A Phase I Study of S-1 and Gemcitabine with Concurrent Radiotherapy in Patients with Non-Metastatic Advanced Pancreatic Cancer.

BACKGROUND/AIMS: To determine the recommended dose (RD) for full-dose S-1 and low-dose gemcitabine combined with radiotherapy in patients with non-metastatic advanced pancreatic cancer. METHODOLOGY: Adult patients with non-metastatic advanced pancreatic cancer (Union for International Cancer Control T stage 3 or 4) were eligible. The weekly intravenous gemcitabine (level 0-1: 200 mg/ml,level 2: 300 mg/m on Days 1, 8, 15, 22, 29, 36) dose was escalated starting from level 1 in a 3+3 design along with full dose twice-daily oral S-1 (level 0: 60 mg/m2/day, level 1-2: 80 mg/ml/day), and was administered on the same days as radiotherapy (1.8 Gy x 28 days). RESULTS: Eight patients were included in this study. A dose-limiting toxicity (DLT) (grade 4 neutropenia) was observed in one of the first three patients in level 1, and three additional patients received the level 1 dose without any severe adverse events. DLTs (grade 3/4 neutropenia) were then observed in the first two patients given level 2 dose. Therefore, level 1 was designated as the RD. Common grade 3/4 toxicities included neutropenia (62.5%), anorexia (37.5%), and pneumonitis (12.5%). CONCLUSIONS: The combination of S-1 and gemcitabine with concurrent radiotherapy is a feasible regimen at the level 1 dose.

Pancreaticoduodenectomy in portal annular pancreas: report of a case.

Portal annular pancreas (PAP) is a rare anatomical anomaly in which the pancreatic parenchyma surrounds the superior mesenteric vein and portal vein (PV) annularly. This anomaly requires careful consideration in pancreatic resection. A case is presented and the technical issues are discussed. A 61-year-old female was referred to the hospital for suspected papilla Vater adenocarcinoma. Preoperative computed tomography showed that the PV was annularly surrounded by pancreatic parenchyma. Surgery revealed the uncinate process extended extensively behind the PV and fused with the pancreatic body. The pancreas was first divided above the PV, and it was divided again in the body after liberating the PV from pancreatic annulation. The postoperative course was uneventful without pancreatic fistula. It is safer to divide the pancreatic body on the left of the fusion between the uncinate process and the pancreatic body to reduce the risk of pancreatic fistula in pancreaticoduodenectomy for PAP.

Pancreatobiliary disorders associated with pancreaticobiliary maljunction.

AIM: To clarify the features of biliary carcinomas and pancreatic disorders associated with pancreaticobiliary maljunction (PBM). METHOD: A total of 107 PBM patients with biliary dilatation were reviewed (52 with and 55 without PBM). Clinicopathological findings of biliary carcinomas, and acute or chronic pancreatitis were examined in association with PBM. We also investigated pancreatographic findings in PBM patients and the relationship to their clinical findings in view of pancreatic juice flow. RESULTS: Gallbladder and bile duct carcinomas were seen in 11 (21%) and 8 (15%) of the 52 patients with PBM and biliary dilatation, respectively. In patients with PBM without biliary dilatation (n = 55), only gallbladder carcinoma was detected in 36 (65%) patients. At diagnosis, patients with gallbladder or bile duct carcinoma associated with PBM were younger than those without PBM (p < 0.01). Gallstones were detected only in 6% of the patients with PBM-associated gallbladder carcinoma. Multiple biliary carcinomas were detected in 3 patients (38%) with PBM-associated bile duct carcinoma. While 48 patients (60%) with biliary carcinoma and PBM had a normal pancreatic duct system, only 2 gallbladder carcinomas occurred in 11 dorsal pancreatic duct (DPD)-dominant patients (p < 0.05). Amylase concentration in the bile of DPD-dominant patients was significantly lower than that of patients with a normal pancreatic duct system (p < 0.05). Ten PBM patients had pancreatic disorders: acute pancreatitis (n = 3), chronic pancreatitis (n = 5), and pancreatic carcinoma (n = 2). CONCLUSIONS: In PBM patients, pancreatobiliary reflux frequently leads to biliary cancer, and biliopancreatic reflux often leads to acute or chronic pancreatitis. The biliary tract of PBM patients can be considered premalignant.

