 5-FU resistance. The therapeutic advantage of a replication-selective adenovirus that expresses UPRT (AxE1AdB-UPRT) was thus evaluated in an intraperitoneum-disseminated tumor model. Combined treatment with 5-FU and AxE1AdB-UPRT dramatically reduced the disseminated tumor burden without causing toxicity in normal tissues. We also clarified the process of AxE1AdB-inhibited tumor angiogenesis through the preserved E1A region: an adenoviral E1A protein binds to pRB, forcing the quiescent cell into the S phase. We constructed a double-mutant, replication-selective adenovirus (AxdAdB-3) containing a mutation in the RB-binding motif of the E1A region and a deletion of large E1B-55kDa. AxdAdB-3 swiftly induced cancer cell death in vitro and showed a potent antitumor effect in vivo. These results strongly suggest that AxdAdB-3 possesses a wider therapeutic potential than previously believed, given that most pancreatic cancers have abnormalities in both the TP53 and RB pathways.

[Chemotherapy for pancreatic cancer].

Pancreatic cancer has one of the worst prognosis of any malignant disease. The National Registry of Japan Pancreas Society has reported that only 13% of patients achieve 5 years survival after surgical resection. The vast majority of patients present with metastatic or unresectable disease. Gemcitabine (GEM) has replaced 5-fluorouracil (5-FU)-based chemotherapy as the standard of care. GEM first generated improvements in symptom control and survival in advanced disease, spurring further research. For locally advanced disease, most recent studies have incorporated GEM into combined-modality therapy. However, subsequent trials have not demonstrated that combinations of other agents with GEM extend clinical benefits yet. Similarly, in surgically resectable disease, current trials are incorporating GEM into adjuvant therapy. According to several clinical trials it has been demonstrated that improvements in locoregional control and survival may be achieved when chemotherapy using 5-FU is added to radiation for locally advanced pancreatic cancer. The new regimen for locally advanced disease has demonstrated that the better outcome is expected by chemoradiation therapy with 5-FU followed by GEM treatment. Furthermore, one of the patients showed the significant regression of pancreas tumor, resulting in the successful surgical resection. In order to develop chemotherapy for pancreatic cancer, we are analyzing mRNA expression of pancreas cancer cell lines and examined their resistant against to GEM. One of the genes is demonstrated to be a responsible for drug sensitivity by clustering analysis.

Gene therapy for pancreatic cancer targeting the genomic alterations of tumor suppressor genes using replication-selective oncolytic adenovirus.

In order to develop an effective therapeutic intervention for patients with pancreatic cancer, we examined the genetic alternations of pancreatic cancer. Based on these results, we are developing a new gene therapy targeting the genetic character of pancreatic cancer using mutant adenoviruses selectively replication-competent in tumor cells. Loss of heterozygosity (LOH) of 30% or more were observed on chromosome arms 17p (47%), 9p (45%), 18q (43%), 12q (34%), and 6q (30%). LOH of 12q, 17p, and 18q showed the significant association with poor prognosis. These data strongly suggest that mutation of the putative suppressor genes, TP53 and SMAD4 play significant roles in the disease progression. Based on this rationale, we are developing a new gene therapy targeting tumors without normal TP53 function. E1B-55kDa-deleted adenovirus (AxE1AdB) can selectively replicate in TP53-deficient human tumor cells but not cells with functional TP53. We evaluated the therapeutic effect of this AxE1AdB on pancreatic cancer without normal TP53 function. The growth of human pancreatic tumor in SCID mice model was markedly inhibited by the consecutive injection of AxE1AdB. Furthermore, AxE1AdB is not only the strong weapon but also useful carrier of genes possessing anti-tumor activities as a virus vector specific to tumors without normal TP53 function. It was reported that uracil phosphoribosyl transferase (UPRT) overcomes 5FU resistance. UPRT catalyzes the synthesis of 5-fluorouridine monophosphate (FUMP) from Uracil and phosphoribosylpyrophosphate (PRPP). The antitumor effect of 5FU is enhanced by augmenting 5-fluorodeoxyuridine monophosphate (FdUMP) converted from FUMP, which inhibits Thymidylate Synthetase (TS). The therapeutic advantage of restricted replication competent adenovirus that expresses UPRT (AxE1AdB-UPRT) was evaluatedin an intra-peritoneal disseminated tumor model. To study the anti-tumor effect of AxE1AdB-UPRT/5FU, mice with disseminated AsPC-1 tumors were administered the adenovirus, followed by the 5FU treatment. It was shown that the treatment with AxE1AdB-UPRT/5FU caused a dramatic reduction of the disseminated tumor burden without toxicity in normal tissues. These results revealed thatthe AxE1AdB-UPRT/5FU system is a promising tool for intraperitoneal disseminated pancreatic cancer.