Anthracycline-based hepatic arterial infusion chemotherapy achieved 17 months of disease regression in a patient with breast cancer liver metastases resistant to multiple systemic chemotherapies.

Hepatic arterial infusion chemotherapy (HAIC) for liver metastases (LMs) from breast cancer is not a standard of care, but its effectiveness in patients with extensive LMs who cannot tolerate systemic therapy has been reported. Herein, we report a case of breast cancer LMs that were controlled by anthracycline-based HAIC. A 46-year-old woman with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer who had multiple LMs and bone metastases underwent seven lines of systemic therapy (paclitaxel/bevacizumab for 38 months; letrozole, nivolumab/fulvestrant, eribulin, gemcitabine/vinorelbine, high-dose toremifene/abemaciclib, and capecitabine for 21 months in total). However, owing to its adverse effects and the continued progression of the LMs, systemic therapy was switched to HAIC (40 mg/body epirubicin on day 1, 4 mg/body mitomycin C on days 1 and 15, and 500 mg/body 5-fluorouracil on days 1, 8, and 15; 28-day courses). In response to HAIC, the LMs remarkably regressed and were controlled for 17 months without severe adverse effects. HAIC was stopped when multiple brain metastases arose, and the patient died 2 months later. This case suggests that HAIC is a reasonable option for patients with extensive LMs, even in the late stage of treatment. HAIC recipients should be carefully selected through multidisciplinary discussions as the survival benefits of HAIC over systemic treatment remain unclear. Our findings identify a potential window for the use of traditional chemotherapeutic agents such as anthracyclines. Novel strategies to improve drug delivery are warranted in the future.

Axial torsion of Meckel's diverticulum causing acute peritonitis in the first trimester of pregnancy: a case report.

BACKGROUND: Meckel's diverticulum is considered the most prevalent congenital anomaly of the gastrointestinal tract. Approximately 4% of patients are symptomatic with complications such as bleeding, intestinal obstruction, and inflammation, while axial torsion of Meckel's diverticulum is rare, particularly in pregnancy. CASE PRESENTATION: A 31-year-old woman in week 15 of pregnancy complained of epigastric pain, nausea and vomiting. Clinical diagnosis was severe hyperemesis gravidarum. Because the symptoms persisted during hospitalization, CT was performed and revealed dilated small bowel loops with multiple air-fluid levels. In the right mid-abdomen, there was a large part of air containing a cavity connected to the small intestine, which was considered a dilated bowel loop. Emergency laparotomy was performed and axial torsion of a large Meckel's diverticulum measuring 11 cm was found at a few centimeters proximal to the ileocecal valve. Ileocecal resection including Meckel's diverticulum was performed. The postoperative course was uneventful. At 40 weeks gestation, she had vaginal delivery of normal baby. CONCLUSION: The physiological and anatomical changes in pregnancy can make a straightforward clinical diagnosis difficult. Prompt diagnosis and management were needed in order to avoid significant maternal and fetal risks. The use of imaging examinations, especially CT examination, with proper timing may be helpful to prevent delay in diagnosis and surgical intervention. Here, we report the case of a patient with axial torsion of Meckel's diverticulum in pregnancy. To our knowledge, axial torsion of Meckel's diverticulum in the first trimester of pregnancy has not been reported in the English medical literature.

Cytoreductive surgery with intraperitoneal chemotherapy to treat pseudomyxoma peritonei at nonspecialized hospitals.

PURPOSE: It has been reported that complete cytoreduction using peritonectomy combined with intraperitoneal chemotherapy improves the prognosis of patients with pseudomyxoma peritonei (PMP); however, this treatment strategy remains controversial, especially at nonspecialized institutes, because of its high morbidity rate. METHODS: We reviewed the clinical records of 15 consecutive patients with PMP, treated in nonspecialized hospitals and observed by one of us between 1999 and 2010. Cytoreductive surgery was done using peritonectomy procedures with intraperitoneal chemotherapy and was performed with curative intent, |in accordance with Sugarbaker. RESULTS: All patients had mucinous tumors disseminated in the peritoneal cavity. Complete cytoreduction was achieved in 12 patients. Morbidity was 40% (6/15) and mortality was 0% (0/15). After a median follow-up period of 43 months, the 12 patients who underwent complete cytoreduction were disease-free with good quality of life, and 1 of the 3 patients who underwent incomplete cytoreduction was alive with disease. CONCLUSIONS: These findings suggest that peritonectomy with intraperitoneal chemotherapy for PMP can provide prognostic benefit, even at nonspecialized hospitals. Considering the treatment risk, it should ideally be performed at a referral center, or at least by an experienced surgeon.