A new embryological theory of the pancreatic duct system.

BACKGROUND/AIMS: To clarify the anatomy of the pancreatic duct system and to investigate its embryology. METHODS: We reviewed pancreatograms of 256 patients with a normal pancreatic head and 36 cases of complete pancreas divisum. RESULTS: Accessory pancreatograms were divided into two patterns. The long-type accessory pancreatic duct (APD) forms a straight line and joins the main pancreatic duct (MPD) at the neck portion of the pancreas. The short-type APD joins the MPD near its first inferior branch. The short-type APD is less likely to have a long inferior branch arising from the APD. The length of the APD from the orifice to the first long inferior branch was similar in the short- and long-type APD. The first long inferior branch from the long-type APD passes through the MPD near the origin of the inferior branch from the MPD. Immunohistochemically, in the short-type APD, the MPD between the junction of the short-type APD and the neck portion originated from the ventral pancreas. CONCLUSION: The long-type APD represents a continuation of the main duct of the dorsal pancreatic bud. The short-type APD is very likely formed by the proximal main duct of the dorsal pancreatic bud and its long inferior branch, with the main duct of the dorsal pancreatic bud at the point of connection with the main duct of the ventral pancreatic bud being obliterated and replaced by this additional communication.

FDG-PET/CT findings of autoimmune pancreatitis.

BACKGROUND/AIMS: This study aimed to evaluate the clinical utility in Fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET)/ computed tomography (CT) in the management of patients with autoimmune pancreatitis (AIP), with special emphasis on differentiating AIP from pancreatic cancer (PC). METHODOLOGY: FDG-PET/CT findings of 10 AIP patients were compared with those of 14 PC patients. RESULTS: There were no significant differences between AIP and PC in early and delayed maximum standardized uptake value (SUV(max)), and in the ratio of delayed to early SUV(max). Abnormal extrapancreatic FDG uptake was observed in 5 AIP patients, in the hilar lymph nodes (n = 4), mediastinal lymph nodes (n = 2), abdominal lymph nodes (n = 2), and bilateral salivary glands (n = 2). After steroid therapy, the abnormal FDG uptake in the pancreas disappeared almost completely in two patients, and the FDG uptake in the hilar, mediastinal and abdominal lymph nodes decreased in one patient. CONCLUSIONS: FDG-PET/CT may be helpful to differentiate AIP from PC by assessing FDG-uptake patterns in the pancreas and extrapancreatic lesions, it may have the potential to assess the disease activity of AIP and its extrapancreatic lesions, and it may be useful as a monitoring marker for tapering or stopping steroid therapy.

[A case report-neoadjuvant chemoradiotherapy with combination of S-1 and gemcitabine in a patient with locally advanced pancreatic cancer].

A 63-year-old woman was pointed out pancreatic tumor by a follow up CT after operation for the corpus uteri cancer. She was diagnosed as having locally advanced pancreatic cancer which involved the superior mesenteric vein (SMV). She was treated with radiation (1.8 Gyx28 Fr) and the combination chemotherapy of S-1 plus gemcitabine (S-1: 80 mg/m2/dayx28 days, gemcitabine 200 mg/m2/dayx6 fr, 1 fr a week). Indeed, grade 3 leukopenia and neutropenia were occurred by this treatment, she could be treated on schedule. Four weeks later from completion date, a reduction of the tumor size and an improvement of involving SMV were observed by diagnostic imaging. Subsequently, pylorus-preserving pancreatoduodenectomy (PpPD) with a partial resection of SMV and intraoperative radiation were undergone. She was discharged 19 days after the operation without any surgical complications, and is undergoing adjuvant chemotherapy.

[Low-dose gemcitabine concurrent with radiation therapy for locally advanced pancreatic carcinoma].

