Gemcitabine (Gem) is a dFdC analogue with activity against several solid tumors. Gem is intracell... more Gemcitabine (Gem) is a dFdC analogue with activity against several solid tumors. Gem is intracellularly phosphorylated by dCK, leading to the production of the metabolite dFdCDP. dFdCDP exhibits the cytotoxic effect by inactivating ribonucleotide reductase larger subunit 1 (RRM1), which is a rate limiting enzyme for de novo DNA synthesis. To date, RRM1 expression is believed to determine sensitivity to Gem in pancreatic and non-small cell lung cancer. In the present study, we found that an anti-allergic drug, tranilast strongly enhanced the sensitivity of pancreatic cancer cell line KP4 to Gem. In growth inhibition assay, 100 microM of tranilast plus 1 microM of Gem more strongly suppressed the growth of KP4 at 12.7-fold in IC50 than single Gem treatment, while this compound no longer affected the sensitivity to other drugs such as 5-fluorouracil, irinotecan or paclitaxel. FACS and TUNEL analysis demonstrated the increased apoptotic population in KP4 cells under tranilast plus Gem, ...
We examined the role of interleukin (IL)-1beta in activation of nuclear factor kappaB (NF-kappaB)... more We examined the role of interleukin (IL)-1beta in activation of nuclear factor kappaB (NF-kappaB) and the biological function of activated NF-kappaB in gastric carcinoma cells. Human gastric carcinoma cell line GCTM-1 was used to examine NF-kappaB activation by immunostaining and electrophoretic mobility shift assay. Matrix metalloproteinase (MMP)-9 expression, which plays an important role in tumor invasion, was assessed by semiquantitative reverse transcription-PCR, Western blotting, and immunostaining. The invasive ability of GCTM-1 cells was measured by Matrigel invasion assay. In vivo expression of IL-1beta and MMP-9 and activation of NF-kappaB in 10 surgically resected gastric carcinoma specimens were examined immunohistochemically. IL-1beta enhanced NF-kappaB activation, MMP-9 expression, and the invasive ability of GCTM-1. A NF-kappaB inhibitor, pyrrolidine dithiocarbamate, suppressed both MMP-9 expression and invasiveness of IL-1beta-treated GCTM-1 cells. IL-1beta did not increase the invasive ability of GCTM-1 cells transfected with MMP-9 antisense oligonucleotide. Concomitant expression of IL-1beta and nuclear NF-kappaB was observed in 3 of 10 gastric carcinoma specimens. Cells producing IL-1beta were tumor-infiltrating macrophages in two specimens and gastric carcinoma cells in one specimen. One of the molecules that may play a role in NF-kappaB activation in some gastric carcinomas is IL-1beta. The present results suggest that IL-1beta increases the invasive ability of carcinoma cells through activation of NF-kappaB and the resulting MMP-9 expression.
Undifferentiated spindle and giant cell carcinoma is an extremely rare malignant neoplasm arising... more Undifferentiated spindle and giant cell carcinoma is an extremely rare malignant neoplasm arising in the extrahepatic bile duct. We herein present the case of a 67-year-old male who developed an undifferentiated spindle and giant cell carcinoma of the proximal bile duct. A nodular infiltrating tumor was located at the proximal bile duct, resulting in obstructive jaundice. Histologically, the tumor was composed of mainly spindle-shaped and giant cells and showed positive immunoreactivity for both cytokeratin and vimentin. Adjuvant chemotherapy was administered following extrahepatic bile duct resection, and he has been doing well for 16 months since the surgical treatment. The literature on this rare malignancy is also reviewed and discussed.
To compare clinicopathological findings in patients with mucinous cystic neoplasms and intraducta... more To compare clinicopathological findings in patients with mucinous cystic neoplasms and intraductal papillary-mucinous tumours. Retrospective study. University department of surgery, Japan. 21 patients with mucinous cystic neoplasms (group 1) and 48 with intraductal papillary-mucinous tumours (group 2). The mean age was younger in group 1 (53(3.4) years) than in group 2 (65(1) years, p < 0.0001). The male:female ratio was smaller in group 1 than in group 2, being 0.17 (3/18) and 1.4 (28/20), respectively, (p = 0.0007). The main sites of the lesions were also significantly different: in group 1 four (19%) were located in the head and 17 in the body or tail, while 32 (67%) were in the head of the pancreas and 16 (33%) in the body or tail in group 2 (p = 0.0007). A unique endoscopic finding, excretion of mucin from the patulous orifice of the papilla, was present in two (9%) of the 21 mucinous cystic tumours and in 21 (45%) of the 47 intraductal papillary-mucinous tumours examined (p = 0.006). Metachronous or synchronous malignant diseases were found in the pancreas or other organs in one (5%) of the 21 patients with mucinous cystic neoplasm and in 13 (27%) of the 48 with intraductal papillary-mucinous tumours (p = 0.03). The three- and five-year survival rates of 11 patients with mucinous cystadenocarcinoma were 45% and 27%, while those of 15 with intraductal papillary-mucinous carcinoma were 85% and 42%. These findings suggest that mucinous cystic neoplasm and intraductal papillary-mucinous tumours are different clinicopathological entities. Aggressive surgery with peripancreatic lymph node dissection is recommended, particularly for mucinous cystadenocarcinoma, and postoperative follow-up with attention given to the presence of other malignancy is necessary as well as to local recurrence and haematogenous spread.
