Highly enantioselective hydroxymethylation of unmodified α-substituted aryl ketones in water.

Catalytic asymmetric direct-type aldol reactions of ketones with aldehydes are a perennial puzzle for organic chemists. Notwithstanding the emergence of a myriad of chiral catalysts to address the inherent reversibility of the aldol products, a general method to access acyclic α-chiral ketones from prochiral aryl ketones has remained an unmet synthetic challenge. The approach outlined herein is fundamentally different to that used in conventional catalysis, which typically commences with an α-proton abstraction by a Brønsted base. The use of a chiral 2,2'-bipyridine scandium complex enabled the hydroxymethylation of propiophenone to be run under base-free conditions, which avails effectual suppression of hydrolytic deactivation of the Lewis acid catalyst. Intriguingly, the use of water as a reaction medium had an overriding effect on the progress of the reaction. The sagacious selection of sodium dodecyl sulfate and lithium dodecyl sulfate as surfactants allowed a variety of propiophenone derivatives to react in a highly enantioselective manner.

Fibroblast activation protein-α-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stromal response. Fibroblast activation protein-α (FAP) is best known for its presence in stromal cancer-associated fibroblasts (CAFs). Our aim was to assess whether FAP expression was associated with the prognosis of patients with PDAC and to investigate how FAP expressing CAFs contribute to the progression of PDAC. METHODS: FAP expression was immunohistochemically assessed in 48 PDAC specimens. We also generated a fibroblastic cell line stably expressing FAP, and examined the effect of FAP-expressing fibroblasts on invasiveness and the cell cycle in MiaPaCa-2 cells (a pancreatic cancer cell line). RESULTS: Stromal FAP expression was detected in 98% (47/48) of the specimens of PDAC, with the intensity being weak in 16, moderate in 19, and strong in 12 specimens, but was not detected in the 3 control noncancerous pancreatic specimens. Patients with moderate or strong FAP expression had significantly lower cumulative survival rates than those with negative or weak FAP expression (mean survival time; 352 vs. 497 days, P = 0.006). Multivariate analysis identified moderate to strong expression of FAP as one of the factors associated with the prognosis in patients with PDAC. The intensity of stromal FAP expression was also positively correlated to the histological differentiation of PDAC (P < 0.05). FAP-expressing fibroblasts promoted the invasiveness of MiaPaCa-2 cells more intensively than fibroblasts not expressing FAP. Coculture with FAP-expressing fibroblasts significantly activated cell cycle shift in MiaPaCa-2 cells compared to coculture with fibroblasts not expressing FAP. Furthermore, coculture with FAP expressing fibroblasts inactivated retinoblastoma (Rb) protein, an inhibitor of cell cycle progression, in MiaPaCa-2 cells by promoting phosphorylation of Rb. CONCLUSIONS: The present in vitro results and the association of FAP expression with clinical outcomes provide us with a better understanding of the effect of FAP-expressing CAFs on the progression of PDAC.

Hepatic oxidative stress in ovariectomized transgenic mice expressing the hepatitis C virus polyprotein is augmented through suppression of adenosine monophosphate-activated protein kinase/proliferator-activated receptor gamma co-activator 1 alpha signaling.

AIM: Oxidative stress plays an important role in hepatocarcinogenesis of hepatitis C virus (HCV)-related chronic liver diseases. Despite the evidence of an increased proportion of females among elderly patients with HCV-related hepatocellular carcinoma (HCC), it remains unknown whether HCV augments hepatic oxidative stress in postmenopausal women. The aim of this study was to determine whether oxidative stress was augmented in ovariectomized (OVX) transgenic mice expressing the HCV polyprotein and to investigate its underlying mechanisms. METHODS: OVX and sham-operated female transgenic mice expressing the HCV polyprotein and non-transgenic littermates were assessed for the production of reactive oxygen species (ROS), expression of inflammatory cytokines and antioxidant potential in the liver. RESULTS: Compared with OVX non-transgenic mice, OVX transgenic mice showed marked hepatic steatosis and ROS production without increased induction of inflammatory cytokines, but there was no increase in ROS-detoxifying enzymes such as superoxide dismutase 2 and glutathione peroxidase 1. In accordance with these results, OVX transgenic mice showed less activation of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), which is required for the induction of ROS-detoxifying enzymes, and no activation of adenosine monophosphate-activated protein kinase-α (AMPKα), which regulates the activity of PGC-1α. CONCLUSION: Our study demonstrated that hepatic oxidative stress was augmented in OVX transgenic mice expressing the HCV polyprotein by attenuation of antioxidant potential through inhibition of AMPK/PGC-1α signaling. These results may account in part for the mechanisms by which HCV-infected women are at high risk for HCC development when some period has passed after menopause.

