Improved Mortality, Morbidity, and Long-Term Outcome After Anatomical Hepatectomy With the Glissonean Pedicle Approach in Patients With Hepatocellular Carcinoma: 30 Years' Experience at a Single Institute.

OBJECTIVE: We evaluated the morbidity and mortality after anatomical hepatectomy with the Glissonean pedicle approach, and long-term outcomes in relation to the morbidity in patients with hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: The mortality, morbidity, and long-term outcomes were evaluated retrospectively. METHODS: A total of 1953 patients with HCC underwent various anatomical hepatectomies with the Glissonean pedicle approach between 1985 and 2014. The mortality (30-day and 90-day) and morbidity (Clavien-Dindo class Ilia or higher) were evaluated among six 5-year eras (1985-1989, 1990-1994, 1995-1999, 2000-2004, 2005-2009, 2010-2014). RESULTS: A total of 460 patients (24%) showed morbidity, and the overall 30-day and 90-day mortality rates were 1.8% and 3.3%, respectively. The 30-day (3.9%, 3.0%, 1.8%, 1.3%, 0.3%, 0.5%: P = 0.0074) and 90-day mortality (6.0%, 4.3%, 3.8%, 2.8%, 2.2%, 1.4%: P = 0.0445) significantly improved over the eras. Blood loss >2 L (odds ratio: 11.808, P = 0.0244) was an independent risk factor for 30-day mortality, and blood loss >2 L (odds ratio: 4.046, P = 0.0271) and bile leakage (odds ratio: 2.122, P = 0.0078) were independent risk factors for 90-day mortality on multivariate analysis. Morbidity was significant independent prognostic factors for overall survival (relative risk: 2.129, P < 0.0001) and recurrence-free survival (relative risk: 1.299, P < 0.0001) in patients with HCC. CONCLUSIONS: Anatomical hepatectomy with the Glissonean pedicle approach was achieved safely in patients with HCC. For more safety and longer survival, blood loss, bile leakage, and morbidity should be reduced. Longterm outcomes after anatomical hepatectomy with the Glissonean pedicle approach in patients with HCC have been improved over 30 years with gradually less mortality and morbidity due to decreases in blood loss >2 L and bile leakage.

Hereditary Apolipoprotein A-1 Amyloidosis With Glu34Lys Mutation Treated by Liver Transplantation: A Case Report.

Hereditary apolipoprotein A-1 (ApoA-1) amyloidosis is a rare disease characterized by progressive deposition of amyloid fibrils in the kidney, heart, and liver. We observed a 45-year-old male patient with liver failure. Liver dysfunction was detected at 30 years of age during an annual health check-up. At 35 years of age, renal dysfunction was also found. At 40 years of age, the pathologic findings of the liver revealed amyloid deposition. A testis biopsy specimen taken at 42 years of age to identify the cause of male infertility showed amyloid accumulation. At 43 years of age, the amyloid results and genetic profile led to a definitive diagnosis of hereditary ApoA-1 amyloidosis caused by Glu34Lys mutation. A family history was absent. Liver failure showed Budd-Chiari-like formation, including enlargement of the caudate lobe and liver congestion. Although the patient showed end-stage liver cirrhosis and renal failure, only liver transplant was performed considering the burden for a living donor. The enlarged liver (4.9 kg) showed amyloid deposition in parenchyma and the space of Disse. Amyloid also accumulated in the giant spleen. The APOA1 mutation Glu34Lys is extremely rare, and in this case hepatic failure was successfully treated by liver transplant to both replace organ function and reduce production of the amyloidogenic ApoA-1-variant protein. Careful observation for reaccumulation of amyloidosis in the organ is required.

A case of hemorrhage of hepatocellular carcinoma resembling a hepatic cyst arising from non-cirrhotic steatohepatitis.

A 70-year-old female was found to have multiple hepatic cysts at her annual checkup. In the posterior segment of the right lobe of the liver, an 81 × 67 mm circular cystic lesion was detected by contrast-enhanced computed tomography (CT). Magnetic resonance imaging (MRI) of the cyst revealed a solid component. The cyst had a capsule-like structure and non-uniform fluid accumulation suggested bleeding. Since the lesion was enlarged and malignancy could not be ruled out, it was surgically resected. Histopathologically, reticular fibers of the liver were seen in necrotic tissue and the lesion was diagnosed as a bleeding hepatocellular carcinoma (HCC). The non-cancerous liver tissue showed non-cirrhotic steatohepatitis. This was an unusual presentation of HCC.