Hepatectomy combined with colectomy is the preferred treatment for patients with synchronous colo... more Hepatectomy combined with colectomy is the preferred treatment for patients with synchronous colorectal cancer and hepatic metastasis. However, the effects on hepatic reserve function of combining colectomy with hepatectomy are unclear. The purpose of this study was to determine liver regeneration and functions after hepatectomy with and without colectomy. 23 rats underwent 70% hepatectomy (Hx group) and 23 rats underwent 70% hepatectomy with ileocecal resection (HCx group), and 6 rats just after surgery (day 0) underwent simple celiotomy. On days 0, 1, 2, 3 and 7 after surgery, the remnant liver weight, DNA synthesis rate, malondialdehyde concentration, hepatic Adenosine monophosphate, ADP, ATP, serum hyaluronic acid concentration and endotoxin level in the portal blood were measured. In HCx group, the hepatic DNA synthesis rate on day 1 (p < 0.01) and the liver weight on day 7 (p < 0.05) were significantly lower, hepatic malondialdehyde concentration on days 1 and 2 (p < 0.05) was significantly higher and serum hyaluronic acid and portal endotoxin levels on day 1 were significantly higher (p < 0.01 and p < 0.05, respectively). Addition of colectomy to hepatectomy impairs regeneration and endothelial cell function of the remnant liver; the impairment is associated with increased levels of portal endotoxin and hepatic lipoperoxide.
Screening with fecal occult blood test has reduced mortality from colorectal cancer (CRC), with f... more Screening with fecal occult blood test has reduced mortality from colorectal cancer (CRC), with fecal immunochemical tests (FIT) widely utilized for CRC screening in Japan. To evaluate the importance of repeated FIT screening, the incidence of CRC was compared in patients undergoing initial and repeated screening. Participants aged ≥40 years in Saga, Japan, were invited to undergo a 2-day FIT. FIT positive subjects were verified by colonoscopy to evaluate the CRC incidence rates. From 2005 to 2007, 55,595 individuals were invited to undergo CRC screening, including 47,168 undergoing repeated and 8,427 undergoing initial screening. Of the 5,832 FIT-positive subjects, 4,615 were assessed by colonoscopy, with 114 diagnosed as having CRC. Of these 114 patients, 67 had early and 47 had advanced CRC. The risk of CRC was 63% lower in the repeated than in the initial screening group (p<0.0001). Of the 67 patients with early CRC, 42 underwent endoscopic resection, with the rate significantly higher in the repeated than in the initial screening group (p = 0.01). Overall survival was longer in screened subjects than in those who visited hospitals with clinical symptoms. Repeated CRC screening with FIT reduced the incidence of CRC in Saga, Japan.
BACKGROUND/AIMS: Even with the recent advances of diagnostic and therapeutic modalities, the clin... more BACKGROUND/AIMS: Even with the recent advances of diagnostic and therapeutic modalities, the clinical course of patients with pancreatic cancer remains dismal. Five-year survivors are rare, cure is exceptional, and the operative mortality rate is significant. In this study, univariate and multivariate retrospective analyses were performed with regard to the prognostic parameters to clarify the problems in order to improve survival rates after surgical resection.METHODOLOGY: Clinical courses of 60 Japanese patients with pancreatic cancer who underwent surgical resection in one Japanese University Hospital were reviewed to scrutinize the influence of 22 prognostic (9 host-side, 5 operative and 8 tumor-side) factors. A special reference was made on intra-operative radiation therapy, portal vein resection, lymph node dissection around the aorta, and conventional pancreatoduodenectomy versus pylorus-preserving pancreatoduodenectomy in pancreatic head cancer.RESULTS: Univariate analysis showed that operation time, comprehensive stage, comprehensive curability, histopathologic grade of differentiation and histopathologic venous invasion were statistically significant factors. Multivariate Cox regression analysis regarding the 5 profound factors showed that histopathologic grade of differentiation and histopathologic venous invasion were independently significant factors. The 1- and 3-year survival rates of 18 patients with intra-operative radiation therapy were 56% and 39%, while those of 36 patients without intra-operative radiation therapy were 54% and 18%. The 1- and 3-year survival rates of 43 patients with PV0,1 were 58% and 28%, while those of 17 with PV2,3 were 50% and 10%. Three patients with PV2 in 1 and PV3 in 2 underwent a portal vein resection. Two of the 3 patients were dead from liver metastasis 3 and 5 months after a surgical resection of liver metastasis. The 1- and 3-year survival rates of 17 with radical lymph node dissection including the para-aortic area were 61% and 26%, while those of 27 without para-aortic lymph node dissection were 66% and 25%. Of the 17 patients, the para-aortic lymph node was metastasized in 1 patient. The 1- and 3-year survival rates of 31 with pancreatoduodenectomy were 53% and 18%, while the 1- and 3-year survival rates with pylorus preserving pancreatoduodenectomy were 68% and 28%, respectively.CONCLUSIONS: These findings suggest that the clinical outcome after surgical resection of pancreatic carcinoma depends on tumor-side factors not operative parameters or host-side parameters. The clinical course seems to rely upon the nature of pancreatic cancer not upon the operative procedure.