We evaluated the efficacy and feasibility of low-dose gemcitabine concurrent with radiation as adjuvant therapy. Nine cases of locally far advanced unresectable pancreatic cancer were enrolled in this study. Intraoperative radiation was carried out in every case using eight or ten centimeter cones with a radiation dose of twenty to twenty five Gy. Postoperative radiation was two Gy per day on weekdays for five weeks. Low-dose gemcitabine (40 mg/m2) once a week was administered prior to radiation. A grade 3 adverse event occurred in three cases. CA19-9 decreased 60.1% and DUPAN-2, 52.6%. CT scan confirmed a necrotic change and a decrease of the tumor size. Average survival time was ten months. Peritoneal dissemination was the recurrence pattern. In conclusion, low-dose gemcitabine concurrent with radiation therapy may contribute to local control of the disease. However, peritoneal dissemination must be overcome to prolong survival.

Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-kappaB inhibitor.

The effects of the nuclear factor (NF)-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), combined with tumor necrosis factor (TNF)-alpha were evaluated in PK-8 pancreatic cancer cells. NF-kappaB was activated by TNF-alpha; however, the administration of DHMEQ abrogated its transcriptional activity. The addition of DHMEQ to TNF-alpha markedly induced apoptosis in PK-8 cells with down-regulation of anti-apoptotic c-FLIP and survivin. Combined treatment significantly suppressed cell viability in vitro, and the anti-tumor effect of DHMEQ was also significant in vivo. We investigated the apoptosis signaling pathway involved in these cell killing effects. Truncated Bid was produced by activated caspase-8, and the subsequent depolarization of the mitochondrial membrane potential (Delta Psi m) peaked at 6 h. Then, the activity of caspase-3 was up-regulated 8-fold. Z-VAD-fmk (a pan-caspase inhibitor) perfectly inhibited the up-regulation of caspase-3 but failed to reverse the cell viability. The above findings indicated that the growth inhibitory effect of combined treatment largely depended on mitochondria-associated caspase-independent apoptosis. The intracellular behavior of apoptosis-inducing factor (AIF) following depolarization of Delta Psi m suggested that AIF executed such a caspase-independent apoptosis. Interestingly, caspase-dependent apoptosis appeared within 6 h, whereas the caspase-independent apoptosis lagged. Thus, the addition of DHMEQ to TNF-alpha was capable of inducing caspase-independent apoptosis in pancreatic cancer cells. Once caspase-independent apoptosis was induced, the apoptosis demonstrated powerful cytotoxicity. Therefore, DHMEQ in combination with TNF-alpha may be a promising treatment for pancreatic cancer.

[Gemcitabine concurrent with radiation for locally advanced pancreatic cancer].

Gemcitabine (GEM) concurrent with radiation is clinically not well defined. We herein report four cases of chemo-radiotherapy against locally advanced pancreatic cancer using low-dose GEM concurrent with extra-beam radiation. A total of eight cases entered the study. Three were resected and five were non-resected cases. Intraoperative radiation was carried out in every case using an 8 or 10 centimeter cone with a radiation dose of 25 Gy. Postoperative radiation was 2 Gy per day on weekdays for 5 weeks. Four cases were concurrent with low-dose GEM (40 mg/m2) twice a week, whereas the other four were radiation only. With the use of GEM concurrent with radiation, tumor markers decreased more than 80 percent regardless of the tumor resection. CT scan confirmed a necrotic change and the decrease of the tumor size. In conclusion, low dose GEM concurrent with radiation therapy may be a promising therapeutic choice for the local control of advanced pancreatic cancers.

Papillary carcinoma of the extrahepatic bile duct: characteristic features and implications in surgical treatment.

BACKGROUND: Papillary carcinoma of the extrahepatic bile duct presents clinically and histologically distinct features relevant to surgical decision-making. STUDY DESIGN: Serial sections of 15 specimens of resected papillary carcinoma of the bile duct were histologically examined to determine mode of spread, possibility of multicentric tumor origins, and coincidence with other neoplastic lesions. The presence of anomalous pancreaticobiliary ductal union was also investigated. These characteristics were considered with regard to surgical treatment. RESULTS: Three patients displaying pancreaticobiliary maljunction and one of three patients with a long common channel (> or = 8 mm) exhibited multicentric tumors. Eight patients (53%) demonstrated superficial spread along a mean length of 37.8 mm (range, 5 to 67 mm) of bile duct mucosa. Multicentric tumors developed synchronously in 4 patients, while metachronous tumors were identified in three patients displaying tumor histology similar to the primary lesions. Two of these three underwent successful repeated resection. Concomitant neoplastic lesions in the biliary tract were identified as mucosal dysplasia in four patients and cholangiocellular carcinoma of the liver in two. All tumors but one were removed via hepatic lobectomy or pancreatoduodenectomy, or both, resulting in a 5-year survival rate of 60%. CONCLUSIONS: Aggressive resection offers clear survival benefits for patients presenting with tumors displaying extensive superficial spread or multicentric origins. Closer attention should be paid to long common channels in relation to carcinogenesis of the bile duct, in addition to pancreaticobiliary maljunction. The risk of secondary tumor development remains, particularly in patients with pancreaticobiliary maljunction even after excision of the tumor-bearing extrahepatic bile duct.