Debulking of giant liver hemangiomas with severe symptoms: a case report.

BACKGROUND: There are no previous reports of debulking of giant liver hemangioma. This report describes our experience with debulking surgery for a patient with bilateral giant liver hemangiomas with severe symptoms. CASE PRESENTATION: We present a case of symptomatic giant liver hemangioma in a 41-year-old woman. She presented with abdominal pain and fullness at a local hospital and underwent trans-arterial embolization (TAE). TAE was not effective, and she was not able to walk a long distance. Giant liver hemangiomas, 30 cm and 15 cm in diameter, were located in the right liver and in the left lateral section, respectively, and normal liver parenchyma with tiny liver hemangiomas was present in segment 4. The liver function was normal. However, right hemi-hepatectomy with left lateral sectionectomy was considered to be risky according to the 3DCT volumetry. Therefore, we performed right hemi-hepatectomy in order to reduce her symptoms. The postoperative course was uneventful, and she was discharged on the 14th day after surgery. The abdominal fullness and abdominal pain disappeared immediately after surgery. The hemangiomas in the remnant liver, 15 cm in diameter, showed no change, and she is well without symptoms 7 years after surgery. CONCLUSIONS: Debulking surgery is one of the options for bilateral giant liver hemangiomas with severe symptoms.

Hepatocellular carcinoma with ring calcification mimicking hydatid disease: a case report.

BACKGROUND: Ring calcification in hepatocellular carcinoma is extremely rare. Untreated hepatocellular carcinoma occasionally includes calcified lesions. Here, we report a case of ring-calcified hepatocellular carcinoma. CASE PRESENTATION: A 60-year-old man with a hepatic tumor was referred to Tokyo Women's Medical University Hospital. He had a history of chronic hepatitis C. Computed tomography showed a liver tumor 20 mm in diameter in segment 6 of the Couinaud classification, with ring calcification. Based on this uncommon imaging presentation and the patient's past exposure to the definitive hosts of Echinococcus multilocularis, he was preoperatively diagnosed with echinococcosis. Partial hepatectomy was performed as a radical treatment for echinococcosis. A final diagnosis of hepatocellular carcinoma was confirmed based on pathological findings. The patient was discharged uneventfully. CONCLUSION: The presentation of an extremely rare hepatocellular carcinoma with ring calcification may be disguised as hydatid disease.

A patient with post-Fontan operation underwent left hepatectomy and caudate lobectomy for hepatocellular carcinoma: a case report.

BACKGROUND: The Fontan procedure has been widely accepted for children with single ventricle physiology and guarantees survival rates of approximately 80% at age 20 years. However, there have been cases of Fontan-associated liver disease (FALD) caused due to congestion, along with recent reports of the development of hepatocellular carcinoma (HCC) in younger patients with FALD. The literature consists of only five previous case reports of patients who underwent hepatectomy for HCC due to poorer cardiac function and liver cirrhosis caused due to congestion. CASE PRESENTATION: The patient was a 37-year-old woman who presented with epigastralgia. Computed tomography (CT) revealed a liver tumor, 8 cm in diameter, in the caudate lobe. Liver damage was A, with an indocyanine green retention rate of 6% at 15 min. The levels of alpha-fetoprotein (AFP) and protein induced by vitamin K antagonists-II (PIVKA-II) were elevated to 81,663 ng/ml (normal < 10 ng/ml) and 238 mAU/ml (normal < 40 mAU/ml), respectively. Left ventricular ejection fraction was 56%, and central venous pressure (CVP) was 12 mmHg. Left hepatectomy and caudate lobe resection were successfully performed in the reverse Trendelenburg position which reduced the CVP. The total operation duration was 450 min, with a total blood loss of 3200 ml. The patient's postoperative course was uneventful, and she is still alive 16 months after surgery. CONCLUSIONS: First left hepatectomy with caudate lobectomy during reverse Trendelenburg position which reduced the CVP was performed in a patient with HCC and FALD.

Hepatocellular carcinoma with a non-smooth tumor margin on hepatobiliary-phase gadoxetic acid disodium-enhanced magnetic resonance imaging. Is sectionectomy the suitable treatment?