Gan to Kagaku Ryoho Cancer Chemotherapy, Jul 1, 2013
INTRODUCTION: Toremifene(TOR)is a selective estrogen receptor modulator(SERM). A high dose of 120... more INTRODUCTION: Toremifene(TOR)is a selective estrogen receptor modulator(SERM). A high dose of 120 mg TOR(HD-TOR) has been used for recurrent breast cancer in Japan, but there is still insufficient evidence regarding the efficacy of HD-TOR.PATIENTS AND METHODS: HD-TOR was administered for recurrent or metastatic breast cancer between January 2003 and May 2012. The primary end point of the study was the tumor response rate. Bone metastasis cases were excluded from the efficacy analysis, but were included in the safety population.RESULTS: A total of 21 patients registered in the study and the 2 patients with bone metastasis only were excluded from the efficacy analysis. The median follow-up period was 8. 3 months. None of the patients in the study had a CR, 4 had a PR(21. 1%), 9 had SD(47. 4%), and 6 had PD(31. 6%). Eight of the 9 SD cases had a long-term SD. The ORR was 21. 1% and the CB rate was 63. 2%. The median TTP of CB cases was 18. 3 months. None of the patients discontinued treatment because of a grade 3 or grade 4 adverse effects.CONCLUSION: In summary, the current study showed that HD-TOR may lead to a CB for recurrent breast cancer in first- or second-line treatment rather than thirdline. In particular, HD-TOR may give a benefit in highly endocrine-sensitive cases.
Solid tumors are often exposed to hypoxia. Hypoxia inducible factor (HIF)-1α upregulates numerous... more Solid tumors are often exposed to hypoxia. Hypoxia inducible factor (HIF)-1α upregulates numerous target genes associated with the malignant behavior of hypoxic cancer cells. A member of the angiopoietin family, angiopoietin-like protein 4 (ANGPTL4) is a hypoxia-inducible gene. The present study aimed to clarify whether ANGPTL4 is regulated by HIF-1α in gastric cancer cells. The study also assessed whether ANGPTL4 expression is associated with clinicopathological factors or HIF-1α expression in gastric cancer tissues. Hypoxia-induced ANGPTL4 expression was quantitatively analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 10 gastric cancer cell lines. RT-qPCR was further employed to investigate the HIF-1α dependency of ANGPTL4 expression using HIF-1α-knockdown transfectant 58As9-KD and control 58As9-SC gastric cancer cells. The HIF-1α and ANGPTL4 expression levels were immunohistochemically analyzed in 170 gastric cancer tissue specimens and were assessed for any correlations with the clinicopathological factors and/or patient survival. Subsequently, hypoxia-induced ANGPTL4 expression was observed in 7 out of 10 gastric cancer cell lines. The hypoxic induction of ANGPTL4 was almost preserved in the 58As9-KD cells compared with that observed in the 58As9-SC cells, while the induction of known HIF-1α target gene, carbonic anhydrase 9, was completely suppressed in the 58As9-KD cells. In the gastric cancer tissues, ANGPTL4 expression was inversely correlated with the tumor depth, whereas HIF-1α expression was positively correlated with venous invasion. A survival analysis revealed that the expression of ANGPTL4 was significantly correlated with a longer survival time, whereas that of HIF-1α was correlated with a shorter survival time. In conclusion, the present findings indicate that hypoxia-induced ANGPTL4 expression is independent of HIF-1α in hypoxic gastric cancer cells. ANGPTL4 may be a favorable marker for predicting a long survival time, whereas HIF-1α predicts a poor prognosis, in gastric cancer patients. The hypoxic environment independently induces ANGPTL4 and HIF-1α, which are believed to exhibit adverse effects on tumor progression.