Focal nodular hyperplasia-like nodule with reduced expression of organic anion transporter 1B3 in alcoholic liver cirrhosis.

We report a patient with alcoholic liver cirrhosis who had a 15 mm focal nodular hyperplasia (FNH)-like nodule in the liver. This FNH-like nodule was diagnosed as hepatocellular carcinoma (HCC) mainly based on hypervascularity during the hepatic arterial phase, washout pattern during the equilibrium phase and low signal intensity during the hepatobiliary phase in gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI; it was surgically resected. Its histology exhibited hepatocyte hyperplasia, fibrous septa containing unpaired small arteries accompanied by reactive bile ductules, remarkable iron deposits and sinusoidal capillarization, and was compatible with the diagnosis of an FNH-like nodule. When we analyzed the images of the present nodule retrospectively, low signal intensity on in-phase and isosignal intensity on opposed-phase T1-weighted MRI may have reflected iron deposits in the FNH-like nodule. In addition, a low signal intensity on T2-weighted MRI and no detection in diffusion-weighted MRI may help in distinguishing FNH-like nodules from HCC, since these image findings are inconsistent with typical HCC. Immunohistochemical analysis revealed a markedly reduced expression of organic anion transporter (OATP) 1B3 in this nodule, which implied decreased Gd-EOB-DTPA uptake by hepatocytes and accounted for the low signal intensity during the hepatobiliary phase on Gd-EOB-DTPA-enhanced MRI. To the best of our knowledge this is the first report in which an FNH-like nodule was assessed for OATP1B3 expression.

Type 1 interferon receptor in peripheral blood mononuclear cells may predict response to intra-arterial 5-fluorouracil + interferon therapy for advanced hepatocellular carcinoma.

BACKGROUND: Type 1 interferon alpha receptor 2 (IFNAR2) in the liver has been reported to be a predictive factor for the response to intra-arterial 5-fluorouracil (5-FU) + systemic interferon (IFN)-alpha combination therapy in patients with advanced hepatocellular carcinoma. We tested whether IFNAR2 expression in peripheral blood mononuclear cells could predict the response to 5-FU + IFN. METHODS: Predictive factors for survival and response to therapy were determined in 30 patients with advanced hepatocellular carcinoma who underwent treatment with 5-FU + IFN. IFNAR2 expression in peripheral blood mononuclear cells was measured in 11 of the 30 patients. RESULTS: With a mean number of 4.2 courses of combination therapy, one patient (3%) showed a complete response, eight (27%) showed partial responses, 13 (43%) had stable disease, and eight (27%) showed progressive disease. The median survival time of responders (complete response/partial response) was 12.7 months and that of nonresponders (stable disease/progressive disease) was 7.5 months. The one-year and two-year cumulative survival rates of responders and nonresponders were 87/69% and 40/11%, respectively (P = 0.019). Multivariate analysis identified response to therapy (P = 0.037) as the sole independent determinant of survival. The expression level of IFNAR2 in peripheral blood mononuclear cells was significantly (P = 0.012) higher in responders (6.5 ± 2.4) than in nonresponders (2.4 ± 0.6), even though no clinical factors were identified as being associated with the response to the combination therapy. CONCLUSION: IFNAR2 expression in peripheral blood mononuclear cells may predict the response to 5-FU + IFN therapy in patients with advanced hepatocellular carcinoma, although these data are preliminary.

[Case of gallbladder cancer in which the surface structure of gallbladder was clarified using the endoscopic double contrast cholecystography].

A 75-year-old woman was admitted to our hospital with a gallbladder tumor by detected ultrasonography (US). On endoscopic ultrasonography (EUS), and abdominal CT, we diagnosed the Is+IIa+IIb-like ss lesion invasive gallbladder cancer, but endoscopic double contrast cholecystography suggested IIa+IIb-like ss invasive gallbladder cancer because the lesion had the same granular membrane a other cancer membrane and cholecystectomy was carried out. The pathologic diagnosis was IIa+IIb-like ss invasive gallbladder cancer.

Comparison of therapeutic effects between radiofrequency ablation and percutaneous microwave coagulation therapy for small hepatocellular carcinomas.