Indocyanine green fluorescence monitoring of perineal wound contamination in abdominoperineal resection: a preliminary report.

PURPOSE: Surgical site infections (SSI) in an abdominoperineal resection (APR) occur more frequently than in other types of operations for patients with colorectal cancer. Perineal wounds are the most vulnerable sites, and they may be caused by stool contamination. Indocyanine green (ICG) fluorescence imaging, by which sensitive detection was possible, was used as a marker of perineal wound contamination. METHOD: Indocyanine green was transanally injected to the rectum before operation, and fluorescence images were obtained during the operation in three patients who underwent APR. RESULTS: One subject, in whom gross contamination was not visible, had an SSI, and a trace of ICG fluorescence was detectable in the perianal skin. The other two subjects, in whom skin preparation was completely performed until ICG contamination was eliminated, were free from SSI. CONCLUSIONS: Our results suggested that a trace of stool contamination remained in the perineal skin field even after the usual antiseptic skin preparation. Furthermore, meticulous skin preparation is required to minimize stool contamination in APR patients.

[Chemotherapy for elderly colorectal cancer patients in a regional hospital--problems in regional cancer care].

At Nara Social Insurance Hospital, from January 2005 to September 2008, chemotherapy for older adult (>or=70) colorectal cancer patients was performed in 18 adjuvant cases and 10 advanced cases. In adjuvant cases, 18 out of 33 patients of >or= stage IIIa received chemotherapy, and 13 completed treatment safely. In advanced cases, all patients received FLOFOX or FOLFIRI, with or without bevacizumab as first-line treatment with a response rate of 50%. Although adverse events were relatively frequent in the older adult patients, there was no difference in the survival rate between elderly and younger patient groups. Cancer chemotherapy for older adults with a high comorbidity rate requires more skill and experience than for younger patients. It was possible even for a small-volume hospital, which plays an important role in regional medical service for elderly patients, to build up a system providing standard chemotherapy for colorectal cancer. However, considering the limited financial and human resources, it is essential to form a regional alliance of designated cancer care hospitals and other clinics in order to maintain the level of practice.

Surgical resection of hilar cholangiocarcinoma: analysis of survival and postoperative complications.

BACKGROUND: Surgery is the only potentially curative treatment for hilar bile duct cancer. This study sought to evaluate the efficacy and feasibility of surgical management of hilar bile duct carcinoma, including radical hepatectomy, at a single institution. METHODS: We performed a retrospective review of 49 consecutive patients who underwent surgery at our hospital between 1990 and 2003. RESULTS: Altogether, 44 of 49 patients underwent radical hepatectomy combined with caudate lobectomy and lymphadenectomy. One and four patients underwent partial hepatectomy or bile duct resection, respectively. No patients underwent preoperative portal vein embolization. The 5-year survival rate was 39.7%, with a median survival time of 3.75 years. The postoperative morbidity and mortality rates were 46.8% and 2.0%, respectively. Cox's proportional hazard model revealed that lymph node status and the residual tumor factor were independent prognostic factors. Multivariate analysis revealed that preoperative hyperbilirubinemia, postoperative complications, and extended surgical procedures were independently associated with postoperative hyperbilirubinemia. After potentially curative resection, 39.4% of patients suffered from disease recurrence. In 60% of the total cases, the sites of recurrence were distant metastases. CONCLUSION: Surgery, including radical hepatectomy combined with caudate lobectomy and lymph node dissection, is a feasible, effective treatment for hilar bile duct cancer.

Implication of frequent local ablation therapy for intrahepatic recurrence in prolonged survival of patients with hepatocellular carcinoma undergoing hepatic resection: an analysis of 610 patients over 16 years old.