This report presents the case of a unique hepatocellular nodule occurring in a 73-year-old Japane... more This report presents the case of a unique hepatocellular nodule occurring in a 73-year-old Japanese male with diabetes mellitus and mild obesity. The nodule consisted of hepatocyte-like tumor cells and abundant foam cell type histiocytes that filled up a sinusoid-like space and formed central loose fibrosis. The superficial area did not contain as many histiocytes and showed hepatocellular adenoma character, but there was a focal hepatocellular carcinoma-like lesion, thus suggesting hepatocellular adenoma with malignant transformation. The background liver showed an almost normal histology except for mild steatosis with no specific infiltration of macrophages. These macrophages contained abundant fat droplets, whereas the tumor cells had no fat droplets. The expressions of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor were significantly higher in the tumor than in the background liver. These findings suggested such macrophage infiltration induced by the...
World journal of gastroenterology : WJG, Jan 14, 2014
Despite a decline in the overall incidence of gastric cancer (GC), the disease remains the second... more Despite a decline in the overall incidence of gastric cancer (GC), the disease remains the second most common cause of cancer-related death worldwide and is thus a significant global health problem. The best means of improving the survival of GC patients is to screen for and treat early lesions. However, GC is often diagnosed at an advanced stage and is associated with a poor prognosis. Current diagnostic and therapeutic strategies have not been successful in decreasing the global burden of the disease; therefore, the identification of reliable biomarkers for an early diagnosis, predictive markers of recurrence and survival and markers of drug sensitivity and/or resistance is urgently needed. The initiation and progression of GC depends not only on genetic alterations but also epigenetic changes, such as DNA methylation and histone modification. Aberrant DNA methylation is the most well-defined epigenetic change in human cancers and is associated with inappropriate gene silencing. T...
The surgical strategy for gallbladder cancer (GBC) depends on the extent of the disease. Thus, th... more The surgical strategy for gallbladder cancer (GBC) depends on the extent of the disease. Thus, the identification of useful prognostic markers exerting strong prognostic impact for each T stage would be beneficial in the development of rational therapeutic strategies. The purpose of this study was to identify useful prognostic markers of GBC for each T stage. CD8(+) tumor-infiltrating lymphocytes (TIL), Ki-67 labeling index (LI), p53 nuclear expression and mitotic count (MC) were investigated as candidate prognostic markers. In total, 86 patients with invasive GBC were included. Of the prognostic markers examined, only MC showed a correlation with reduced survival (P=0.0383) in the univariate analysis of overall T stage. In the univariate analysis of T2 stage (n=31), only high p53 expression correlated with survival showing a positive correlation (P=0.0154). In the univariate analysis of T3 stage (n=40), the only factor showing a significant correlation with survival was MC (P=0.011...
The molecular mechanisms underlying the peritoneal dissemination of gastric cancer remain unclear... more The molecular mechanisms underlying the peritoneal dissemination of gastric cancer remain unclear. Using in vivo metastatic models, this study attempted to clarify the role of hypoxia inducible factor (HIF)-1α in the development of peritoneal dissemination of gastric cancer. HIF-1α knockdown (KD) cells were established in the scirrhous gastric cancer cell line 58As9. Using KD and control (SC) cells, the presence of peritoneal dissemination was assessed in orthotopic implantation (o.i.) and intraperitoneal injection (i.p.) models. A series of in vitro analyses were also conducted. Finally, tumor angiogenesis was immunohistochemically analyzed. In the o.i. model, peritoneal dissemination was more frequently observed in the SC mice (93%) compared to the KD mice (13%) (P<0.001). In the i.p. model, peritoneal dissemination occurred at a high rate in both types of mice; however, a greater number of nodules was observed in the KD mice (P=0.017). The in vitro assays showed that HIF-1α ex...
The management of hepatocellular carcinoma with hypersplenic thrombocytopenia remains controversi... more The management of hepatocellular carcinoma with hypersplenic thrombocytopenia remains controversial, because of the high surgical morbidity and mortality. Splenectomy has been reported to be useful for patients with hypersplenic thrombocytopenia, but the timing and route of splenectomy and hepatic resection remains unclear. This report evaluated the efficacy of laparoscopic surgery for simultaneous splenectomy and hepatic resection in the treatment of hepatocellular carcinoma with hypersplenic thrombocytopenia. Among 65 patients with hypersplenic thrombocytopenia who underwent hepatic resection for hepatocellular carcinoma, 20 patients underwent simultaneous splenectomy and hepatic resection. Initially, ten patients underwent the procedure by conventional laparotomy (open group) and ten patients underwent by laparoscopy (laparoscopic group). The clinicopathological results from the two groups were compared retrospectively. The blood loss in the laparoscopic group was significantly l...