Survival benefit of KRN7000 immune therapy in combination with TNP470 in hamster liver metastasis model of pancreatic cancer.

Pancreatic cancer is a solid malignancy with the poor prognosis largely due to frequent and lethal liver metastases. The combination of immunotherapy and anti-angiogenesis therapy might be a hopeful strategy for the treatment of distant metastases. The benefits of the combination therapy by an immune stimulator alpha-galactosylceramide (KRN7000) and an angiogenesis inhibitor AGM-1470 (TNP470) were evaluated on the hamster highly aggressive liver metastasis model using the syngeneic pancreatic cancer cell line HPD-NR. KRN7000 immediately activated hepatic mono-nuclear cells to produce IFN-gamma in vitro. Intraportal injection of KRN7000 exhibited a dense accumulation of CD4-CD8- natural killer T cells, around the liver metastases in vivo. KRN7000 treatment significantly inhibited the growth of liver metastases, and importantly, significant survival prolongation was confirmed when TNP470 treatment was added to it. Furthermore, cytotoxic T lymphocytes were induced at the sites of a few residual metastases in the liver of a long-term survivor. Thus, the combination of KRN7000 and TNP470 showed a high effectiveness for the treatment of liver metastases of pancreatic cancer.

DFU, a selective COX-2 inhibitor, suppresses MCF-7 xenograft tumor growth in mice.

Cyclooxygenase-2 (COX-2) inhibitors are regarded as potentially important in strategies for cancer treatment. however, the precise mechanisms of these anti-inflammatory drugs as anti-cancer therapy are still unknown. In this study, we examined the effect of DFU both in vitro on MCF-7 cell growth, as well as in vivo on tumor growth produced by MCF-7 cell injection in mice. DFU has growth inhibitory effects on tumor growth in mice compared to the control group. We examined the tumor tissues for apoptosis and angiogenesis by immunostaining. Apoptosis was detected only in the treatment group. DFU treatment also resulted in the inhibition of angiogenesis, as well as decreased COX-2 expression. Results of this study suggest that inhibitory effects of DFU might be COX-2 dependent.

Impact of selective Glisson transection on survival of hepatocellular carcinoma.

BACKGROUND/AIMS: The aim of this study is to assess whether selective transection of tumor-bearing portal pedicle before dissection of the liver parenchyma in hepatectomy for hepatocellular carcinoma can prevent intraoperative spread of the tumor and can lead to the prolongation of postoperative survival. METHODOLOGY: Survival for 159 patients who underwent hepatectomies with selective portal transection by Glissonean pedicle transection method was retrospectively compared with that of 100 patients who underwent hepatectomies with Pringle maneuver. According to the number of recurrent tumors, intrahepatic recurrence was divided into two types: nodular type of 3 or less, diffuse type of 4 or more. RESULTS: The 5-year survival for the patients who underwent hepatectomies with Glissonean pedicle transection method was significantly higher than that with Pringle maneuver (64.7% vs. 36.4%, p < 0.0001, log-rank test). The diffuse type recurrence, which occurred early and resulted in the unfavorable prognosis compared with the nodular type, was significantly reduced in patients treated with Glissonean pedicle transection method compared with those with Pringle maneuver (p = 0.0013). Multivariate analyses demonstrated that Glissonean pedicle transection method was a potent independent prognostic indicator for survival. CONCLUSIONS: Glissonean pedicle transection method prevented intraoperative metastasis and significantly improved the postoperative survival in patients with hepatocellular carcinoma.

