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Hirofumi Kogure,
Hiroyuki Isayama,
Yousuke Nakai,
Takeshi Tsujino,
Saburo Matsubara,
Yoko Yashima,
Yukiko Ito,
Tsuyoshi Hamada,
Naminatsu Takahara, Koji Miyabayashi,
Suguru Mizuno,
Dai Mohri,
Kazumichi Kawakubo,
Takashi Sasaki,
Natsuyo Yamamoto,
Kenji Hirano,
Naoki Sasahira,
Minoru Tada,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Endoscopic bilateral self-expandable metallic stent (SEMS) placement in a stent-in-stent method for malignant hilar biliary obstruction is technically challenging. Technical difficulties in the initial placement and reinterventions for stent occlusion are disadvantages inherent to this stent-in-stent method. We previously reported the feasibility of Niti-S large cell D-type biliary stents (LCD). This multicenter prospective consecutive study evaluated the efficacy of bilateral SEMS placement using modified LCD with large and uniform cells, a slimmer delivery system and high radial force. PATIENTS AND METHODS: From July 2010 to June 2011, 26 consecutive patients with unresectable malignant hilar biliary obstruction underwent endoscopic bilateral placement of modified LCD in a stent-in-stent method at three tertiary hospitals. Ten patients had gallbladder cancer, eight had cholangiocarcinoma, four had lymph node metastasis, two had intrahepatic cholangiocarcinoma, and two had liver metastasis. RESULTS: Single-session and final technical success rate was 96% and 100%, respectively. Functional success rate was 89%. Stent occlusion occurred in 11 patients (42%) because of sludge (n = 7) or tumor ingrowth (n = 4). Endoscopic bilateral reintervention was technically easy and successful: six patients had stent clearance by balloon sweeping and five had plastic stent placement. According to Kaplan-Meier analysis, median survival and stent patency were 220 days and 157 days, respectively. CONCLUSIONS: Modified LCD achieved a high technical success rate both in the initial stent-in-stent placement and in bilateral reinterventions in patients with malignant hilar biliary obstruction.
Digestive Endoscopy 03/2013; · 1.19 Impact Factor
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Kazumichi Kawakubo,
Hiroyuki Isayama,
Naoki Sasahira,
Yousuke Nakai,
Hirofumi Kogure,
Tsuyoshi Hamada, Koji Miyabayashi,
Suguru Mizuno,
Takashi Sasaki,
Yukiko Ito,
Natsuyo Yamamoto,
Kenji Hirano,
Minoru Tada,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: The endoscopic ultrasound-guided rendezvous techniques (EUS-rendezvous) provide reliable biliary access after failed endoscopic retrograde cholangiopancreatography (ERCP) cannulation. We evaluated the clinical utility of an EUS-rendezvous technique using various approach routes. METHODS: Patients undergoing EUS-rendezvous for biliary access after failed bile duct cannulation in ERCP were included. EUS-rendezvous was performed via three approach routes depending on the patient's condition: transgastric, transduodenal in a short endoscopic position, or transduodenal in a long endoscopic position. The main outcomes were the technical success rates. Secondary outcomes were procedure time and complications. RESULTS: Fourteen patients (median age, 77 years) underwent EUS-rendezvous for biliary access resulting from failed biliary cannulation. The reasons for biliary drainage were malignant biliary obstruction in five patients and choledocholithiasis in nine. Transgastric, transduodenal in a short position, and transduodenal in a long position EUS-rendezvous was performed in five, five, and four patients, respectively. Bile duct puncture occurred in the left intrahepatic duct in four patients, right hepatic duct in one, middle common bile duct in four, and lower common bile duct in five. The technical success rate was 100 %. In four patients, the approach route was modified from transduodenal in a short position to transduodenal in a long position or transgastric route. The median procedure time was 81 min. One case each of biliary peritonitis and pancreatitis occurred and were managed conservatively. CONCLUSIONS: EUS-rendezvous provided safe and reliable transpapillary bile duct access after failed ERCP cannulation. The selection of the appropriate approach routes, depending on patient condition, is critical.