Gemcitabine (Gem) is a dFdC analogue with activity against several solid tumors. Gem is intracell... more Gemcitabine (Gem) is a dFdC analogue with activity against several solid tumors. Gem is intracellularly phosphorylated by dCK, leading to the production of the metabolite dFdCDP. dFdCDP exhibits the cytotoxic effect by inactivating ribonucleotide reductase larger subunit 1 (RRM1), which is a rate limiting enzyme for de novo DNA synthesis. To date, RRM1 expression is believed to determine sensitivity to Gem in pancreatic and non-small cell lung cancer. In the present study, we found that an anti-allergic drug, tranilast strongly enhanced the sensitivity of pancreatic cancer cell line KP4 to Gem. In growth inhibition assay, 100 microM of tranilast plus 1 microM of Gem more strongly suppressed the growth of KP4 at 12.7-fold in IC50 than single Gem treatment, while this compound no longer affected the sensitivity to other drugs such as 5-fluorouracil, irinotecan or paclitaxel. FACS and TUNEL analysis demonstrated the increased apoptotic population in KP4 cells under tranilast plus Gem, ...
We examined the role of interleukin (IL)-1beta in activation of nuclear factor kappaB (NF-kappaB)... more We examined the role of interleukin (IL)-1beta in activation of nuclear factor kappaB (NF-kappaB) and the biological function of activated NF-kappaB in gastric carcinoma cells. Human gastric carcinoma cell line GCTM-1 was used to examine NF-kappaB activation by immunostaining and electrophoretic mobility shift assay. Matrix metalloproteinase (MMP)-9 expression, which plays an important role in tumor invasion, was assessed by semiquantitative reverse transcription-PCR, Western blotting, and immunostaining. The invasive ability of GCTM-1 cells was measured by Matrigel invasion assay. In vivo expression of IL-1beta and MMP-9 and activation of NF-kappaB in 10 surgically resected gastric carcinoma specimens were examined immunohistochemically. IL-1beta enhanced NF-kappaB activation, MMP-9 expression, and the invasive ability of GCTM-1. A NF-kappaB inhibitor, pyrrolidine dithiocarbamate, suppressed both MMP-9 expression and invasiveness of IL-1beta-treated GCTM-1 cells. IL-1beta did not increase the invasive ability of GCTM-1 cells transfected with MMP-9 antisense oligonucleotide. Concomitant expression of IL-1beta and nuclear NF-kappaB was observed in 3 of 10 gastric carcinoma specimens. Cells producing IL-1beta were tumor-infiltrating macrophages in two specimens and gastric carcinoma cells in one specimen. One of the molecules that may play a role in NF-kappaB activation in some gastric carcinomas is IL-1beta. The present results suggest that IL-1beta increases the invasive ability of carcinoma cells through activation of NF-kappaB and the resulting MMP-9 expression.
Undifferentiated spindle and giant cell carcinoma is an extremely rare malignant neoplasm arising... more Undifferentiated spindle and giant cell carcinoma is an extremely rare malignant neoplasm arising in the extrahepatic bile duct. We herein present the case of a 67-year-old male who developed an undifferentiated spindle and giant cell carcinoma of the proximal bile duct. A nodular infiltrating tumor was located at the proximal bile duct, resulting in obstructive jaundice. Histologically, the tumor was composed of mainly spindle-shaped and giant cells and showed positive immunoreactivity for both cytokeratin and vimentin. Adjuvant chemotherapy was administered following extrahepatic bile duct resection, and he has been doing well for 16 months since the surgical treatment. The literature on this rare malignancy is also reviewed and discussed.
To compare clinicopathological findings in patients with mucinous cystic neoplasms and intraducta... more To compare clinicopathological findings in patients with mucinous cystic neoplasms and intraductal papillary-mucinous tumours. Retrospective study. University department of surgery, Japan. 21 patients with mucinous cystic neoplasms (group 1) and 48 with intraductal papillary-mucinous tumours (group 2). The mean age was younger in group 1 (53(3.4) years) than in group 2 (65(1) years, p &lt; 0.0001). The male:female ratio was smaller in group 1 than in group 2, being 0.17 (3/18) and 1.4 (28/20), respectively, (p = 0.0007). The main sites of the lesions were also significantly different: in group 1 four (19%) were located in the head and 17 in the body or tail, while 32 (67%) were in the head of the pancreas and 16 (33%) in the body or tail in group 2 (p = 0.0007). A unique endoscopic finding, excretion of mucin from the patulous orifice of the papilla, was present in two (9%) of the 21 mucinous cystic tumours and in 21 (45%) of the 47 intraductal papillary-mucinous tumours examined (p = 0.006). Metachronous or synchronous malignant diseases were found in the pancreas or other organs in one (5%) of the 21 patients with mucinous cystic neoplasm and in 13 (27%) of the 48 with intraductal papillary-mucinous tumours (p = 0.03). The three- and five-year survival rates of 11 patients with mucinous cystadenocarcinoma were 45% and 27%, while those of 15 with intraductal papillary-mucinous carcinoma were 85% and 42%. These findings suggest that mucinous cystic neoplasm and intraductal papillary-mucinous tumours are different clinicopathological entities. Aggressive surgery with peripancreatic lymph node dissection is recommended, particularly for mucinous cystadenocarcinoma, and postoperative follow-up with attention given to the presence of other malignancy is necessary as well as to local recurrence and haematogenous spread.