BACKGROUND: Although thermal ablation therapies have gained fairly wide acceptance as an effective treatment for small hepatocellular carcinoma (HCC), there have been only a few clinical studies comparing the response to radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT). We evaluated the therapeutic efficacy and safety of these two procedures for the treatment of small HCC measuring < or = 2 cm in diameter. METHODS: Thirty-four patients who had 37 nodules were treated by RFA and were compared with 49 patients (56 nodules) who underwent PMCT. Treatment was repeated until complete tumor necrosis was confirmed by contrast computed tomography (CT) scanning. The therapeutic efficacy and complications were retrospectively compared between the two procedures. RESULTS: (i) There were significantly fewer treatment sessions (P < 0.001) in the RFA group than in the PMCT group, but the necrotic area was significantly larger (P < 0.001) in the former group. (ii) The local recurrence rate was significantly lower (P = 0.031) after RFA than after PMCT, although the ectopic recurrence rate showed no significant difference. (iii) The cumulative survival rate was significantly higher (P = 0.018) after RFA than after PMCT. (iv) The incidence of pain and fever after treatment was significantly higher in the PMCT group. Bile duct injury, pleural effusion, and ascites were also significantly more common in the PMCT group. CONCLUSIONS: RFA is more useful than PMCT for the treatment of small HCC because it is minimally invasive and achieves a low local recurrence rate, high survival rate, and extensive necrosis after only a few treatment sessions.

[Pyogenic liver abscess complicated by gastric fistula and bacterial meningitis].

A 77-year-old woman was admitted suffering from fever and headache. On laboratory examination, bacterial meningitis and sepsis due to Klebsiella pneumoniae were diagnosed. In addition, a hepatic cystic lesion measuring 13 cm in diameter in the left lobe was indicated on diagnostic imaging. After treatment with antibiotics, her signs of infection improved and the hepatic lesion decreased in size. After discharge, however, the cystic liver mass increased and a gastric fistula developed. Hepatic and gastric resections were performed because of the possibility of biliary cystadenocarcinoma and gastric invasion. Pathologically, a pyogenic liver abscess complicated by gastric fistula was diagnosed.

Radiofrequency ablation versus percutaneous microwave coagulation therapy for small hepatocellular carcinomas: a retrospective comparative study.

BACKGROUND/AIMS: Although local ablation procedures are useful in eradication treatment for small hepatocellular carcinoma (HCC), there have only been a few clinical studies comparing the response to radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT). We evaluated the clinical effect and safety of these two procedures for the treatment of small HCCs measuring 2cm or less in diameter. METHODOLOGY: Twenty-four patients with HCC who were treated by RFA and were compared with 39 patients with HCC who underwent PMCT. These procedures were repeated until complete tumor necrosis was achieved. The therapeutic and adverse effects were retrospectively compared between the two procedures. RESULTS: (1) There were significantly fewer treatment sessions (P < 0.001) in the RFA group than the PMCT group, and the necrotic area was significantly larger (P < 0.001) in the former group. (2) The local recurrence rate was significantly lower (P = 0.012) after RFA than after PMCT, even though the ectopic recurrence rate showed no significant difference. 3) The cumulative survival rate was significantly higher (P = 0.028) in the RFA group. (4) The incidence of pain and fever after treatment was significantly higher after PMCT than after RFA. Bile duct injury and pleural effusion were also more frequent in the PMCT group. CONCLUSIONS: RFA is more useful than PMCT in the treatment of small HCCs because it is minimally invasive and achieves a low local recurrence rate, high survival rate, and extensive necrosis after only a few treatment sessions.

[Hepatocellular carcinoma occurring after 11 year-long sustained viral response to interferon therapy for chronic hepatitis C].

The patient was a 61-year-old man with chronic hepatitis C who achieved a sustained virological response to interferon therapy in 1993. As a result, the status of his liver improved pathologically from F2A2 to F1A1. Eleven years later, however, a tumor measuring 15 mm in diameter in segment 6 of the liver was indicated by CT. A well-differentiated hepatocellular carcinoma was detected by a fine needle biopsy. The lesion was treated by transcatheter arterial chemoembolization combined with radiofrequency ablation. Even if patients with chronic hepatitis C have achieved a sustained virological response to interferon therapy, patients with risk factors for the development of hepatocellular carcinoma, such as being a male of advanced age and with progressive fibrosis of the liver, should receive careful long-term follow-up.