BACKGROUND/PURPOSE: Anatomical sectionectomy or larger resection is known to be effective in patients with hepatocellular carcinoma (HCC) with microvascular invasion. A non-smooth tumor margin on hepatobiliary-phase gadoxetic acid disodium-enhanced magnetic resonance imaging (EOB-MRI) can predict microvascular invasion of HCC. We evaluated the usefulness of EOB-MRI for operative planning. METHODS: We evaluated 224 patients with single HCC who underwent hepatectomy between 2010 and 2013. The tumor margin was determined preoperatively. The hepatic resection was determined based on tumor location, liver function, 3D CT simulation and functional liver reserve. To control for confounding variable distributions, propensity score match was applied to compare the outcomes. Multivariate analysis was conducted to identify independent predictors of 5-year recurrence-free survival (RFS) and overall survival (OS). RESULTS: Of 113 patients with a non-smooth tumor margin, 40 patients (35%) showed microscopic portal invasion. The 5-year RFS and OS rates were significantly higher after sectionectomy or larger hepatectomy (hemihepatectomy) than after segmentectomy or smaller hepatectomy (non-anatomical resection). Of 111 patients with a smooth tumor margin, eight patients (7%) showed microscopic portal invasion. The 5-year RFS and OS rates did not differ significantly between patients who underwent sectionectomy and those who underwent segmentectomy. CONCLUSIONS: Our preliminary results appear to recommend that HCC with a non-smooth margin on HB-phase images is treated with anatomical sectionectomy or larger hepatectomy.

Cavo-atrial thrombectomy prior to hepatectomy for hepatocellular carcinoma with tumor thrombus in the right atrium: a case report.

BACKGROUND: Hepatocellular carcinoma (HCC) with tumor thrombus (TT) in the right atrium is a critical condition. The general consensus is to perform hepatectomy prior to cavo-atrial thrombectomy because of the risk of uncontrollable bleeding during the liver transection after heparinization. However, sudden cardiac arrest due to the ball-valve effect and pulmonary embolism have been reported in cases of TT. Cavo-atrial thrombectomy prior to hepatectomy for HCC with TT in the right atrium was successfully performed to prevent sudden cardiac arrest and pulmonary embolism. CASE PRESENTATION: Tumor thrombectomy under cardiopulmonary bypass with heparin and electrical ventricular fibrillation prior to hepatectomy was successfully performed to prevent sudden cardiac arrest or pulmonary embolism in a 75-year-old woman with a huge HCC and TT in the right atrium. After the neutralization of heparin, right hepatectomy with tumor thrombectomy in the inferior vena cava was performed. The total operation time was 9 h, and the total blood loss was 8200 mL. The patient's postoperative course was uneventful, and she was discharged 14 days after surgery. One year after surgery, she is alive with HCC recurrence in the lung. CONCLUSIONS: Cavo-atrial thrombectomy prior to hepatectomy for HCC with TT in the right atrium can be performed safely to prevent sudden cardiac arrest and pulmonary embolism by collaboration of cardiovascular surgeons and gastroenterological surgeons.

Staging of gastric cancer with the Clinical Stage Prediction score.

BACKGROUND: Chemotherapy with or without surgery is the first-line treatment for stage III/IV gastric cancer, while surgery is the first-line treatment for stage I/II gastric cancer. Accordingly, it is important to distinguish between stage III/IV and stage I/II gastric cancer, but clinical staging is less accurate than pathological staging. This study was performed to develop a clinical score that could distinguish stage III/IV gastric cancer from stage I/II gastric cancer. METHODS: We reviewed 2722 patients who underwent gastrectomy at our hospital from January 1996 to December 2015. As pretreatment factors potentially related to tumor stage, we assessed age, sex, tumor markers, tumor diameter, tumor location, tumor histology, and macroscopic type. Factors showing significance on multivariate analysis were used to develop the Clinical Stage Prediction score (CSP score), and a cutoff value for the score was determined by receiver operating characteristics analysis. RESULTS: According to multivariate analysis, clinical factors associated with stage III/IV disease were elevation of the carcinoembryonic antigen level, tumor diameter ≥ 60 mm, circumferential gastric involvement, esophageal infiltration, mucinous adenocarcinoma, and macroscopic types 2-4. The CSP score was obtained by weighting these factors according to the non-standardized ß-coefficient. Receiver operating characteristics analysis indicated that the optimum cutoff value of the CSP score was 17 points. Among 1042 patients with a CSP score ≥ 17 points, 820 patients (78.7%) had stage III/IV gastric cancer. Conversely, among 1680 patients with a CSP score < 17 points, 1547 patients (92.1%) had stage I/II gastric cancer. When discrimination of stage III/IV gastric cancer from stage I/II gastric cancer by the CSP score was assessed, the sensitivity was 78.7%, specificity was 92.1%, positive predictive value was 86.0%, and negative predictive value was 87.5%. CONCLUSIONS: The CSP score can be helpful for differentiating stage III/IV gastric cancer from stage I/II gastric cancer based on pretreatment clinical factors.