Hepatectomy combined with colectomy is the preferred treatment for patients with synchronous colo... more Hepatectomy combined with colectomy is the preferred treatment for patients with synchronous colorectal cancer and hepatic metastasis. However, the effects on hepatic reserve function of combining colectomy with hepatectomy are unclear. The purpose of this study was to determine liver regeneration and functions after hepatectomy with and without colectomy. 23 rats underwent 70% hepatectomy (Hx group) and 23 rats underwent 70% hepatectomy with ileocecal resection (HCx group), and 6 rats just after surgery (day 0) underwent simple celiotomy. On days 0, 1, 2, 3 and 7 after surgery, the remnant liver weight, DNA synthesis rate, malondialdehyde concentration, hepatic Adenosine monophosphate, ADP, ATP, serum hyaluronic acid concentration and endotoxin level in the portal blood were measured. In HCx group, the hepatic DNA synthesis rate on day 1 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) and the liver weight on day 7 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) were significantly lower, hepatic malondialdehyde concentration on days 1 and 2 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) was significantly higher and serum hyaluronic acid and portal endotoxin levels on day 1 were significantly higher (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01 and p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05, respectively). Addition of colectomy to hepatectomy impairs regeneration and endothelial cell function of the remnant liver; the impairment is associated with increased levels of portal endotoxin and hepatic lipoperoxide.
Screening with fecal occult blood test has reduced mortality from colorectal cancer (CRC), with f... more Screening with fecal occult blood test has reduced mortality from colorectal cancer (CRC), with fecal immunochemical tests (FIT) widely utilized for CRC screening in Japan. To evaluate the importance of repeated FIT screening, the incidence of CRC was compared in patients undergoing initial and repeated screening. Participants aged ≥40 years in Saga, Japan, were invited to undergo a 2-day FIT. FIT positive subjects were verified by colonoscopy to evaluate the CRC incidence rates. From 2005 to 2007, 55,595 individuals were invited to undergo CRC screening, including 47,168 undergoing repeated and 8,427 undergoing initial screening. Of the 5,832 FIT-positive subjects, 4,615 were assessed by colonoscopy, with 114 diagnosed as having CRC. Of these 114 patients, 67 had early and 47 had advanced CRC. The risk of CRC was 63% lower in the repeated than in the initial screening group (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). Of the 67 patients with early CRC, 42 underwent endoscopic resection, with the rate significantly higher in the repeated than in the initial screening group (p = 0.01). Overall survival was longer in screened subjects than in those who visited hospitals with clinical symptoms. Repeated CRC screening with FIT reduced the incidence of CRC in Saga, Japan.
BACKGROUND/AIMS: Even with the recent advances of diagnostic and therapeutic modalities, the clin... more BACKGROUND/AIMS: Even with the recent advances of diagnostic and therapeutic modalities, the clinical course of patients with pancreatic cancer remains dismal. Five-year survivors are rare, cure is exceptional, and the operative mortality rate is significant. In this study, univariate and multivariate retrospective analyses were performed with regard to the prognostic parameters to clarify the problems in order to improve survival rates after surgical resection.METHODOLOGY: Clinical courses of 60 Japanese patients with pancreatic cancer who underwent surgical resection in one Japanese University Hospital were reviewed to scrutinize the influence of 22 prognostic (9 host-side, 5 operative and 8 tumor-side) factors. A special reference was made on intra-operative radiation therapy, portal vein resection, lymph node dissection around the aorta, and conventional pancreatoduodenectomy versus pylorus-preserving pancreatoduodenectomy in pancreatic head cancer.RESULTS: Univariate analysis showed that operation time, comprehensive stage, comprehensive curability, histopathologic grade of differentiation and histopathologic venous invasion were statistically significant factors. Multivariate Cox regression analysis regarding the 5 profound factors showed that histopathologic grade of differentiation and histopathologic venous invasion were independently significant factors. The 1- and 3-year survival rates of 18 patients with intra-operative radiation therapy were 56% and 39%, while those of 36 patients without intra-operative radiation therapy were 54% and 18%. The 1- and 3-year survival rates of 43 patients with PV0,1 were 58% and 28%, while those of 17 with PV2,3 were 50% and 10%. Three patients with PV2 in 1 and PV3 in 2 underwent a portal vein resection. Two of the 3 patients were dead from liver metastasis 3 and 5 months after a surgical resection of liver metastasis. The 1- and 3-year survival rates of 17 with radical lymph node dissection including the para-aortic area were 61% and 26%, while those of 27 without para-aortic lymph node dissection were 66% and 25%. Of the 17 patients, the para-aortic lymph node was metastasized in 1 patient. The 1- and 3-year survival rates of 31 with pancreatoduodenectomy were 53% and 18%, while the 1- and 3-year survival rates with pylorus preserving pancreatoduodenectomy were 68% and 28%, respectively.CONCLUSIONS: These findings suggest that the clinical outcome after surgical resection of pancreatic carcinoma depends on tumor-side factors not operative parameters or host-side parameters. The clinical course seems to rely upon the nature of pancreatic cancer not upon the operative procedure.