OBJECTIVE: By comparing cohorts in 2 exclusive time frames, the factors that affected the surgical outcomes of patients with hepatocellular carcinoma (HCC) are presented. SUMMARY BACKGROUND DATA: Reportedly, survival results of patients with HCC who underwent hepatectomy have improved in recent years. However, the major factors contributing to these favorable outcomes have not been fully explained. METHODS: Between January 1985 and December 2000, 610 patients with HCC underwent liver resections as a primary and curative resection. They were categorized into 2 groups according to the year in which the surgeries were performed: before 1990 (n = 212; early group); and after 1991 (n = 398; late group). Clinicopathologic data, survival data, type of recurrence, and treatment of intrahepatic recurrence were compared between the 2 groups. RESULTS: Clinicopathologic data were almost identical between the groups except for age, blood loss, and duration of surgery. The overall survival rate was significantly better in the late group compared with the early group (58.0% vs. 39.1% at 5 years, P < 0.0001). By contrast, disease-free survival remained unchanged (27.8% vs. 26.2% at 5 years, P = 0.2887). The most common type of recurrence was intrahepatic relapse, and there was no difference in the rate and the type of recurrence between the 2 groups. The 5-year survival rate after recurrence was increased in the late group (21.8% vs. 11.6%, P = 0.0002). Stratified analysis by the type of initial recurrence revealed that better survival in the late group was achieved only in solitary intrahepatic recurrences, not in multiple intrahepatic or extrahepatic recurrences. Changes in modality of treatment of recurrence were observed only in the management of solitary intrahepatic recurrences, where percutaneous ablation therapies were more frequently applied with new ablation techniques. Patients that had undergone ablation therapies in the late group had better postrecurrent survival than those in the early group. Multivariate analysis showed that presence of local ablation therapies was an independent favorable prognostic factor only in the late group. CONCLUSIONS: Significant improvements in outcomes were achieved in patients with HCC who underwent curative liver resections. Percutaneous ablation therapy for intrahepatic recurrence was considered to be a major contributory factor for improving survival after recurrence, as well as for overall survival.

Pancreatic arteriovenous malformation with portal hypertension.

A 45-year-old man with recurrent episodes of hematemesis caused by extensive varices in the esophagus and stomach was admitted. He had a history of liver cirrhosis with hepatitis C virus infection. Computed tomography revealed a conglomeration of small strong nodular stains in the pancreatic head. Angiography revealed a racemose vascular network at the same site and early appearance of the portal venous system in the arterial phase. With a diagnosis of pancreatic arteriovenous malformation with portal hypertension, he underwent pylorus-preserving pancreaticoduodenectomy, preceded, 2 days earlier, by transcatheter arterial embolization of some of the feeding arteries. The varices observed preoperatively in the esophagus and stomach disappeared, and he has been well for 6 years after the operation. We reviewed 47 cases of pancreatic arteriovenous malformation previously reported in the English-language literature, with a focus on the clinical manifestations, treatment approaches, and etiological relationship with portal hypertension and liver cirrhosis.

Preoperative positron emission tomography with fluorine-18-fluorodeoxyglucose is predictive of prognosis in patients with hepatocellular carcinoma after resection.

BACKGROUND: Hepatocellular carcinomas (HCCs) accumulate fluorine-18 fluorodeoxyglucose (FDG) to various degrees. The standardized uptake values (SUVs) of FDG-positron emission tomography (PET) in high-grade HCCs are significantly higher than those in low-grade HCCs. AIM: The aim of this study was to evaluate the possible usefulness of FDG-PET in predicting the prognosis of HCC patients after resection. We analyzed the relationship between the tumor to non-tumor SUV ratios (SUV ratio) and surgical outcome in 31 patients. RESULTS: Of the 31 cases of HCC studied, seven (23%) exhibited SUV ratios greater than 2, as the cutoff value. The percentage of patients with poorly differentiated HCC was greater in the higher SUV ratio group (SUV ratio >2) than in the lower SUV ratio group (SUV ratio <2) (57 vs. 32%). The overall survival was significantly longer in the lower SUV ratio group than in the higher SUV ratio group (5-year-survival rate: 63 vs. 29% P = 0.006) (median survival time: 2310 vs.182 days). CONCLUSION: The SUV ratio was related significantly to disease-related death as well as other predictive factors, including the number of tumors, the size, stage, and involvement of vessels, and the involvement of the capsule. Consequently, we conclude that the SUV ratio provides information of prognostic relevance in patients with HCC before surgery.