Inflammatory hepatocellular adenoma in a patient with Turner's syndrome: A case report.

INTRODUCTION: Hepatocellular adenoma (HCA) is a rare benign tumor and is related to the use of an oral contraceptive pill. Turner's syndrome requires various hormone replacement therapies, including the pill which is used as a female hormone replacement therapy. Herein we report a case of Turner's syndrome with HCA treated by liver segmentectomy. PRESENTATION OF CASE: A 36-year-old woman with Turner's syndrome was treated with oral contraceptive pills as a female hormone replacement therapy for 20 years. She presented with fatigue and liver tumor. Liver tumors in the posterior lobe measuring 60 mm and 10 mm in diameter were detected on CT; hence, she was referred to our department. Both the tumors showed high intensity in the arterial phase, iso-intensity in the portal and late phases, and low intensity in the hepatobiliary phase on Gb-EOB-MRI. She was diagnosed with multiple HCAs and underwent segmentectomy Section 7. Pathologically, both the tumors were diagnosed as HCAs, and inflammatory markers were detected by immunohistochemistry. Thirteen months postoperatively, she was doing well and there was no evidence of recurrence of HCA without the pill. DISCUSSION: There is only one report of HCA in patients with TS (Espat et al., 2000). We reported a case of multiple HCAs in a patient with TS underwent hepatectomy. CONCLUSION: With the use of the contraceptive pill as a long-term female hormone replacement therapy for Turner's syndrome, careful attention is required for HCA.

A successful surgical repair of intraoperative pneumothorax and the diffuse dissection of visceral pleura during liver transplantation surgery via trans-diaphragmatic approach.

BACKGROUND: Pneumothorax during surgery under general anesthesia is a life-threatening situation for the patient because it can progress easily to the tension pneumothorax due to positive pressure ventilation unless appropriate treatments such as inserting a drainage tube in the thoracic cavity are initiated. The authors experienced a case of intraoperative pneumothorax and the diffuse dissection of visceral pleura during liver transplantation surgery, and achieved successful repair by a trans-diaphragmatic approach without changing patient's body position. CASE PRESENTATION: A 66-year-old male with multiple liver and renal cysts caused by autosomal dominant polycystic kidney disease (ADPKD) was admitted to the authors' hospital for treating the infection of the liver cysts. The infection was unable to be controlled by conservative treatments. Therefore, the patient was planned to undergo living-donor liver transplantation. Intraoperatively, the liver was found to swell markedly and to firmly adhere to the right diaphragm. After the extraction of the liver, because the right diaphragm swelled markedly, pneumothorax was suspected. Chest tube was inserted immediately, and the small incision was made in the right diaphragm. Thoracoscopic observation revealed that (1) the visceral pleura of the bottom of the right lung widely expanded like a giant cyst due to the dissection from the lung parenchyma and (2) a large air leakage from a pin hole appeared in the dissected pleura. After the completion of the liver transplantation, the thoracoscopic leakage-closing operation was performed through the right diaphragm incision. Because the dissection of visceral pleura was too wide to perform plication or cystectomy by a stapler or sutures, the dissected pleura was opened, and absorbable fibrin sealant patches and fibrin glue were put or injected between the lung parenchyma and the pleura. Although, after being observed postoperatively, prolonged minor air leakage disappeared by a conservative drainage treatment, and the cyst on the bottom of the right lung disappeared on chest computed tomography (CT). CONCLUSIONS: Although intraoperative pneumothorax and broad dissection of visceral pleura during laparotomy is a complicated situation, the authors successfully repaired air leakage via a trans-diaphragmatic approach without changing the patient's body position.