Gan to Kagaku Ryoho Cancer Chemotherapy, Jul 1, 2013
INTRODUCTION: Toremifene(TOR)is a selective estrogen receptor modulator(SERM). A high dose of 120... more INTRODUCTION: Toremifene(TOR)is a selective estrogen receptor modulator(SERM). A high dose of 120 mg TOR(HD-TOR) has been used for recurrent breast cancer in Japan, but there is still insufficient evidence regarding the efficacy of HD-TOR.PATIENTS AND METHODS: HD-TOR was administered for recurrent or metastatic breast cancer between January 2003 and May 2012. The primary end point of the study was the tumor response rate. Bone metastasis cases were excluded from the efficacy analysis, but were included in the safety population.RESULTS: A total of 21 patients registered in the study and the 2 patients with bone metastasis only were excluded from the efficacy analysis. The median follow-up period was 8. 3 months. None of the patients in the study had a CR, 4 had a PR(21. 1%), 9 had SD(47. 4%), and 6 had PD(31. 6%). Eight of the 9 SD cases had a long-term SD. The ORR was 21. 1% and the CB rate was 63. 2%. The median TTP of CB cases was 18. 3 months. None of the patients discontinued treatment because of a grade 3 or grade 4 adverse effects.CONCLUSION: In summary, the current study showed that HD-TOR may lead to a CB for recurrent breast cancer in first- or second-line treatment rather than thirdline. In particular, HD-TOR may give a benefit in highly endocrine-sensitive cases.
Solid tumors are often exposed to hypoxia. Hypoxia inducible factor (HIF)-1α upregulates numerous... more Solid tumors are often exposed to hypoxia. Hypoxia inducible factor (HIF)-1α upregulates numerous target genes associated with the malignant behavior of hypoxic cancer cells. A member of the angiopoietin family, angiopoietin-like protein 4 (ANGPTL4) is a hypoxia-inducible gene. The present study aimed to clarify whether ANGPTL4 is regulated by HIF-1α in gastric cancer cells. The study also assessed whether ANGPTL4 expression is associated with clinicopathological factors or HIF-1α expression in gastric cancer tissues. Hypoxia-induced ANGPTL4 expression was quantitatively analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 10 gastric cancer cell lines. RT-qPCR was further employed to investigate the HIF-1α dependency of ANGPTL4 expression using HIF-1α-knockdown transfectant 58As9-KD and control 58As9-SC gastric cancer cells. The HIF-1α and ANGPTL4 expression levels were immunohistochemically analyzed in 170 gastric cancer tissue specimens and were assessed for any correlations with the clinicopathological factors and/or patient survival. Subsequently, hypoxia-induced ANGPTL4 expression was observed in 7 out of 10 gastric cancer cell lines. The hypoxic induction of ANGPTL4 was almost preserved in the 58As9-KD cells compared with that observed in the 58As9-SC cells, while the induction of known HIF-1α target gene, carbonic anhydrase 9, was completely suppressed in the 58As9-KD cells. In the gastric cancer tissues, ANGPTL4 expression was inversely correlated with the tumor depth, whereas HIF-1α expression was positively correlated with venous invasion. A survival analysis revealed that the expression of ANGPTL4 was significantly correlated with a longer survival time, whereas that of HIF-1α was correlated with a shorter survival time. In conclusion, the present findings indicate that hypoxia-induced ANGPTL4 expression is independent of HIF-1α in hypoxic gastric cancer cells. ANGPTL4 may be a favorable marker for predicting a long survival time, whereas HIF-1α predicts a poor prognosis, in gastric cancer patients. The hypoxic environment independently induces ANGPTL4 and HIF-1α, which are believed to exhibit adverse effects on tumor progression.