Surgical Endoscopy 03/2013; · 4.01 Impact Factor
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Natsuyo Yamamoto,
Hiroyuki Isayama,
Hiroshi Kawakami,
Naoki Sasahira,
Tsuyoshi Hamada,
Yukiko Ito,
Naminatsu Takahara,
Rie Uchino, Koji Miyabayashi,
Suguru Mizuno,
Hirofumi Kogure,
Takashi Sasaki,
Yousuke Nakai,
Masaki Kuwatani,
Kenji Hirano,
Minoru Tada,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Endoscopic transluminal treatment of pancreatic fluid collections (PFC) has been reported as an effective alternative approach to surgical treatment. A wide, short stent with an anti-migration system has been developed. OBJECTIVE: To evaluate a newly developed, fully covered, self-expandable metal stent (FCSEMS) customized for cystogastrostomy. DESIGN: Retrospective case series. SETTING: Tertiary-care academic medical centers and affiliated hospitals. PATIENTS: Nine patients who underwent endoscopic treatment of PFCs (5 with pseudocysts and 4 with walled-off pancreatic necrosis). INTERVENTION: Stent deployment after endoscopic US-guided puncture. Irrigation and necrosectomy were performed at the discretion of the endoscopist. MAIN OUTCOME MEASUREMENTS: Technical and clinical success rate, complications, and removability. RESULTS: The FCSEMS was inserted successfully in all cases (9/9, 100%). Clinical success was achieved in 7 of 9 cases (77.8%). No early complications associated with the procedure were observed. Late complications were observed in 2 cases (bleeding and asymptomatic migration). The FCSEMS was removed without any complications in all 6 cases where it was attempted after the procedure had been completed (100%). LIMITATIONS: This was a retrospective evaluation of a small number of cases. The FCSEMS was always inserted via the transgastric route. Follow-up duration was short. CONCLUSION: The endoscopic approach that uses this new FCSEMS is feasible for the treatment of PFCs. However, further evaluation is required.
Gastrointestinal endoscopy 02/2013; · 6.71 Impact Factor
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Koji Miyabayashi,
Hideaki Ijichi,
Dai Mohri,
Motohisa Tada,
Keisuke Yamamoto,
Yoshinari Asaoka,
Tsuneo Ikenoue,
Keisuke Tateishi,
Yousuke Nakai,
Hiroyuki Isayama,
Yasuyuki Morishita,
Masao Omata,
Harold L Moses,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide. Although many regimens have been used for PDAC treatment, the combination of the epidermal growth factor receptor (EGFR) inhibitor, erlotinib with gemcitabine has been the only molecular targeted drug tested so far which has been superior to gemcitabine alone. The mechanism underlying this effective combinational regimen remains unknown. Here we demonstrate that the combination is superior to gemcitabine alone in blocking progression and prolonging survival in a murine model of PDAC (Kras activation with Tgfbr2 knockout). We found that gemcitabine induced MAPK signaling, which was dramatically inhibited by erlotinib even in the Kras-activated PDAC cells in the mouse model. Mechanistic investigations suggested that gemcitabine induces EGFR ligand expression and ERBB2 activation by increasing heterodimer formation with EGFR, thereby maintaining high levels of ERBB2 protein in PDAC cells. Overall, our findings suggest a significant role of ERBB in PDAC treatment.
Cancer Research 02/2013; · 7.86 Impact Factor
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Kazumichi Kawakubo,
Minoru Tada,
Hiroyuki Isayama,
Naoki Sasahira,
Yousuke Nakai,
Naminatsu Takahara, Koji Miyabayashi,
Keisuke Yamamoto,
Suguru Mizuno,
Dai Mohri,
Hirofumi Kogure,
Takashi Sasaki,
Natsuyo Yamamoto,
Ryosuke Tateishi,
Kenji Hirano,
Hideaki Ijichi,
Keisuke Tateishi,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVES: The long-term prognosis in patients with intraductal papillary mucinous neoplasm (IPMN) has not been determined. The aim of this study was to elucidate the risk for nonpancreatic cancer-specific mortality in patients with IPMN. METHODS: Seven hundred ninety-three patients with IPMN who were followed up more than 1 year were included in this study. Fine and Gray competing risk regression was used to assess the risk for mortality unrelated to pancreatic cancer. A comorbidity score at diagnosis was assigned using the Adult Comorbidity Evaluation 27. RESULTS: After a median follow-up of 50 months, a high comorbidity score and age at diagnosis were significantly associated with a risk for mortality unrelated to pancreatic cancer. Adjusted hazards ratio and 95% confidence interval of each comorbidity burden were as follows: none, 1; mild, 2.68 (0.76-9.45; P = 0.124); moderate, 10.9 (3.19-37.1; P < 0.001); and severe, 32.0 (9.41-108.8; P < 0.001). Comorbidity burden did not affect the risk for pancreatic cancer-specific mortality. CONCLUSIONS: Comorbidity and age at diagnosis was significantly related to mortality unrelated to pancreatic cancer in patients with IPMN. For patients at high risk for nonpancreatic cancer mortality, a follow-up management may be more reasonable than surgery.
