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Masaru Morita,
Yasushi Toh,
Hiroshi Saeki,
Masahiko Sugiyama,
Kippei Ohgaki, Shin-Ichiro Maehara,
Kazuhito Minami,
Yasuharu Ikeda,
Yoshihisa Sakaguchi,
Takeshi Okamura,
Satoru Uehara,
Yoshihiko Maehara
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ABSTRACT: To clarify the clinical significance of definitive chemoradiotherapy (CRT) and CRT followed by esophagectomy for cT4 esophageal cancer.
The treatment results for cT4 esophageal cancer were examined in 81 patients who received definitive CRT [radiation 50-70 Gy, cisplatin and 5-fluorouracil; group I] and 19 patients who underwent esophagectomy after preoperative CRT [40Gy, Group II].
Among the 81 patients in group I, toxicities (grade 3 or 4) were observed in 32 patients, while partial response and complete response were recognized in 8 and 47 patients, respectively. Of the 19 group II patients, an R0 resection was performed in 16 patients, and the mortality rate was 5%. The 5-year survival rates were 19% and 42% in groups I and II, respectively.
Long-term survival can be expected after multimodal therapy, even for patients with cT4 esophageal cancer. Esophagectomy is therefore a valid treatment option when down-staging can be achieved.
Anticancer research 08/2012; 32(8):3275-82. · 1.73 Impact Factor
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ABSTRACT: Our previous proteomic study demonstrated that expression of heat shock protein 27 (HSP27) is upregulated in gemcitabine (GEM)-resistant pancreatic cancer cells and that it suppressed the cytotoxic effect of GEM on the cells. This report describes the benefits of a treatment strategy combining the HSP inhibitor KNK437 with GEM for GEM-resistant pancreatic cancer cells.
We used 2 human pancreatic cancer cell lines, GEM-sensitive KLM1 and GEM-resistant KLM1-R. KLM1-R was treated with KNK437, and we examined the expression of HSP27 by Western blotting. The cytotoxicity of GEM and KNK437 for KLM1-R was investigated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay.
The expression of HSP27 in KLM1-R was dramatically reduced by KNK437. In addition, the in vitro antitumor cytotoxic effect of GEM on KLM1-R was enhanced by combination treatment with KNK437 compared to GEM alone.
This study supports the potential therapeutic benefits of a treatment strategy combining KNK437 with GEM.
Chemotherapy 12/2010; 57(1):12-6. · 1.82 Impact Factor
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ABSTRACT: The prognosis of patients with pancreatic cancer is very poor because of late diagnosis and the lack of response to various therapies. Pancreatic cancer is generally resistant to chemotherapy and is highly fatal. Gemcitabine (GEM) appears to be the only effective agent for treatment of pancreatic cancer. However, a high level of inherent and acquired tumor resistance makes the clinical impact of GEM modest. Proteomic differential display analysis for GEM-sensitive human pancreatic adenocarcinoma cell line KLM1 and GEM-resistant KLM1-R cells by using two-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry produced 33 protein spots. Of these, 23 were up-regulated and 10 were down-regulated in KLM1-R compared to KLM1 cells. The up-regulated proteins include acidic leucine-rich nuclear phosphoprotein 32 family member A, reticulocalbin-1, gamma-synuclein, microtubule-associated protein RP/EB family, sialic acid synthase, peptidyl-prolyl cis-trans isomerase A, far upstream element-binding protein 2 and catalase. The down-regulated proteins include far upstream element-binding protein 1, gamma-synuclein, galectin-1 and stathmin. Two spots of heat-shock protein 27 were up-regulated in KLM1-R cells. These results suggest an important complementary role for proteomics in the identification of proteins which may play a role in the poor response of pancreatic cancer to GEM.
Anticancer research 09/2010; 30(9):3367-72. · 1.73 Impact Factor
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ABSTRACT: Gemcitabine (2'-deoxy-2'-difluorodeoxycytidine: Gemzar) (GEM) appears to be the only effective anticancer drug for pancreatic cancer, but it has little impact on outcome due to a high level of inherent and acquired tumor resistance. Our previous proteomic study demonstrated that the expression of three spots of heat-shock protein 27 (HSP27) was increased in GEM-resistant pancreatic cancer cells and could play a role in determining the sensitivity of pancreatic cancer to GEM. Materials and Methods and
In the present study, using one-dimensional and two-dimensional Western blotting, we elucidated that these three spots of HSP27 were phosphorylated in GEM-resistant pancreatic cancer cell line, KLM1-R.