[Novel chemoradiotherapy for locally advanced pancreatic cancer using arterial infusion chemotherapy following the alteration of peripancreatic blood flow].

Radiotherapy employing intraoperative radiation therapy (IORT) in combination with postoperative external beam radiation therapy (EBRT) is an effective treatment for unresectable pancreatic cancer. To achieve an even greater therapeutic outcome, 13 patients with unresectable pancreatic cancer were treated by IORT in combination with EBRT plus locally intensive arterial infusion chemotherapy. In order to increase drug delivery to the primary tumor, the splenic and major pancreatic arteries, except for the gastroduodenal artery (GDA), were embolized by radiological intervention prior to the arterial infusion chemotherapy, and the administration of gemcitabine, CDDP, and 5-FU to the primary tumors via GDA was followed during EBRT. The values of serum tumor markers were decreased in all patients, and tumor regression was detected on CT scans in 6 patients. The evaluation of survival benefit of this treatment modality is ongoing, but it did not prolong the survival time of patients with second stage lymph node metastases. One of the advantages of this method was able to perform also in charge of hepatic arterial infusion chemotherapy concurrently, but we experienced liver abscess in 2 patients.

[Successful hepatic arterial infusion therapy of CDDP/5-FU/IFN-beta3 for recurrent hepatocellular carcinoma].

A 52-year-old male patient was admitted to our hospital for a further examination of liver tumor. He was positive for hepatitis C virus antibody. CT scanning revealed two hyper vascular tumors at the lateral segment of the liver and another one located at segment 8, an indication of hepatocellular carcinoma (HCC). Ascites were not detected and major serological findings were T-Bil 1.1 mg/dl, Alb 3.5 g/dl, ICG R15 12% and PT 88%. Lateral segmentectomy and a partial resection of the segment 8 were performed at the same time. An insertion of catheter in hepatic artery via gastroduodenal artery was carried out. Dehydropyrimidine dehydrogenase (DPD) activity of the tumor was 157 pmol/min/mg proteins. Recurrence was detected one year after the operation at segments 4 and 8. Arterial infusion chemotherapy using CDDP (10 mg), 5-FU (1,000 mg) and IFN-beta 3MU (continuous infusion for 5 days) was started two months later, and a complete response was achieved. The chemotherapy continued as long as severe adverse effects were not observed. However, two months after the tumor disappearance, the treatment discontinued due to occlusion of the infusion system. Recurrence occurred in two months at the same location where the previous tumor was. In conclusion, these results suggest that arterial chemotherapy using CDDP/5-FU/IFN-beta against HCC may be beneficial.

[Metastatic gastrointestinal stromal tumors responded to the treatment with STI571 after polysurgery for recurrent lesions--report of two cases].

Two cases of metastatic gastrointestinal stromal tumors (GIST) that had responded to the treatment with STI571 were presented. Case 1 was a 49-year-old woman who had undergone proximal gastrectomy because of a giant submucosal tumor of the stomach. For 21 months after surgery, the patient received repeated tumor removal four times due to hepatic metastasis and/or peritoneal recurrence. Thereafter, the treatment with STI571 at a dose of 400 mg/day was initiated. Eight months after the administration, only a small hepatic metastasis was detected on a film of CT scan, and any signs of peritoneal recurrence were observed. Case 2 was a 61-year-old man who underwent emergency surgery for a retroperitoneal tumor that had caused massive intestinal hemorrhage resulting in critical shock. The patient underwent the surgery three times for recurrent lesions. Because further tumor removal had become nearly impossible, STI571 at a dose of 400 mg/day was administered 35 months after initial surgery. Six months after treatment the hepatic lesions were shrunk, but the number of retroperitoneal lesions increased. At present, the patient has no abdominal complaints and has a good quality of life. GIST was confirmed in both cases, by histopathological analyses of the resected specimens: positive expression of c-kit and CD34. These clinical observations suggest that ST1571 therapy for metastatic lesions from GIST may be preferred over aggressive, repeated tumor removal.

Differentiating immunoglobulin g4-related sclerosing cholangitis from hilar cholangiocarcinoma.