Androgen Regulates Mafb Expression Through its 3'UTR During Mouse Urethral Masculinization.

External genitalia are prominent organs showing hormone-dependent sexual differentiation. Androgen is an essential regulator of masculinization of the genital tubercle, which is the anlage of external genitalia. We have previously shown that v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is an androgen-inducible regulator of embryonic urethral masculinization in mice. However, it remains unclear how androgen regulates Mafb expression. The current study suggests that the Mafb 3' untranslated region (UTR) is an essential region for its regulation by androgen. We identified 2 functional androgen response elements (AREs) in Mafb 3'UTR. Androgen receptor is bound to such AREs in 3'UTR during urethral masculinization. In addition to 3'UTR, Mafb 5'UTR also showed androgen responsiveness. Moreover, we also demonstrated that ß-catenin, one of genital tubercle masculinization factors, may be an additional regulator of Mafb expression during urethral masculinization. This study provides insights to elucidate mechanisms of gene regulation through AREs present in Mafb 3'UTR for a better understanding of the processes of urethral masculinization.

[Multiple large hepatocellular adenomas in a patient with glycogen storage disease type Ia].

A man diagnosed at birth with glycogen storage disease type Ia was found to have multiple hepatocellular adenomas at 15 years of age. At 18 years of age, he underwent transarterial tumor embolization in segments 4 and 5. At 27 years of age, the tumor in segment 4 had increased in size on follow-up computed tomography, and he was referred to our hospital. Because the tumor was large, increasing in size, and we could not exclude malignancy, we performed resection of segments 4 and 8 of the liver and partial resection of segment 5 for excisional biopsy. The pathological diagnosis was multiple inflammatory hepatocellular adenomas.

Essential roles of epithelial bone morphogenetic protein signaling during prostatic development.

Prostate is a male sex-accessory organ. The prostatic epithelia consist primarily of basal and luminal cells that differentiate from embryonic urogenital sinus epithelia. Prostate tumors are believed to originate in the basal and luminal cells. However, factors that promote normal epithelial differentiation have not been well elucidated, particularly for bone morphogenetic protein (Bmp) signaling. This study shows that Bmp signaling prominently increases during prostatic differentiation in the luminal epithelia, which is monitored by the expression of phosphorylated Smad1/5/8. To elucidate the mechanism of epithelial differentiation and the function of Bmp signaling during prostatic development, conditional male mutant mouse analysis for the epithelial-specific Bmp receptor 1a (Bmpr1a) was performed. We demonstrate that Bmp signaling is indispensable for luminal cell maturation, which regulates basal cell proliferation. Expression of the prostatic epithelial regulatory gene Nkx3.1 was significantly reduced in the Bmpr1a mutants. These results indicate that Bmp signaling is a key factor for prostatic epithelial differentiation, possibly by controlling the prostatic regulatory gene Nkx3.1.

Novel virtual hepatectomy is useful for evaluation of the portal territory for anatomical sectionectomy, segmentectomy, and hemihepatectomy.

BACKGROUND: The novel technique of virtual hepatectomy is useful for evaluation of the portal territory of the liver, since this software program includes functions for liver surgery planning. We evaluated the accuracy of virtual hepatectomy for anatomical hepatectomy. METHODS: Between 2010 and 2011, 92 patients with liver tumors underwent virtual hepatectomy preoperatively. The predicted liver volume was compared with the actual liver volume among patients who underwent anatomical sectionectomy, segmentectomy, and hemihepatectomy. RESULTS: Ninety of 92 patients underwent anatomical hepatectomy on the basis of virtual hepatectomy. According to the surgical procedure, the predicted liver resection volume showed a strong correlation with the actual liver volume in patients who underwent sectionectomy (r = 0.985, p < 0.0001, n = 44, median error rate 9 %), segmentectomy (r = 0.949, p < 0.0001, n = 17, median error rate 12 %), and hemihepatectomy (r = 0.967, p < 0.0001, n = 29, median error rate 7 %). CONCLUSIONS: The novel technique of virtual hepatectomy is useful for evaluation of the portal territory for anatomical sectionectomy, segmentectomy, and hemihepatectomy.