Phosphorylated HSP27 may play an important role in the resistance to GEM, and it could also be a possible biomarker for predicting the response of pancreatic cancer patients to treatment with GEM.
Anticancer research 07/2010; 30(7):2539-43. · 1.73 Impact Factor
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Pancreas 04/2009; 38(2):224-6. · 2.39 Impact Factor
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Journal of the American College of Surgeons 01/2008; 205(6):816-8. · 4.55 Impact Factor
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ABSTRACT: Pancreatic cancer remains a devastating disease and >96% of patients with pancreatic cancer do not survive for more than 5 years. Gemcitabine (2'-deoxy-2'-difluoro-deoxycytidine: Gemzar) appears to be the only clinically effective drug for pancreatic cancer, but it has little impact on outcome. Proteomic analysis of gemcitabine-sensitive cells (KLM1) and resistant pancreatic cells (KLM1-R) was performed to identify target proteins of the gemcitabine. We found seven proteins, HSP27, peroxiredoxin 2, endoplasmic reticulum protein ERp29 precursor, 6-phosphogluconolactonase, triosphospate isomerase, alpha enolase, and nucleophosmine that could play a role in determining the sensitivity of pancreatic cancer to gemcitabine. We knocked down HSP27 in KLM1-R and the sensitivity to gemcitabine was restored. In addition, increased HSP27 expression in tumor specimens was related to higher resistibility to gemcitabine in patients of pancreatic cancer. HSP27 may play an important role in the resistibility to gemcitabine, and it could also be a possible biomarker for predicting the response of pancreatic cancer patients to treatment with gemcitabine.
International Journal of Oncology 12/2007; 31(6):1345-50. · 2.40 Impact Factor
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ABSTRACT: We herein present an exceedingly rare case of intrathoracic ganglioneuroma that was surgically resected in an elderly patient over 70 years of age. A 74-year-old woman was asymptomatic, but a computed tomography (CT) scan of the thorax indicated the presence of a posterior mediastinal mass paravertebrally. A thoracotomy was thus performed under a strongly suggested diagnosis of a neurogenic tumor because of the appearance and position of the mass on the chest CT and magnetic resonance imaging findings, and measuring 6.9 x 5.8 x 1.6 cm. Not only tumors originating from the nerve sheath, but also neurogenic tumors occurring in young patients such as ganglioneuroma, should be included in the different diagnosis of posterior mediastinal tumor occurring in elderly patients.
General Thoracic and Cardiovascular Surgery 11/2007; 55(10):437-9.
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ABSTRACT: Oxaliplatin, Irinotecan, 5-fluorouracil and leucovorin are commonly used to treat advanced colorectal cancer in Western countries. Here, we investigated the efficacy and safety of FOLFOX/FOLFIRI in Japanese colorectal cancer patients.
FOLFOX4, modified FOLFOX6 and FOLFIRI was administered to a total of 23 patients with far advanced or recurrent colorectal cancer in our institute. Tumor response rate and toxicity were analyzed with these patients.
Partial response and stable disease was observed in 28.6% of patients, respectively. There was no therapy-related death. Neutropenia was observed in 12 cases (52.2%), anemia was in 12 cases (52.2%) and thrombocytopenia was in 6 cases (26.1%), respectively; among them, 9 patients (39.1%) experienced a Grade 3 of bone marrow suppression. Fatigue was observed in 8 cases (34.8%), nausea/vomiting was in 4 cases (17.4%), diarrhea was in 4 cases (17.4%) and neurotoxicity was in 8 cases (34.8%), respectively. All nonhematological toxicities were Grade 1 or 2.
FOLFOX/FOLFIRI can contribute to efficacy and safety in cases of advanced colorectal cancer. In order to evaluate the long-term clinical results in Japanese patients, prospective controlled studies are urgently called for.
Fukuoka igaku zasshi = Hukuoka acta medica 07/2007; 98(6):253-9.
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ABSTRACT: Hepatocellular carcinoma (HCC) originating in the caudate lobe is rare, and the treatment for this type of carcinoma is difficult because of its unique anatomic location.
This retrospective study assessed the surgical outcome of patients with caudate lobe HCC. There were 20 cases of HCC originating in the caudate lobe among 435 patients with primary HCC who underwent hepatic resection in our department from 1990 to 2002. The caudate tumors were located in the Spiegel lobe in 3 patients, the paracaval portion in 15 patients, and the caudate process in 2 patients. Surgical procedures consisted of limited resection of the caudate lobe in 6 patients and extended caudate lobectomy in 14 patients. Recurrence was recognized in 12 patients, including 8 patients with multiple intrahepatic recurrences, 1 with peritoneal dissemination, and 1 with lymph node metastasis.