BACKGROUND/AIMS: Few studies have differentiated immunoglobulin G (IgG) 4-related sclerosing cholangitis (IgG4-SC) from hilar cholangiocarcinoma (CC). Thus, we sought to investigate useful features for differentiating IgG4-SC from hilar CC. METHODS: We retrospectively compared clinical, serological, imaging, and histological features of six patients with IgG4-SC and 42 patients with hilar CC. RESULTS: In patients with hilar CC, obstructive jaundice was more frequent (p<0.01), serum total bilirubin levels were significantly higher (p<0.05), serum CA19-9 levels were significantly higher (p<0.01), and serum duke pancreatic monoclonal antigen type 2 levels were frequently elevated (p<0.05). However, in patients with IgG4-SC, the serum IgG (p<0.05) and IgG4 (p<0.01) levels were significantly higher and frequently elevated. The pancreas was enlarged in all IgG4-SC patients but only in 17% of hilar CC patients (p<0.01). Salivary and/or lacrimal gland swelling was detected in only 50% of IgG4-SC patients (p<0.01). Endoscopic retrograde cholangiography revealed that the hilar or hepatic duct was completely obstructed in 83% of hilar CC patients (p<0.01). Lower bile duct stenosis, apart from hilar bile duct stenosis, was more frequent in IgG4-SC patients (p<0.01). Bile duct wall thickening in areas without stenosis was more frequent in IgG4-SC patients (p<0.01). CONCLUSIONS: An integrated diagnostic approach based on clinical, serological, imaging, and histological findings is necessary to differentiate IgG4-SC from hilar CC.

Importance of early diagnosis of pancreaticobiliary maljunction without biliary dilatation.

AIM: To clarify the strategy for early diagnosis of pancreaticobiliary maljunction (PBM) without biliary dilatation and to pathologically examine gallbladder before cancer develops. METHODS: The anatomy of the union of the pancreatic and bile ducts was assessed by using endoscopic retrograde cholangiopancreatography (ERCP). Patients with a long common channel in which communication between the pancreatic and bile ducts was maintained even during sphincter contraction were diagnosed as having PBM. Of these, patients in which the maximal diameter of the bile duct was less than 10 mm were diagnosed with PBM without biliary dilatation. The process of diagnosing 54 patients with PBM without biliary dilatation was retrospectively investigated. Histopathological analysis of resected gallbladder specimens from 8 patients with PBM without biliary dilatation or cancer was conducted. RESULTS: Thirty-six PBM patients without biliary dilatation were diagnosed with gallbladder cancer after showing clinical symptoms such as abdominal or back pain (n = 16) or jaundice (n = 12). Radical surgery for gallbladder cancer was only possible in 11 patients (31%) and only 4 patients (11%) survived for 5 years. Eight patients were suspected as having PBM without biliary dilatation from the finding of gallbladder wall thickening on ultrasound and the diagnosis was confirmed by ERCP and/or magnetic resonance cholangiopancreatography (MRCP). The median age of these 8 patients was younger by a decade than PBM patients with gallbladder cancer. All 8 patients underwent prophylactic cholecystectomy and bile duct cancer has not occurred. Wall thickness and mucosal height of the 8 resected gallbladders were significantly greater than controls, and hyperplastic changes, hypertrophic muscular layer, subserosal fibrosis, and adenomyomatosis were detected in 7 (88%), 5 (63%), 7 (88%) and 5 (63%) patients, respectively. Ki-67 labeling index was high and K-ras mutation was detected in 3 of 6 patients. CONCLUSION: To detect PBM without biliary dilatation before onset of gallbladder cancer, we should perform MRCP for individuals showing increased gallbladder wall thickness on ultrasound.

Large cystic acinar cell carcinoma of the pancreas.

Acinar cell carcinoma of the pancreas is a rare neoplasm exhibiting pancreatic enzyme production by the neoplastic cells. It has a highly characteristic cellular arrangement reflecting its acinar derivation, and a definite diagnosis is made based on immunohistochemical and ultrastructural results. Such tumors are often large but rather well circumscribed. Some cases have a cystic appearance due to hemorrhage or necrosis, but a large cystic mass appearing as a pseudocyst is quite rare. We present a large cystic acinar cell carcinoma of the pancreas.