Epithelial Bmp (Bone morphogenetic protein) signaling for bulbourethral gland development: a mouse model for congenital cystic dilation.

The bulbourethral gland (BUG) is a male-specific organ, which secretes part of the semen fluid. As the BUG is located in the deep pelvic floor, its developmental process is still unclear. Bone morphogenetic protein (Bmp) signaling plays pivotal roles in various organs. However, the function of Bmp signaling for BUG development is still unclear. The present study aimed to elucidate the role of Bmp signaling in the development of the BUG. We observed the prominent nuclear accumulation of phosphorylated (p) SMAD1/5/8, the downstream molecules of Bmp signaling, during BUG epithelial development. These results suggest that Bmp signaling contributes to BUG development. Bmp receptor1a (Bmpr1a) is known as the major type 1 signal transducer in some organogeneses. To analyze the Bmp signaling function for BUG development, we examined epithelial cell-specific Bmpr1a gene conditional mutant mice utilizing the tamoxifen-inducible Cre recombinase system. We observed cystic dilation and epithelial hyperplasia of the BUG in the Bmpr1a conditional knockout mice. The mutant cystic BUG specimens also showed inflammatory lesions. These BUG abnormalities resembled some of the BUG malformations observed in human congenital syndromes. The current study suggests that Bmp signaling possesses an essential role in BUG development and homeostasis. This would be the first report showing that the mutation of the Bmpr1a gene in the BUG epithelia phenocopied some abnormalities of human congenital syndromes affecting the BUG duct.

The role of sonic hedgehog-Gli2 pathway in the masculinization of external genitalia.

During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling.

Messenger RNA expression of TS and ERCC1 in colorectal cancer and matched liver metastasis.

5-fluorouracil (5-FU) and oxaliplatin play important roles in chemotherapy for patients with colorectal cancer. The expression levels of thymidylate synthase (TS) and excision repair cross-complementing factor 1 (ERCC1) have been reported to be prognostic markers for patients with 5-FU/oxaliplatin chemotherapy. The aim of this study was to clarify the association between messenger RNA (mRNA) levels of TS and ERCC1 in primary colorectal cancer and those in corresponding liver metastasis. Formalin-fixed paraffin-embedded tumor specimens of 31 patients with resection for both colorectal cancer and liver metastasis were dissected by laser capture microdissection. After RNA extraction, TS and ERCC1 mRNA levels in both primary tumor and corresponding liver metastasis were measured by real-time reverse transcription-polymerase chain reaction. Both TS and ERCC1 mRNA levels in primary tumors were significantly associated with those in synchronous liver metastases (TS, rs=0.875, p=0.0024; ERCC1, rs=0.835, p=0.0038). TS mRNA levels in primary tumors were also associated with those in metachronous liver metastases (rs=0.659, p=0.0065), but not in ERCC1 (rs=0.319, p=0.19). In both genes, mRNA levels in metachronous liver metastases were higher than those in primary tumors (TS, p=0.0084; ERCC1, p=0.037). However, there was no difference in the TS and ERCC1 mRNA levels between primary tumors and synchronous liver metastasis. The measurement of TS and ERCC1 mRNA levels in primary colorectal cancer can predict those in synchronous liver metastases, but not in metachronous ones.

Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities.

cAMP response element (CRE) transcription is dysregulated in neurodegenerative disorders in the central nervous system (CNS), including polyglutamine diseases. As the first step to find natural compounds with protective action against neurodegeneration in the CNS, we here examined whether six citrus flavonoids, namely nobiletin, 5-demethylnobiletin, tangeretin, sinensetin, 6-demethoxytangeretin, and 6-demethoxynobiletin, stimulated CRE-dependent transcription and induced neurite outgrowth in PC12D cells. Among the compounds, nobiletin most potently enhanced CRE-dependent transcription and neurite outgrowth by activating ERK/MAP kinase-dependent signalling to increase CREB phosphorylation. The transcription and neurite outgrowth were stimulated by nobiletin in a concentration-dependent manner, with a strong correlation between them. Furthermore, a 11-day oral administration of nobiletin rescued impaired memory in olfactory-bulbectomized mice documented to be accompanied by a cholinergic neurodegeneration. These results suggest that nobiletin with the activity to improve impaired memory may become a potential leading compound for drug development for neurodegenerative disorders exhibiting the dysregulated CRE-dependent transcription.