There was no significant difference in postoperative survival rate between patients who underwent limited resection of the caudate lobe and those who underwent extended caudate lobectomy. Compared with 415 patients with HCC originating in other locations, the 20 patients with caudate lobe HCC showed significantly more intraoperative blood loss (P<.05), longer operation time (P<.0001), and more postoperative complications (P<.005). Intrahepatic recurrence was more frequent in the caudate lobe HCC compared with HCC originating in other locations (40% vs 17.6%; P<.05). There was a significantly poor survival rate in the postoperative patients with caudate HCC (25.9% vs 54.1% for five-year survival; P=.01). Intrahepatic multiple recurrences were frequently recognized in the patients with caudate lobe HCC, indicating no significance for extended caudate lobectomy.
Because of the relatively poor prognosis in patients with caudate lobe HCC, adjuvant therapy combined with surgical operation should be considered.
The American Journal of Surgery 10/2005; 190(3):451-5. · 2.78 Impact Factor
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ABSTRACT: To assess the role of femorofemoral or iliofemoral crossover bypass grafting, the early and late results of crossover bypasses were reviewed and compared with those of anatomic bypasses.
The clinical records of 164 patients with arteriosclerosis obliterans who underwent 99 crossover bypasses and 65 anatomic ones from 1982 to 2002 were retrospectively evaluated. The early and late results including operative mortality and morbidity, graft patency rate, limb salvage rate, and survival rate of the patients as well as backgrounds of the patients were compared between the two kinds of bypass procedures. In addition, perioperative factors including bypass procedures affecting graft patency were evaluated by a multivariate analysis.
The percentage of high-risk patients was higher in the crossover bypass group than in the anatomic bypass group. The operative mortality and morbidity were similar between both bypass groups. The primary and secondary patency rates of crossover bypass grafts (93% and 97%, 83% and 92%, and 65% and 63% at 2, 5, and 10 years, respectively) were lower than those of anatomic ones (95% and 98%, 93% and 98%, and 90% and 98% at 2, 5, and 10 years, respectively). The late survival of the patients in the crossover bypass group was significantly lower than that in the anatomic bypass group. A multivariate analysis revealed the operative method, namely the crossover bypass, to be the only significant risk factor of late graft failure.
A crossover bypass was thus determined to be an acceptable procedure only in high-risk patients with a limited life expectancy.
Surgery Today 02/2005; 35(6):453-8. · 1.22 Impact Factor
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ABSTRACT: Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine-sensitive pancreatic cancer cell line KLM1, we established a resistant cell line KLM1-R exhibiting a 20-fold IC50-value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P, one of the anti-oxidants, in the KLM1-R cell line but not in the KLM1 cell line. Administration of selenoprotein P inhibited the gemcitabine-induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLM1 cells by gemcitabine, but selenoprotein P suppressed the gemcitabine-induced ROS levels. Furthermore interferon-gamma suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLM1-R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine.
International Journal of Cancer 12/2004; 112(2):184-9. · 5.44 Impact Factor
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Norifumi Harimoto,
Mitsuo Shimada,
Shin-ichi Aishima,
Dai Kitagawa,
Shinji Itoh,
Eiji Tsujita, Shin-ichiro Maehara,
Akinobu Taketomi,
Shinji Tanaka,
Ken Shirabe,
Yoshihiko Maehara
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ABSTRACT: A recent report showed that heat shock protein (HSP)-27 expression was related to histological grade and survival of patients with hepatocellular carcinoma (HCC).
The aim of this study was to examine the effect of expression of HSP-27 on clinicopathological variables in Japanese patients with HCC.
An immunohistochemical study for HSP-27 was performed on 60 HCC cases using a monoclonal anti-HSP-27 antibody. We divided 60 patients into two groups, patients with a low expression of HSP-27 (n = 34) and those with a high expression of HSP-27 (n = 26). Forty patients tested positive for the hepatitis C virus (HCV) antibody and 20 tested positive for the hepatitis B surface antigen.
There appeared to be no relationship between HSP expression and clinicopathologic factors and no differences were observed between the high expression group and the low expression group. In the hepatitis B virus (HBV) group (n = 20), HSP-27 expression correlated significantly with prognosis, disease-free survival (DFS) and overall survival. High expression was significantly associated with poor prognosis in the HBV group. In contrast, patients with a high expression tended to have a good prognosis in the HCV group (n = 40): DFS and overall survival.