High volume hydrodynamic injection of plasmid DNA via the hepatic artery results in a high level of gene expression in rat hepatocellular carcinoma induced by diethylnitrosamine.

BACKGROUND: Hydrodynamic injection of naked plasmid DNA (pDNA) via the tail vein is a safe and effective method of gene transfer to the liver. However, successful gene transfer has yet to be shown for hepatocellular carcinoma (HCC); therefore, we investigated the feasibility and efficacy of hydrodynamic injection via the tail vein and hepatic artery in a diethylnitrosamine (DEN)-induced HCC model in rats. METHODS: HCC was induced in Sprague-Dawley rats by 100 ppm DEN in drinking water. pCMV-SPORT-beta-galactosidase (beta-gal, 400 microg) was injected (i) via the tail vein in a volume of 0.1 ml/g in 30 s or (ii) via the hepatic artery in a volume of 5 or 10 ml at 1 ml/s, either with or without temporary occlusion of the inferior vena cava (IVC) and portal vein (PV). The liver was harvested 24 h after administration, and beta-gal expression was evaluated with X-gal staining and measurement of enzymatic activity in tissue homogenates. RESULTS: Hydrodynamic injection via the tail vein achieved transgene expression only in non-cancerous tissue (tumor: 0.16 +/- 0.04%, non-tumor: 5.07 +/- 1.66%). Hydrodynamic injection via the hepatic artery was tolerated, but failed to produce efficient transgene expression in tumor and non-tumor cells. On the other hand, concomitant use of temporary IVC/PV occlusion with hydrodynamic injection via the hepatic artery dramatically increased transgene expression in cancer cells, but tumor-selective gene transfer was not achieved with this procedure (tumor: 7.38 +/- 3.66%, non-tumor: 7.77 +/- 1.06%). CONCLUSIONS: High-volume hydrodynamic injection of a pDNA solution via the hepatic artery with IVC/PV occlusion achieved a high level of gene expression in a HCC rat model. This gene transfer technique may have potential in clinical gene therapy for HCC.

Expression of nerve growth factor receptors is correlated with progression and prognosis of human pancreatic cancer.

BACKGROUND AND AIM: The aim of the present study was to investigate the prognostic value of the two types of nerve growth factor receptors (NGFR), namely high-affinity receptor TrkA and low-affinity receptor p75NGFR, in pancreatic cancer. METHODS: The mRNA expression of NGFR for TrkA and p75NGFR was examined in 56 human primary pancreatic cancers using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Nerve growth factor (NGF) receptors were found in all tumor specimens. It appears that the growth of pancreatic cancer cells stimulated by NGF depended on the expression levels and the ratio of TrkA to p75NGFR. TrkA and p75NGFR were negatively correlated and both were associated with abdominal or back pain and perineural invasion. Regarding this, patients with high TrkA expression levels exhibited more frequent perineural invasion and a higher degree of pain, whereas the results of p75NGFR were opposite. For Cox univariate analyses in the overall survival study, high expression of p75NGFR was associated with longer overall survival, but TrkA exhibited opposite effects and included an effect on perineural invasion and pain. Histoprognostic grading, tumor size and node involvement were not prognostic factors. In Cox multivariate analyses, TrkA and p75NGFR were both prognostic parameters. CONCLUSIONS: The present study found that the expression of TrkA in pancreatic cancer is a marker of tumor aggressiveness. Conversely, we also found that elevated p75NGFR expression is associated with a favorable prognosis. We demonstrated that NGF exerts both stimulatory and inhibitory effects on pancreatic cancers, with the overall effect determined by the expression levels and the ratio of TrkA to p75NGFR.

Signal transducers and activators of transcription 3 activation is involved in nuclear accumulation of beta-catenin in colorectal cancer.