This report presents the case of a unique hepatocellular nodule occurring in a 73-year-old Japane... more This report presents the case of a unique hepatocellular nodule occurring in a 73-year-old Japanese male with diabetes mellitus and mild obesity. The nodule consisted of hepatocyte-like tumor cells and abundant foam cell type histiocytes that filled up a sinusoid-like space and formed central loose fibrosis. The superficial area did not contain as many histiocytes and showed hepatocellular adenoma character, but there was a focal hepatocellular carcinoma-like lesion, thus suggesting hepatocellular adenoma with malignant transformation. The background liver showed an almost normal histology except for mild steatosis with no specific infiltration of macrophages. These macrophages contained abundant fat droplets, whereas the tumor cells had no fat droplets. The expressions of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor were significantly higher in the tumor than in the background liver. These findings suggested such macrophage infiltration induced by the...
World journal of gastroenterology : WJG, Jan 14, 2014
Despite a decline in the overall incidence of gastric cancer (GC), the disease remains the second... more Despite a decline in the overall incidence of gastric cancer (GC), the disease remains the second most common cause of cancer-related death worldwide and is thus a significant global health problem. The best means of improving the survival of GC patients is to screen for and treat early lesions. However, GC is often diagnosed at an advanced stage and is associated with a poor prognosis. Current diagnostic and therapeutic strategies have not been successful in decreasing the global burden of the disease; therefore, the identification of reliable biomarkers for an early diagnosis, predictive markers of recurrence and survival and markers of drug sensitivity and/or resistance is urgently needed. The initiation and progression of GC depends not only on genetic alterations but also epigenetic changes, such as DNA methylation and histone modification. Aberrant DNA methylation is the most well-defined epigenetic change in human cancers and is associated with inappropriate gene silencing. T...
The surgical strategy for gallbladder cancer (GBC) depends on the extent of the disease. Thus, th... more The surgical strategy for gallbladder cancer (GBC) depends on the extent of the disease. Thus, the identification of useful prognostic markers exerting strong prognostic impact for each T stage would be beneficial in the development of rational therapeutic strategies. The purpose of this study was to identify useful prognostic markers of GBC for each T stage. CD8(+) tumor-infiltrating lymphocytes (TIL), Ki-67 labeling index (LI), p53 nuclear expression and mitotic count (MC) were investigated as candidate prognostic markers. In total, 86 patients with invasive GBC were included. Of the prognostic markers examined, only MC showed a correlation with reduced survival (P=0.0383) in the univariate analysis of overall T stage. In the univariate analysis of T2 stage (n=31), only high p53 expression correlated with survival showing a positive correlation (P=0.0154). In the univariate analysis of T3 stage (n=40), the only factor showing a significant correlation with survival was MC (P=0.011...
The molecular mechanisms underlying the peritoneal dissemination of gastric cancer remain unclear... more The molecular mechanisms underlying the peritoneal dissemination of gastric cancer remain unclear. Using in vivo metastatic models, this study attempted to clarify the role of hypoxia inducible factor (HIF)-1α in the development of peritoneal dissemination of gastric cancer. HIF-1α knockdown (KD) cells were established in the scirrhous gastric cancer cell line 58As9. Using KD and control (SC) cells, the presence of peritoneal dissemination was assessed in orthotopic implantation (o.i.) and intraperitoneal injection (i.p.) models. A series of in vitro analyses were also conducted. Finally, tumor angiogenesis was immunohistochemically analyzed. In the o.i. model, peritoneal dissemination was more frequently observed in the SC mice (93%) compared to the KD mice (13%) (P<0.001). In the i.p. model, peritoneal dissemination occurred at a high rate in both types of mice; however, a greater number of nodules was observed in the KD mice (P=0.017). The in vitro assays showed that HIF-1α ex...
The management of hepatocellular carcinoma with hypersplenic thrombocytopenia remains controversi... more The management of hepatocellular carcinoma with hypersplenic thrombocytopenia remains controversial, because of the high surgical morbidity and mortality. Splenectomy has been reported to be useful for patients with hypersplenic thrombocytopenia, but the timing and route of splenectomy and hepatic resection remains unclear. This report evaluated the efficacy of laparoscopic surgery for simultaneous splenectomy and hepatic resection in the treatment of hepatocellular carcinoma with hypersplenic thrombocytopenia. Among 65 patients with hypersplenic thrombocytopenia who underwent hepatic resection for hepatocellular carcinoma, 20 patients underwent simultaneous splenectomy and hepatic resection. Initially, ten patients underwent the procedure by conventional laparotomy (open group) and ten patients underwent by laparoscopy (laparoscopic group). The clinicopathological results from the two groups were compared retrospectively. The blood loss in the laparoscopic group was significantly l...
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Papers by Hirokazu Noshiro