This study showed the possibility that HSP-27 plays different roles in HBV- and HCV-associated HCCs.
Liver international: official journal of the International Association for the Study of the Liver 09/2004; 24(4):316-21. · 3.82 Impact Factor
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Gastroenterology 12/2003; 125(5):1563-4. · 11.68 Impact Factor
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ABSTRACT: Family members of the connective tissue growth factor, cysteine-rich 61, nephroblastoma over-expressed gene (CCN) encode cysteine-rich secreted proteins with roles in human fibrotic disorders and tumor progression. In this study, we identified a CCN family member, WISP1v, as over-expressed in human cholangiocarcinomas. Genetic analysis of WISP1v was performed on surgically resected specimens of cholangiocarcinoma. The WISP1v biological effects were analyzed using the HuCCT1 human cholangiocarcinoma cell line. The WISP1v gene was expressed in 19 of 39 cholangiocarcinoma tissues (49%) but not in normal livers. Expression of WISP1v was significantly associated with lymphatic and perineural invasion of tumor cells (P <.05), as well as a poor clinical prognosis (P <.01). In the intraductal papillary cholangiocarcinomas, WISP1v was detected only in the cases with duct wall invasion but not in the cases without duct wall invasion (P <.05). No mutation of WISP1v gene was detected in the examined samples. In vitro analysis revealed that WISP1v stimulated the invasive phenotype of cholangiocarcinoma cells with activation of both p38 and p42/p44 mitogen-activated protein kinases (MAPKs). Furthermore, WISP1v-induced cholangiocarcinoma invasion was significantly suppressed by the p38 MAPK inhibitor SB203580 but not by the p42/p44 MAPK kinase (MEK) inhibitor PD98059. Our findings suggest that WISP1v-mediated signaling is involved in the generation of invasive cellular properties and leads to progression of cholangiocarcinoma.
Hepatology 06/2003; 37(5):1122-9. · 11.66 Impact Factor
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ABSTRACT: Discoveries of oncogenic signaling molecules lead to the comprehension of molecular mechanisms of tumor progression, as well as to the development of novel therapeutic tools for hepatocellular carcinoma. We have identified critical functions of intracellular signals transmitted from insulin-like growth factor and Wnt oncoprotein in carcinogenesis. The insulin-like growth factor system activates a number of signaling cascades resulting not only in hepatic mitogenesis, but also in cell survival. The secreted oncoprotein Wnt transforms beta-catenin potentials as a component of cell adhesion complexes with cadherins, into a transcription factor in the nucleus. Here, the important role of such signal transduction is reviewed, and we emphasize its control as a promising approach for the treatment of hepatocellular carcinoma.
Surgery 02/2002; 131(1 Suppl):S142-7. · 3.10 Impact Factor
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ABSTRACT: The long-term prognosis after resection for patients with hepatocellular carcinoma is still unsatisfactory because of the high recurrence rate. The survival of patients with multiple intrahepatic or extrahepatic recurrence is especially poor.
Among the patients who underwent hepatic resection for hepatocellular carcinoma between 1981 and 2000, 216 patients with 3 or less than 3 intrahepatic recurrences (group B); 156 patients with more than 3 intrahepatic recurrences, extrahepatic recurrences, or both (group C); and 51 patients who survived more than 5 years without recurrence (group A) were clinicopathologically studied.
The period to recurrence of group C was significantly earlier than that of group B and also showed a significantly poor prognosis after recurrence. Tumor factors, including size, portal venous invasion, intrahepatic metastasis, histologic grade, or the number of tumors at resection in group C was significantly worse than in groups A and B. Although no differences are recognized in the tumor factors between groups A and B, except for the alpha-fetoprotein level, liver function in group B was significantly worse than that in group A. In addition, the frequency of hepatitis B surface antigen in group B and that of hepatitis C virus in group B was significantly less and higher than that in group A, respectively.
Similar to extrahepatic metastasis, multinodular recurrences are also mainly caused by metastatic recurrence from the main tumor by means of the portal system, and recurrences with up to 3 intrahepatic nodules are mainly caused by metachronous multicentric hepatocarcinogenesis. Because the mechanisms of recurrence differed, determining the patterns of recurrence on the basis of the clinicopathologic findings is important for selecting the optimal postoperative therapy for each individual patient.