Nuclear accumulation of beta-catenin is a key event for the development of colorectal cancer. Little is known, however, about the mechanisms underlying translocation of beta-catenin from the cytoplasm or the membrane to the nucleus. The present study examined whether signal transducers and activators of transcription 3 (STAT3) activation is involved in the nuclear accumulation of beta-catenin in colorectal cancer cells. Of the 90 primary colorectal cancer tissues, 40 (44.4%) were positive for nuclear staining of p-STAT3 and 63 (70.0%) were positive for nuclear staining of beta-catenin. The nuclear staining of both p-STAT3 and beta-catenin were observed predominantly in the periphery of the cancer tissues. Importantly, of the 40 tumors with p-STAT3 nuclear staining, 37 (92.5%) were also positive for nuclear beta-catenin staining and there was a significant correlation between p-STAT3 and beta-catenin nuclear staining (P < 0.01). Coexpression of nuclear p-STAT3 and beta-catenin was associated with lower patient survival (P < 0.01). In an in vitro study using a human colon cancer cell line, SW480, inhibition of STAT3 by dominant negative STAT3 or the Janus kinase inhibitor, AG490, induced translocation of beta-catenin from the nucleus to the cytoplasm or membrane. Luciferase assays revealed that STAT3 inhibition resulted in significant suppression of beta-catenin/T-cell factor transcription in association with significant inhibition of cell proliferation (P < 0.05). These findings suggest that in colorectal cancer, STAT3 activation is involved in the nuclear accumulation of beta-catenin, resulting in poor patient survival.

Prognostic index for patients with hepatocellular carcinoma combined with tumor thrombosis in the major portal vein.

BACKGROUND: This study sought to analyze prognostic factors in patients with hepatocellular carcinoma and tumor thrombosis in the first branch or trunk of the portal vein, and to provide a prognostic index. STUDY DESIGN: We performed a retrospective cohort study of 78 consecutive patients with hepatocellular carcinoma and tumor thrombosis in the first branch or trunk of the portal vein who underwent liver resection. Multivariate analysis of survival used the Cox's proportional hazard model. RESULTS: Median survival time and 3-year survival rate were 0.74 years and 21.7%, respectively. Six factors, ie, absence of ascites, average elimination rate constant of indocyanine green, prothrombin activity, serum albumin level, maximal tumor diameter, and blood loss at operation were univariately related to survival time. By multivariate analysis, absence of ascites (hazard ratio, 2.23; 95% confidence interval, 1.10 to 4.52; p = 0.027), prothrombin activity > or = 75% (hazard ratio, 2.37; confidence interval, 1.30 to 4.32; p = 0.005), and maximal tumor diameter < 5 cm (hazard ratio, 2.37; confidence interval, 1.14 to 4.94; p = 0.021) were independent prognostic factors with similar hazard ratios. We calculated a prognostic index from these factors as follows: (ascites: absent = 0, present = 1) + (prothrombin activity: > or = 75% = 0, < 75% = 1) + (maximal tumor diameter: < 5 cm = 0, > or = 5 cm = 1). This index provided good stratification ability (log-rank, p < 0.001). Median survival times for patients with prognostic index 0, 1, 2, and 3 were 5.6, 1.6, 0.5, and 0.1 years, respectively. CONCLUSION: This prognostic index is a useful for making appropriate treatment strategy decisions for patients with hepatocellular carcinoma and tumor thrombosis in the major portal vein.

Complete response by a combination of 5-fluorouracil and interferon-alpha chemotherapy for lung metastasis of hepatocellular carcinoma after hepatic resection with portal and hepatic vein tumor thrombectomy.

A 75-year-old female was admitted to our hospital and diagnosed with hepatocellular carcinoma (HCC). Computed tomography (CT) revealed a liver tumor with tumor thrombi in the portal trunk and main hepatic vein, as well as small lung metastases. The patient had good liver function with no sign of hepatitis B or C infection. She underwent right trisectionectomy of the liver with tumor thrombectomy. Intrahepatic recurrence and progression of lung metastases were observed 4 months later. Intrahepatic recurrent tumors were treated with transcatheter arterial chemoembolization (TACE), and lung metastases were treated with systemic combination chemotherapy of 5-fluorouracil (5FU) and interferon-alpha (IFN-alpha). Computed tomography showed no viable lesions in the liver and lung 6 months after these treatments. The patient has been disease free for 18 months. Prognosis is poor for patients with hepatocellular carcinoma with portal vein tumor thrombus (PVVT) or extrahepatic metastasis. This systemic combination chemotherapy with 5-fluorouracil and interferon-alpha might be effective for patients with good liver function when intrahepatic lesions are well controlled by multidisciplinary treatments, including hepatic resection with tumor thrombectomy.