CO2-enhanced sonographically guided radiofrequency ablation and transcatheter arterial chemoembolization for small hepatocellular carcinoma poorly defined on conventional sonography.

We report a case of hepatocellular carcinoma located just below the right hemidiaphragm that was diagnosed as having hepatitis C virus-related cirrhosis 12 years ago. Although the lesion was not clear on conventional sonography, it was clearly defined on CO(2)-enhanced sonography, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, extensive cauterization and complete tumor necrosis were obtained with only 1 session of treatment. The patient had no serious adverse effects and has shown no recurrence during 35 months of follow-up.

Thermal ablation therapy for hepatocellular carcinoma: comparison between radiofrequency ablation and percutaneous microwave coagulation therapy.

BACKGROUND/AIMS: To evaluate the initial therapeutic effect and safety of radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT) for the treatment of small hepatocellular carcinomas (HCCs). METHODOLOGY: Forty-eight patients with HCC were treated by RFA and 70 patients with HCC were treated by PMCT. These procedures were repeated until complete tumor necrosis was confirmed by contrast CT scanning. The therapeutic and adverse effects were compared between the two procedures. RESULTS: 1) The number of treatment sessions was significantly lower in RFA patients, and the necrotic area was significantly larger. 2) The local recurrence rate was significantly lower after RFA than after PMCT, while the ectopic recurrence rate showed no significant difference between the two procedures. 3) The survival rate was significantly higher after RFA compared with PMCT. 4) The incidence of pain and fever after treatment was significantly higher in PMCT patients. Occurrence of bile duct injury, pleural effusion and ascites were also significantly more common in PMCT patients. CONCLUSIONS: RFA is more useful for the treatment of small HCCs compared with PMCT because it is minimally invasive and achieves a low local recurrence rate, a high survival rate, and extensive necrosis after only a few treatment sessions.

Use of intra-arterial carbon-dioxide-enhanced ultrasonography for guidance of radiofrequency ablation and transcatheter arterial chemoembolization in hepatocellular carcinoma.

A 73-year-old man with hepatitis-C-related cirrhosis and an elevated alpha-fetoprotein level and tumor in segment 3 of his liver was referred for interventional radiologic treatment. He was not a candidate for surgical resection due to impaired liver function and his personal preferences. On conventional ultrasonography no lesion could be detected, but the tumor was clearly depicted by intra-arterial carbon-dioxide-enhanced ultrasonography. Radiofrequency ablation was performed safely and accurately under the guidance of carbon-dioxide-enhanced ultrasonography. By concomitant performance of transcatheter arterial chemoembolization with radiofrequency ablation, extensive necrosis was obtained and adequate tumor volume reduction achieved with only one treatment session.

Carbon dioxide-enhanced sonographically guided radiofrequency ablation plus transcatheter arterial chemoembolization for hepatocellular carcinoma.

A 78-year-old man had a history of blood transfusion and hepatitis C virus-related liver cirrhosis. He was admitted to the authors' hospital with a hepatocellular carcinoma just below the right hemidiaphragm. Although the lesion was not well visualized with standard sonography, it was clearly defined by performance of sonography with intraarterial injection of carbon dioxide, allowing safe and accurate radiofrequency ablation. To increase the extent of tumor ablation, transcatheter arterial chemoembolization was performed immediately before radiofrequency ablation. By concomitant application of these two techniques, complete tumor necrosis was achieved without the need to perform additional ablation.

Carbon dioxide-enhanced sonographically guided radiofrequency ablation combined with transcatheter arterial chemoembolization for sonographically undetectable hepatocellular carcinoma.

A 73-year-old man was diagnosed as having hepatitis C virus-related liver cirrhosis 11 years ago. Two years ago, he developed hepatocellular carcinoma in segment 6 of the right lobe and received radiofrequency ablation. This time, he was admitted to our hospital with a local recurrence in segment 6 of the liver. Standard sonography could not visualize the lesion clearly. However, carbon dioxide-enhanced sonogram clearly showed the whole lesion, so a needle electrode could be inserted precisely, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, complete tumor necrosis was achieved without the need to perform additional ablation. In conclusion, carbon dioxide-enhanced sonographically guided radiofrequency ablation combined with transcatheter arterial chemoembolization is useful for complete cure of localized tumors, such as recurrent hepatocellular carcinoma, which cannot be detected clearly by conventional sonography.