Surgery 02/2002; 131(1 Suppl):S148-52. · 3.10 Impact Factor
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ABSTRACT: A new concept of surgical stress has been proposed that consists of both aggressiveness of operation and systemic reactions to an operation.
We have investigated a possible modulation of such systemic reactions to operation and have demonstrated the following 3 points: (1) coagulation and fibrinolytic systems are independently activated during hepatectomy and such activation can be modulated by protease inhibitors such as nafamostat mesilate and antithrombin III; (2) elevated thromboxane A2 during hepatectomy is characterized in the prostanoid system, the elevation of thromboxane A2 is inhibited by thromboxane A2 synthetase inhibitor, and postoperative liver injury is reduced; (3) cytokine response induced by hepatectomy is modulated by preoperative administration of methylprednisolone, leading to possible prevention of bacterial translocation. Therefore, modulating systemic reactions to hepatectomy may be important for successful minimally invasive hepatectomy. Another important option for minimally invasive hepatectomy is the use of operative procedures such as laparoscope or thoracoscope. We have investigated the usefulness of a laparoscopic hepatectomy from the standpoints of early and long-term outcome after hepatectomy. Laparoscopic hepatectomy, which is a difficult and dangerous procedure, can be a feasible option and can result in better short-term outcome and a similar long-term outcome after hepatectomy when compared with conventional open hepatectomy. Therefore, the laparoscopic approach is also a viable option for minimally invasive hepatectomy.
Modulation of systemic reactions to the operation itself and laparoscopic hepatectomy may be new strategies for performing minimally invasive hepatectomy.
Surgery 02/2002; 131(1 Suppl):S312-7. · 3.10 Impact Factor
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ABSTRACT: Advanced hepatocellular carcinoma (HCC) with portal vein invasion and/or intrahepatic metastasis has an unfavorable prognosis even after radical hepatic resection. The aim of this study was to evaluate the effectiveness of a novel postoperative adjuvant chemotherapy given through the hepatic artery and based on biochemical modulation using cisplatin (CDDP) and 5-fluorouracil (5-FU).
Fifteen patients with advanced HCC with portal vein invasion into the main trunk and/or intrahepatic metastases of more than 3 segments were included in this study. After radical hepatic resection, the patients were divided to two groups: the adjuvant chemotherapy group (n=7) given the novel arterial infusion regimen with CDDP and 5-FU, and the control group (n=8) given no adjuvant chemotherapy.
Three-year survival rate of the adjuvant chemotherapy group tended to be significantly longer compared to that for the control group (p < 0.05). Most of the tumor recurrence was in the remnant liver, 5 cases in both of the groups. Significant difference of the recurrence patterns was recognized, rather than difference of the disease-free survival rate between the two groups. All of the intrahepatic recurrences are multiple in the control group, but in the adjuvant chemotherapy group, 2 cases of the recurrences showed a localized tumor surgically resected. It is noteworthy that the occurrence of multiple recurrence was significantly later in the adjuvant chemotherapy group compared to the control group (18.9 months vs. 6.5 months; p<0.05).
Our data suggest that this novel adjuvant chemotherapy can improve the postoperative prognosis of patients with the advanced HCC.
Hepato-gastroenterology 52(63):862-5. · 0.66 Impact Factor
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ABSTRACT: The role of trace elements in liver fibrosis, carcinogenesis and progression of hepatocellular carcinoma (HCC) has not yet been clarified. The aim of this study is to analyze the characteristics of trace elements in liver cancers and non-cancerous liver and to discuss their role in hepatic fibrosis, hepatocarcinogenesis and progression of HCC.
The amount of zinc (Zn), iron (Fe), and copper (Cu) in 20 HCCs, 2 cholangiocellular carcinomas (CCC), 7 metastatic liver cancers (Meta) and their non-tumorous liver parenchyma were measured using an atomic absorption spectrophotometer.
The amounts of Zn and Fe in non-tumorous liver parenchyma were reduced by liver fibrosis, and the amounts were lower in HCC tissue compared to non-tumorous liver parenchyma. The amounts of Zn and Cu were higher in HCC than the amounts found in CCC and Meta. The amount of Zn in HCC tissue decreased, but the amount of Fe increased in tumors more than 4cm in diameter.
These results suggest that the decrease in the amount of Zn and Fe found in non-tumorous liver parenchyma correlates with liver fibrosis leading to cirrhosis and hepatocarcinogenesis. Also that decreases in Zn and increases of Fe in HCC tissue correlates with HCC tumor progression.
Hepato-gastroenterology 52(61):187-90. · 0.66 Impact Factor