[Combined chemotherapy with oral leucovorin (LV) + tegafur/uracil (UFT) and hepatic arterial infusion (HAI) therapy for liver metastasis of colorectal cancer].

The liver is the most frequent metastatic site from colorectal cancer, and the control of liver metastasis is an important issue in the treatment of progressive colorectal cancer. Hepatic arterial infusion (HAI) therapy can achieve a high drug concentration in the liver and relatively low level in the systemic circulation because of the first pass effect of the drug metabolism. With the high response rate, several reports have failed to show a significant survival benefit of HAI monotherapy, partially due to its inability to control extrahepatic metastasis. In this report, we used oral tegafur/uracil (UFT) and Leucovorin (LV) combined with HAI of 5-FU for four patients with liver metastasis of colorectal carcinoma. One of two patients with unresectable multiple hepatic metastases could undergo resectional surgery after 5 courses of this therapy. Two other cases in an adjuvant setting have been surviving free of tumors. In this series, adverse effects of this therapy were acceptable, including one case of grade 3 thrombocytopenia. The benefit of this combined therapy for survival in a case of liver metastasis from CRC remains to be evaluated. We are planning phase I and II clinical studies to evaluate the efficiency and feasibility of this combination therapy.

Expression of nerve growth factor receptors and their prognostic value in human pancreatic cancer.

Nerve growth factor (NGF), the prototypic member of the neurotrophin family of growth factors, exerts both stimulatory and inhibitory effects on neuronal and certain non-neuronal tumors, depending on the type of tumor. It has been reported that two types of NGF receptors, high-affinity receptor, TrkA, and low-affinity receptor, p75NGFR, play important roles in this process. Moreover, it has also been detected that high levels of TrkA expression have a more favorable overall survival prognosis in breast cancer patients, but the relationships between the two receptors according to the prognosis in pancreatic cancer patients are unknown. We investigated the expression of NGF receptors (NGFRs: TrkA and p75NGFR) mRNA in 56 human primary pancreatic cancers, using real-time quantitative reverse transcription-PCR. Moreover, pancreatic cancer cell lines were used to validate if the effects of NGF on pancreatic cancer cell growth are dependent on the expression levels and the balance of TrkA and P75 receptors. NGFRs were found in all of the tumor specimens and cell lines. It appears that in pancreatic cancer cells the growth effects of NGF depend on the expression levels and the ratio of TrkA and p75NGFR. TrkA and p75NGFR negatively correlated and were both associated with abdominal or back pain and perineural invasion. Regarding this, high TrkA expression levels exhibited more frequent perineural invasion and a higher degree of pain, whereas the results of p75NGFR are on the contrary. For Cox univariate analyses in the OS study, high expression of p75NGFR was associated with longer overall survival yet TrkA exhibited opposite effects and included the effect of pain. HPG, tumor size, node involvement, and perineural invasion were not prognostic factors. In Cox multivariate analyses, TrkA and p75NGFR were both prognostic para-meters. In conclusion, our study found that the expression of TrkA in pancreatic cancer is a marker of tumor aggressiveness. Conversely, we also found that elevated p75NGFR expression is associated with a favorable prognosis; we demonstrated that NGF exerts both stimulatory and inhibitory effects on pancreatic cancers with the effect based on the expression levels and the ratio of TrkA and p75NGFR.

Blocking of PI3K/Akt pathway enhances apoptosis induced by SN-38, an active form of CPT-11, in human hepatoma cells.

Hepatocellular carcinoma (HCC) is a common malignancy and often resistant to chemotherapy. Many chemotherapy regimens have been tried to control advanced HCC, but have produced a low response rate and no clear impact. CPT-11, a derivative of camptothecin, works as type-I DNA topoisomerase inhibitor and showed a major objective response rate in patients with metastatic colorectal cancer. In this study, the mechanism underlying chemo-resistance to SN-38, an active form of CPT-11, in HCC was investigated in relation to anti-apoptotic pathways NF-kappaB and PI3K/Akt. Hep3B was the most resistant to SN-38 among three hepatoma cell lines. NF-kappaB was constitutively activated in Hep3B, and SN-38 further enhanced the nuclear translocation of NF-kappaB. However, inactivation of NF-kappaB by adenovirus expressing IkappaB super-repressor or MG-132, proteasome inhibitor, did not sensitize Hep3B to SN-38-induced apoptosis. On the other hand, SN-38 phosphorylated Akt and pretreatment with PI3K inhibitors increased SN-38-induced apoptosis, indicating that resistance to SN-38 in Hep3B occurs partly through the PI3K/Akt not the NF-kappaB pathway. Blocking of PI3K/Akt may thus be helpful for overcoming chemo-resistance of HCC.