Pancreas 12/2012; · 2.39 Impact Factor
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Kenji Hirano,
Minoru Tada,
Hiroyuki Isayama,
Takeo Watanabe,
Tomotaka Saito,
Rie Uchino,
Tsuyoshi Hamada, Koji Miyabayashi,
Suguru Mizuno,
Dai Mohri,
Takashi Sasaki,
Hirofumi Kogure,
Natsuyo Yamamoto,
Naoki Sasahira,
Nobuo Toda,
Naminatsu Takahara,
Hiroshi Yagioka,
Dai Akiyama,
Yukiko Ito,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVES: This study aimed to investigate risk factors for pancreatic stones and atrophy in autoimmune pancreatitis (AIP). METHODS: Seventy-one patients with AIP observed for more than 1 year were enrolled. The frequency of pancreatic stone development and atrophy on computed tomography as well as their risk factors were examined. RESULTS: Pancreatic stones and atrophy were observed in 13 and 43 patients, respectively. Alcohol consumption of greater than 50 g/d was the only significant risk factor for pancreatic atrophy in univariate analysis. Alcohol intake of greater than 50 g/d was observed in 6 of 13 patients with stones and 10 of 58 patients without stones (46% vs 17%, P = 0.059). Alcohol intake of greater than 50 g/d was observed in 14 of 43 patients with atrophy and 2 of 28 patients without atrophy (33% vs 7.1%, P = 0.018). In multivariate analysis, alcohol consumption was a significant risk factor both for pancreatic stone formation (odds ratio [OR], 7.47; P = 0.040) and atrophy (OR 6.24; P = 0.034). Higher age at onset was another significant risk factor for pancreatic atrophy (OR 1.07 per year; P = 0.029). CONCLUSIONS: Alcohol consumption of greater than 50 g/d increases the risk of pancreatic stone development and atrophy in patients with AIP.
Pancreas 11/2012; · 2.39 Impact Factor
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Naminatsu Takahara,
Yousuke Nakai,
Hiroyuki Isayama,
Takashi Sasaki,
Yumiko Satoh,
Daiya Takai,
Tsuyoshi Hamada,
Rie Uchino,
Suguru Mizuno, Koji Miyabayashi,
Dai Mohri,
Kazumichi Kawakubo,
Hirofumi Kogure,
Natsuyo Yamamoto,
Naoki Sasahira,
Kenji Hirano,
Hideaki Ijichi,
Minoru Tada,
Yutaka Yatomi,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: PURPOSE: The aim of this study was to evaluate the efficacy and safety of irinotecan monotherapy in patients with advanced pancreatic cancer (APC). METHODS: Patients with APC refractory to gemcitabine and S-1 were included. Irinotecan (100 mg/m(2)) was administered on days 1, 8, and 15 every 4 weeks until disease progression or unacceptable toxicity was observed. The relationship between uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms and clinical outcomes was evaluated. RESULTS: Between January 2007 and December 2011, 231 cycles were delivered in 56 patients. Irinotecan was administered as second-line chemotherapy in 35.7 % of patients and as third-line chemotherapy or later in 64.3 %. A partial response was achieved in two (3.6 %) and stable disease in 23 patients (41.0 %), giving a disease control rate of 44.6 %. The median time to progression (TTP) and overall survival (OS) were 2.9 (95 % confidence interval [CI] 1.8-3.5) months and 5.3 (95 % CI 4.5-6.8) months, respectively. Median survival from the first-line chemotherapy was 19.5 (95 % CI 15.3-23.8) months. Major grade 3/4 adverse events included neutropenia (28.6 %), anemia (12.5 %), and anorexia (10.7 %). Patients with *6 and/or *28 allele(s) (n = 15) were associated with grade 3/4 neutropenia and anorexia but showed longer TTP (5.3 vs. 1.8 months; p = 0.05), and OS (8.0 vs. 4.8 months; p = 0.09) than those without *6 and/or *28 (n = 29). CONCLUSIONS: Salvage chemotherapy with irinotecan was moderately effective and well-tolerated in patients with APC refractory to gemcitabine and S-1. UGT1A1 polymorphisms were associated with toxicity and efficacy.
Cancer Chemotherapy and Pharmacology 09/2012; · 2.83 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Covered self-expandable metal stents were developed to overcome tumor in-growth through the metal mesh. Stent migration is one of their malfunctions. Recently, the partially covered wallflex stent (PCWS) was developed with flared ends to prevent migration However, difficulty has been reported in its removal. We describe the removal of a PCWS embedded in mucosal hyperplasia at the uncovered proximal flared end, visualized by using SpyGlass cholangioscopy.
World journal of gastrointestinal endoscopy. 09/2012; 4(9):432-3.
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Suguru Mizuno,
Yousuke Nakai,
Hiroyuki Isayama,
Ayako Yanai,
Naminatsu Takahara, Koji Miyabayashi,
Keisuke Yamamoto,
Kazumichi Kawakubo,
Dai Mohri,
Hirofumi Kogure,
Takashi Sasaki,
Natsuyo Yamamoto,
Naoki Sasahira,
Kenji Hirano,
Takeshi Tsujino,
Hideaki Ijichi,
Keisuke Tateishi,
Masao Akanuma,
Minoru Tada,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Diabetes mellitus (DM) has long been recognized as a risk factor for pancreatic cancer (PaC) and recently has attracted attention as a manifestation of PaC. Diabetes is expected to be a clue for the early detection of PaC; however, no effective screening strategy has been established. METHODS: Forty diabetic patients with PaC were identified and compared with 120 diabetic patients without any malignancies. We analyzed risk factors for and early signs of PaC, focusing on the DM-onset age. RESULTS: As there were peaks at 40-45 years and 60-65 years in the distribution of DM-onset age, we analyzed the clinical characteristics of and risk factors for PaC according to DM-onset age: i.e., early-onset (<55 years) and late-onset (≥55 years). PaC was diagnosed within 2 years of DM onset (new-onset) in 0 % of the patients with early-onset DM, and in 33 % of those with late-onset DM. The mean duration of DM in patients with early-onset DM with PaC was longer than that in the late-onset patients (26 vs. 9 years; P < 0.01). A family history of DM (odds ratio [OR] 3.60) and use of insulin (OR 3.52) were significant risk factors in patients with early-onset DM, while the onset age of DM (OR 1.12) and multiple diabetic patients in the family (OR 6.13) were risk factors in those with late-onset DM. Body weight loss and exacerbation of DM were seen 12 months prior to PaC diagnosis in both groups. CONCLUSIONS: Our study revealed specific risk factors for and similar early signs of PaC in early-onset and late-onset DM. Thus, we could develop a screening strategy, combining these risk factors specific for DM-onset age with early signs of disease.
Journal of Gastroenterology 06/2012; · 4.16 Impact Factor
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Yousuke Nakai,
Hiroyuki Isayama,
Hideaki Ijichi,
Takashi Sasaki,
Hirofumi Kogure,
Hiroshi Yagioka, Koji Miyabayashi,
Suguru Mizuno,
Keisuke Yamamoto,
Dai Mouri,
Kazumichi Kawakubo,
Natsuyo Yamamoto,
Kenji Hirano,
Naoki Sasahira,
Keisuke Tateishi,
Minoru Tada,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: Our retrospective study showed inhibition of the renin-angiotensin system was associated with better outcomes in patients with advanced pancreatic cancer receiving gemcitabine. The primary objective of this phase I study was to determine the recommended dose of candesartan in combination with gemcitabine in normotensive patients with advanced pancreatic cancer. Candesartan was given orally at an escalating dose (4, 8, 16, and 32 mg) q.d. daily, and gemcitabine was given 1000 mg/m(2) 30 min i.v. on days 1, 8, and 15, repeated every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicities, grade 2 hypotension, abnormal creatinine or potassium, and grade 3 or 4 other non-hematological toxicities. A standard "3+3" phase I dose-escalation design was used. A total of 14 patients (candesartan 4 mg, three patients; 8 mg, three patients; 16 mg, six patients; 32 mg, two patients) were enrolled. One of six patients at 16 mg showed DLT of grade 4 neutropenia and two of two patients at 32 mg showed DLT of grade 2 hypotension. Response rate and disease control rate were 0% and 79%, respectively. Progression-free survival and overall survival were 7.6 and 22.9 months, respectively. Candesartan 16 mg is the recommended dose in combination with gemcitabine in the treatment of advanced pancreatic cancer. (UMIN CTR: UMIN000002152).
Cancer Science 04/2012; 103(8):1489-92. · 3.33 Impact Factor
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Kazumichi Kawakubo,
Hiroyuki Isayama,
Naoki Sasahira,
Hirofumi Kogure,
Naminatsu Takahara, Koji Miyabayashi,
Suguru Mizuno,
Keisuke Yamamoto,
Dai Mohri,
Takashi Sasaki,
Natsuyo Yamamoto,
Yousuke Nakai,
Kenji Hirano,
Minoru Tada,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: A single-operator cholangiopancreatoscopy was developed to overcome a problem in conventional peroral cholangiopancreatoscopy. The aim of this pilot study was to clarify the clinical utility of single-operator cholangiopancreatoscopy using a SpyGlass probe through an endoscopic retrograde cholangiopancreatography (ERCP) catheter.
Patients undergoing ERCP with a SpyGlass probe passed through a catheter were included in this study. The SpyGlass probe was inserted into the catheter following successful cannulation, and cholangiopancreatoscopy was performed by a single operator. We retrospectively analyzed the successful visualization rate of this technique.
Fifteen patients were included in this study. SpyGlass cholangiopancreatoscopy was technically successful in all patients. Successful visualization was obtained in nine patients (60%). The median SpyGlass procedure time was 10 min. Cholangiopancreatoscopic diagnoses were as follows: bile duct carcinoma in three patients; intraductal papillary mucinous adenoma in two; and intraductal pancreatic stone, benign biliary stricture, gallbladder cholesterolosis, and gallbladder carcinoma in one each. There were no cases of post-ERCP pancreatitis.
While the low rate of successful visualization must be improved, single-operator cholangiopancreatoscopy using a SpyGlass probe through an ERCP catheter is a safe and effective procedure.
Journal of Gastroenterology and Hepatology 03/2012; 27(8):1371-6. · 2.87 Impact Factor
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Dai Mohri,
Yoshinari Asaoka,
Hideaki Ijichi, Koji Miyabayashi,
Yotaro Kudo,
Motoko Seto,
Miki Ohta,
Motohisa Tada,
Yasuo Tanaka,
Tsuneo Ikenoue,
Keisuke Tateishi,
Hiroyuki Isayama,
Fumihiko Kanai,
Noriyoshi Fukushima,
Minoru Tada,
Takao Kawabe,
Masao Omata,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes.
Surgically resected IPMNs (n = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS, BRAF, and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined.
There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type (p < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p < 0.05%).
There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.
Journal of Gastroenterology 02/2012; 47(2):203-13. · 4.16 Impact Factor
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Kenji Hirano,
Akihiro Isogawa,
Minoru Tada,
Hiroyuki Isayama,
Naminatsu Takahara, Koji Miyabayashi,
Suguru Mizuno,
Dai Mohri,
Kazumichi Kawakubo,
Takashi Sasaki,
Hirofumi Kogure,
Natsuyo Yamamoto,
Naoki Sasahira,
Nobuo Toda,
Rie Nagano,
Hiroshi Yagioka,
Yoko Yashima,
Tsuyoshi Hamada,
Yukiko Ito,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: Glucose intolerance is often observed in autoimmune pancreatitis (AIP), although its long-term prognosis after steroid treatment (ST) is still unclear.
A total of 47 patients with AIP were enrolled. On the basis of the change in hemoglobin A1c (HbA1c) and the use of diabetic medication, prognosis was classified into 3 categories, namely, "improved," "aggravated," and "unchanged." The relation between the result of an initial glucagon tolerance test (ΔCPR) and the later use of insulin during maintenance ST was examined in 20 patients. The transitions of homeostasis model assessment β cell and insulin resistance (HOMA-β and HOMA-R) were analyzed in 16 patients.
Glucose tolerance was improved in 6 patients (13%), aggravated in 9 patients (19%), and unchanged in 32 patients (68%). All patients with ΔCPR less than 0.6 ng/mL were obliged to use insulin even after long-term observation, whereas all patients with ΔCPR more than 1.0 ng/mL were free from insulin therapy. Moreover, HOMA-β showed significant improvement after ST (43.9% → 56.0% in median, P = 0.030), and HOMA-R showed significant aggravation (1.30 → 1.78, P = 0.039).
Glucose tolerance that is too severely damaged may not recover fully even after ST. Thus, ST should be performed to preserve insulin secretion at the early stage of AIP.
Pancreas 01/2012; 41(5):691-5. · 2.39 Impact Factor
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Kenji Hirano,
Minoru Tada,
Suguru Mizuno,
Hiroyuki Isayama,
Naminatsu Takahara,
Rie Nagano,
Tsuyoshi Hamada, Koji Miyabayashi,
Yukiko Ito,
Dai Mohri,
Kazumichi Kawakubo,
Takashi Sasaki,
Hirofumi Kogure,
Natsuyo Yamamoto,
Naoki Sasahira,
Noriyo Yamashiki,
Yasuhiko Sugawara,
Norihiro Kokudo,
Nobuo Toda,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: High serum levels of immunoglobulin (Ig)E often are detected in patients with primary sclerosing cholangitis (PSC), but the clinical significance is not known.
We analyzed data from 44 patients with PSC and known serum levels of IgE. They were divided into groups called high IgE (>170 IU/mL; n = 17) or normal IgE (n = 27). We compared occurrence of biliary carcinoma including cholangiocellular and gallbladder carcinoma, liver transplantation, and death between groups.
The high IgE group had a later age of onset of PSC than the normal IgE group (54 ± 20 y vs 39 ± 16 y; P = .010); they also had a higher serum level of IgG (2078 ± 638 vs 1517 ± 475 mg/dL; P = .002) and IgG4 (104 ± 102 vs 38 ± 16 mg/dL; P = .002). Association with inflammatory bowel disease did not differ significantly between groups (5 of 17 vs 11 of 27; P = .661). No patient had biliary carcinoma in the high IgE group, but biliary carcinoma was observed during the follow-up period in 8 patients in the normal IgE group (0 of 17 vs 8 of 27; P = .016). The occurrence of biliary carcinoma, liver transplantation, or death did not differ between groups (4 of 17 vs 13 of 27; P = .124).
High serum levels of IgE often are observed in older patients with PSC and are associated with a reduced incidence of biliary carcinoma.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 09/2011; 10(1):79-83. · 5.64 Impact Factor
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Hideaki Ijichi,
Anna Chytil,
Agnieszka E Gorska,
Mary E Aakre,
Brian Bierie,
Motohisa Tada,
Dai Mohri, Koji Miyabayashi,
Yoshinari Asaoka,
Shin Maeda,
Tsuneo Ikenoue,
Keisuke Tateishi,
Christopher V E Wright,
Kazuhiko Koike,
Masao Omata,
Harold L Moses
[show abstract]
[hide abstract]
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium-specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC.
The Journal of clinical investigation 09/2011; 121(10):4106-17. · 15.39 Impact Factor
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Minoru Tada,
Yousuke Nakai,
Takashi Sasaki,
Tsuyoshi Hamada,
Rie Nagano,
Dai Mohri, Koji Miyabayashi,
Keisuke Yamamoto,
Hirofumi Kogure,
Kazumichi Kawakubo,
Yukiko Ito,
Natsuyo Yamamoto,
Naoki Sasahira,
Kenji Hirano,
Hideaki Ijichi,
Keishuke Tateishi,
Hiroyuki Isayama,
Masao Omata,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: Gemcitabine chemotherapy has been the standard for advanced pancreatic cancer for more than a decade. New oral fluoropyrimidines such as S-1 and capecitabine are other key drugs. Gemcitabine plus erlotinib was the only combination therapy that significantly prolonged survival, although the effect was minimal. Little or no improvement in survival with recent molecular-targeted drugs might be attributed to the very high incidence of K-ras gene mutation in pancreatic cancer. Recently, the non-gemcitabine-based-regimen of FOLFIRINOX showed significantly greater overall survival compared with gemcitabine for the first time. For biliary tract cancer, gemcitabine plus cisplatin combination chemotherapy has been proved to significantly prolong survival and will become the standard therapy. Further improvement in survival is expected by the addition of cetuximab.
World journal of clinical oncology. 03/2011; 2(3):158-63.
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Hiroshi Yagioka,
Kenji Hirano,
Hiroyuki Isayama,
Takeshi Tsujino,
Naoki Sasahira,
Rie Nagano,
Tsuyoshi Hamada, Koji Miyabayashi,
Yukiko Ito,
Dai Mohri,
Kazumichi Kawakubo,
Hirofumi Kogure,
Takashi Sasaki,
Minoru Tada,
Kazuhiko Koike
[show abstract]
[hide abstract]
ABSTRACT: In patients in whom there is a suspicion of malignant biliary strictures, bile cytology via an endoscopic nasobiliary drainage tube (ENBD cytology) is often performed, in addition to aspirated bile cytology, brush cytology, and forceps biopsy, during the initial endoscopic retrograde cholangiopancreatography (ERCP). We aimed to reveal the significance of ENBD cytology for the pathological diagnosis of malignant biliary strictures.
We studied 214 patients with malignant biliary strictures. We performed aspirated bile cytology, brush cytology, and forceps biopsy in 93, 130, and 114 patients, respectively. ENBD cytology was performed one or more times in 79 patients. We examined the sensitivity of each sampling method, and analyzed the utility of ENBD cytology.
The sensitivities of each sample acquisition method were as follows: 30% (28/93) for aspirated bile cytology, 48% (62/130) for brush cytology, 41% (47/114) for forceps biopsy, and 24% (19/79) for ENBD cytology. In 19 patients who showed positive ENBD cytology, other methods were performed in 11. Aspirated bile cytology, brush cytology, and forceps biopsy, were performed in 7, 5, and 6 patients, and the results were negative in 3 (43%), 2 (40%), and 1 (17%) patient, respectively. Three patients showed positive results only on ENBD cytology.
Although the sensitivity of ENBD cytology was inferior to that of the other methods used, ENBD cytology may contribute to the improvement of the total diagnostic sensitivity for malignancy.
Journal of hepato-biliary-pancreatic sciences. 10/2010; 18(2):211-5.
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Yoshinari Asaoka,
Motohisa Tada,
Tsuneo Ikenoue,
Motoko Seto,
Mitsuho Imai, Koji Miyabayashi,
Keisuke Yamamoto,
Shinzo Yamamoto,
Yotaro Kudo,
Dai Mohri,
Yoshihiro Isomura,
Hideaki Ijichi,
Keisuke Tateishi,
Fumihiko Kanai,
Seishi Ogawa,
Masao Omata,
Kazuhiko Koike
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ABSTRACT: Receptor tyrosine kinases (RTKs) are involved in oncogenesis and disease progression for many cancers. Inhibitors targeting them are vigorously developed and some of them are tested in the clinical setting. Amplifications of certain RTKs (c-Met, FGFR2 and ErbB2) have been associated with human gastric cancer progression. According to our genome-wide scans of genetic lesions in 34 gastric cancer cell lines using high-density single-nucleotide polymorphism genotyping microarrays, we confirmed that the c-met locus was amplified in four gastric cancer cell lines (Hs746T, MKN45, NUGC4 and SNU5). It was reported that somatic mutation is occasionally detected in tumor samples of a certain type of cancer with gene amplification. Previous reports showed gastric cancers harbored mutations of FGFR2 and ErbB2, but c-Met oncogenic mutation had not yet been reported. We performed mutational analysis of the cytoplasmic domains of c-Met using the genome DNA of the gastric cancer cell lines, and found that Hs746T cells had a splice site mutation of exon 14. By cDNA sequencing and Western blotting, we showed that the mutation caused juxtamembrane domain deletion. Previously, this mutation had been detected only in lung cancer specimens and this deletion resulted in the loss of Cbl E3-ligase binding causing decreased ubiquitination and delayed down-regulation. In conclusion, four gastric cancer cell lines harbored amplification of c-met locus, and among them, Hs746T had a putative oncogenic mutation with amplification. This information will be useful for screening of inhibitors targeting gastric cancer with c-Met aberration.
Biochemical and Biophysical Research Communications 03/2010; 394(4):1042-6. · 2.48 Impact Factor
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Motoko Seto,
Miki Ohta,
Yoshinari Asaoka,
Tsuneo Ikenoue,
Motohisa Tada, Koji Miyabayashi,
Dai Mohri,
Yasuo Tanaka,
Hideaki Ijichi,
Keisuke Tateishi,
Fumihiko Kanai,
Takao Kawabe,
Masao Omata
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ABSTRACT: The hedgehog and mitogen-activated protein kinase (MAPK) signaling pathways regulate growth in many tumors, suggesting cooperation between these two pathways in the regulation of cell proliferation. However, interactions between these pathways have not been extensively studied. We assessed cross-talk between hedgehog and MAPK signaling in the regulation of cell proliferation in gastric cancer. We showed that PTCH expression was significantly correlated with extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (P = 0.016) as well as SHH expression (P = 0.034) in the 35 gastric cancers assessed by immunohistochemistry. Indeed, MAPK signaling increased the GLI transcriptional activity and induced the expression of hedgehog target genes in gastric cancer cells. The inductive effect of activated KRAS and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1 was blocked by the suppressor of fused (SUFU), indicating that MAPK signaling regulates GLI activity via a SUFU-independent process. Moreover, the deletion of the NH2-terminal domain of GLI1 gene resulted in reduced response to MEK1 stimulation. Our results suggest that the KRAS-MEK-ERK cascade has a positive regulatory role in GLI transcriptional activity in gastric cancer.
Molecular Carcinogenesis 02/2009; 48(8):703-12. · 3.16 Impact Factor
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Miki Ohta,
Motoko Seto,
Hideaki Ijichi, Koji Miyabayashi,
Yotaro Kudo,
Dai Mohri,
Yoshinari Asaoka,
Motohisa Tada,
Yasuo Tanaka,
Tsuneo Ikenoue,
Fumihiko Kanai,
Takao Kawabe,
Masao Omata
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ABSTRACT: Although colorectal cancer (CRC) progression has been associated with alterations in KRAS and RAS signaling, not all CRC cells have KRAS gene mutations. RAS activity is modulated by RAS-GTPase-activating proteins (RASGAPs), so we investigated the role of RASGAPs in CRC progression.
The level of RASGAP expression in CRC cells was analyzed using quantitative real-time polymerase chain reaction. The expression of the RAS protein activator like-1 (RASAL1) was examined in clinical colorectal neoplasms using immunohistochemistry. The clinicopathologic (age, sex, and tumor site and grade) and molecular (KRAS gene mutation, as well as CTNNB1 and TP53 expression patterns) factors that could affect RASAL1 expression were examined.
Of 12 RASGAPs examined, expression levels of only RASAL1 decreased in CRC cells; RASAL1 expression decreased in most CRC cells with wild-type KRAS gene but rarely in those with mutant KRAS gene. A transfection assay showed that RASAL1 repressed RAS/mitogen-activated protein kinase signaling in response to growth factor stimulation and reduced proliferation of CRC cells that contained wild-type KRAS gene. RASAL1 expression was detected in 46.9% (30/64) of adenocarcinoma, 17.4% (8/46) of large adenoma, and no (0/42) small adenoma samples. RASAL1 expression levels were correlated with the presence of wild-type KRAS gene in CRC tumor samples (P= .0010), distal location (P= .0066), and abnormal expression of TP53 (P= .0208).
RASAL1 expression is reduced in CRC cells that contain wild-type KRAS gene. Reductions in RASAL1 expression were detected more frequently in advanced lesions than in small adenomas, suggesting that RASAL1 functions in the progression of benign colonic neoplasms.
Gastroenterology 11/2008; 136(1):206-16. · 11.68 Impact Factor