Overexpression of thioredoxin prevents thioacetamide-induced hepatic fibrosis in mice.

BACKGROUND/AIMS: Thioredoxin is a small redox-active protein with anti-oxidant and anti-apoptotic effects. We have previously reported that thioacetamide-induced acute hepatitis was attenuated in thioredoxin transgenic mice. The aim of the present study was to investigate the protective effect of thioredoxin for hepatic fibrosis. METHODS: We subjected thioredoxin transgenic mice to thioacetamide-induced hepatic fibrosis. We also studied the effect of thioredoxin on the activation process of primary-cultured hepatic stellate cell. RESULTS: The expression of endogenous thioredoxin was induced in hepatocytes of thioacetamide-induced murine and rat fibrotic livers. Overexpression of thioredoxin inhibited tumor necrosis factor-alpha-induced apoptosis of HepG2 cells. Thioacetamide-induced fibrosis and accumulation of malondialdehyde were suppressed in transgenic mice as compared with wild type mice. Hepatic stellate cells isolated from transgenic mice were less proliferative than those isolated from wild type mice. Recombinant thioredoxin significantly inhibited DNA synthesis of primary-cultured stellate cells under serum or platelet-derived growth factor stimulation. CONCLUSIONS: Thioredoxin has a potential to attenuate hepatic fibrosis via suppressing oxidative stress and inhibiting proliferation of stellate cells.

Effectiveness of endoscopic nasobiliary drainage for postoperative bile leakage after hepatic resection.

The effectiveness of endoscopic nasobiliary drainage (ENBD) for postoperative bile leakage after hepatic resection was investigated retrospectively. Between 1997 and 2002 a series of 486 hepatectomies without biliary reconstruction were performed. Bile leakage was divided into two categories. Type A was defined as bile leakage communicating with the main bile tree fistulographically or endoscopic cholangiographically, and type B was bile leakage without such a patency of bile flow. Bile leakage developed in 31 patients (6.4%) (types A/B = 16/15). Type A frequently occurred at the major Glisson's sheath. In contrast, most type B cases occurred at the peripheral bile duct at the cut surface of the liver. Among the type A patients, 10 of 11 were effectively treated with ENBD. For the type B patients, 12 of 15 patients were successfully treated with intraabdominal drainage via surgical drains inserted during the operation or percutaneous tubes newly inserted for biliary fluid collection. ENBD was effective in two of three type B patients. The duration of bile leakage significantly shortened after initiation of ENBD in type A patients (15.3 +/- 6.9 vs. 25.8 +/- 13.2 days, p < 0.05). The classification based on communication with the main bile tree is useful for determining therapeutic strategy. Type A leakage has a good indication for ENBD, whereas type B can be treated with intraabdominal drainage in most cases, although ENBD may be effective in some intractable type B cases. It is preferable to initiate ENBD as early as possible to shorten the duration of bile leakage and the subsequent hospital stay.

Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer.

In gastric cancer, lymph node metastasis is one of the major prognostic factors and forms the basis for surgical removal of local lymph nodes. Recently, several studies have demonstrated that overexpression of lymphangiogenic growth factor VEGF-C or VEGF-D induces tumor lymphangiogenesis and promotes lymphatic metastasis in mouse tumor models. We examined whether these processes could be inhibited in naturally metastatic tumors by blocking of their cognate receptor VEGFR-3 signaling pathway. Using a mouse orthotopic gastric cancer model which has a high frequency of lymph node metastasis, we estimated lymphatic vessels in gastric cancers by immunostaining for VEGFR-3 and other specific lymphatic markers, LYVE-1 and prox-1. Then we systemically administered anti-VEGFR-3 blocking antibodies. This treatment resulted in the inhibition of regional lymph node metastasis and reduction of lymphatic vessel density in the primary tumors. In addition, increased density of LYVE-1-positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Antilymphangiogenesis by inhibiting VEGFR-3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer.