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.

A case of rapidly progressing sarcomatous intrahepatic cholangiocarcinoma with suddenly appearing lymph node metastasis.

BACKGROUND: The sarcomatous variant of carcinoma is relatively rare in intrahepatic cholangiocarcinoma (ICC). Sarcomatous ICC (SICC) is associated with a poorer prognosis compared with ICC. SICC is rarely diagnosed before surgery due to non-descriptive findings; it progresses rapidly, resulting in miserable prognosis. Here, we report a case of rapidly progressing SICC that showed a clinically significant tumor growth rate. CASE PRESENTATION: A 77-year-old woman who had undergone ileocecal resection for cecal cancer 5 years previously was found to have elevated levels of the tumor marker carbohydrate antigen 19-9. Although an abdominal computed tomography (CT) scan did not detect any liver mass lesions until 3 months before this serum examination, the subsequent CT scan revealed a hypodensity 20 mm mass lesion in the right anterior section. Contrast-enhanced CT and magnetic resonance imaging revealed peripheral enhancement in the arterial-to-equilibrium phase. Fluorodeoxyglucose positron emission tomography revealed uptake in the lesion. None of the imaging modalities showed lymph node swelling or distant metastases. She underwent hepatectomy under the diagnosis of ICC or an atypical metastasis from previous cecal cancer. Although preoperative images showed no suspicious lymph node metastasis 3 weeks prior, the hilar lymph node swelled 3 cm and contained adenocarcinoma. Consequently, the patient underwent right anterior sectionectomy and lymph node dissection of the hepatoduodenal ligament. Histopathological examination revealed that the liver tumor was a poorly differentiated adenocarcinoma with sarcomatous pattern. While the patient received adjuvant gemcitabine and S-1 therapy, lymph node metastasis appeared in the mediastinum 13 months after the surgery. She received gemcitabine + cisplatin + S-1 therapy but died 20 months after surgery. CONCLUSION: SICC and lymph node metastasis clinically appeared within 3 months and 3 weeks, respectively. Suspected ICC that rapidly progresses should be considered SICC and treated with early resection. SICC is often missed in clinical diagnosis and has a poor prognosis, even after curative resection. While an alternative strategy involving preoperative biopsy and neoadjuvant therapy may be beneficial, it should be approached with discretion due to the potential risks of tumor progression and peritoneal dissemination.

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.

Non-functioning pancreatic neuroendocrine tumor accompanied with multiple liver metastases: remorseful case and literature review.

CONTEXT: Pancreatic neuroendocrine tumor (P-NET) is a rare and slow-growing tumor. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases, although current reports refer to liver surgery including LT for unresectable liver metastases. CASE REPORT: A thirty-nine-year-old man was diagnosed with nonfunctioning pancreatic neuroendocrine tumor (P-NET) in the pancreatic head, with multiple liver metastases. The tumor was 2.5 cm in diameter and he was asymptomatic. Small but multiple metastases were detected in the liver, and no extrahepatic metastases were observed. We initially intended to control the liver metastases before resection of the primary tumor. To begin with, transarterial chemoembolization (TACE) and transcatheter arterial infusion (TAI) were repeated. Thereafter, systemic chemotherapy and biotherapy were introduced according to follow-up assessments. Unfortunately, imaging assessment at about 10 months later revealed that liver metastases were partially enlarged, although some were successfully treated. Therefore, these therapies were switched to other regimens, and TACE/TAI, systemic chemotherapies and biotherapies were repeated. Although liver metastases seemed to be stable for a while, the primary tumor was enlarged even after therapy. At 3.5 years after initial diagnosis, the primary tumor became symptomatic (pain and jaundice). Liver metastases enlarged and massive swelling of the para-aortic lymph nodes was observed. Thereafter, palliative therapy was the main course of action. He died at 4.3 years after initial diagnosis. CONCLUSION: Our young patient could have been a candidate for initial surgery for primary tumor and might have had a chance of subsequent liver transplantation for unresectable metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with liver metastases.

Effects of oral intake of hydrogen water on liver fibrogenesis in mice.

AIM: Liver fibrosis is the universal consequence of chronic liver diseases. Sustained hepatocyte injury initiates an inflammatory response, thereby activating hepatic stellate cells, the principal fibrogenic cells in the liver. Reactive oxygen species are involved in liver injury and are a promising target for treating liver fibrosis. Hydrogen water is reported to have potential as a therapeutic tool for reactive oxygen species-associated disorders. This study aimed to investigate the effects of hydrogen water on liver fibrogenesis and the mechanisms underlying these effects. METHODS: C57BL/6 mice were fed with hydrogen water or control water, and subjected to carbon tetrachloride, thioacetamide and bile duct ligation treatments to induce liver fibrosis. Hepatocytes and hepatic stellate cells were isolated from mice and cultured with or without hydrogen to test the effects of hydrogen on reactive oxygen species-induced hepatocyte injuries or hepatic stellate cell activation. RESULTS: Oral intake of hydrogen water significantly suppressed liver fibrogenesis in the carbon tetrachloride and thioacetamide models, but these effects were not seen in the bile duct ligation model. Treatment of isolated hepatocyte with 1 µg/mL antimycin A generated hydroxyl radicals. Culturing in the hydrogen-rich medium selectively suppressed the generation of hydroxyl radicals in hepatocytes and significantly suppressed hepatocyte death induced by antimycin A; however, it did not suppress hepatic stellate cell activation. CONCLUSION: We conclude that hydrogen water protects hepatocytes from injury by scavenging hydroxyl radicals and thereby suppresses liver fibrogenesis in mice.

A single-center analysis of the survival benefits of adjuvant gemcitabine chemotherapy for biliary tract cancer.

BACKGROUND: Surgical resection is the only curative treatment of biliary tract cancer (BTC). However, the prognosis of BTC remains unsatisfactory. The aim of this study is to evaluate the benefits of adjuvant gemcitabine chemotherapy for BTC. METHODS: We performed a historical cohort study that involved 198 patients who underwent R0 surgical resection. Patients who underwent major hepatectomy were administered biweekly intravenous gemcitabine at a dose of 800 mg/m(2). Otherwise, patients were administered intravenous gemcitabine at a dose of 1,000 mg/m(2) in 3 weekly infusions, which were followed by a 1-week pause. The primary outcome was overall survival. The hazard ratio (HR) of adjuvant chemotherapy was estimated by propensity score-stratified Cox regression that was adjusted for confounders. RESULTS: Forty patients received adjuvant chemotherapy. The HR of adjuvant chemotherapy was 0.47 [95 % confidence interval (CI) 0.28-0.95; P = 0.03]. Subgroup analysis showed that the survival benefits were possibly modified by lymph node positivity (HR 0.19; 95 % CI 0.07-0.58; interaction, P = 0.22), stage III (HR 0.11; 95 % CI 0.02-0.50; interaction, P < 0.01), intrahepatic cholangiocarcinoma (ICC) (HR 0.09; 95 % CI 0.01-0.67; interaction, P = 0.05), and poorly differentiated tumor (HR 0.16; 95 % CI 0.03-0.85; interaction, P = 0.13). CONCLUSIONS: Adjuvant gemcitabine chemotherapy for BTC may be effective, particularly for patients with stage III and ICC.

Effect of olprinone on liver microstructure in rat partial liver transplantation.

BACKGROUND: Donor safety is a major concern in living-donor liver transplantation. However, partial grafts do not meet the functional demands of recipients and lead to small-for-size syndrome (SFSS). In a previous study, we showed that olprinone (OLP), a selective phosphodiesterase ІІІ inhibitor, up-regulates endothelial nitric oxide synthase level in the liver and attenuates shear stress, sinusoidal endothelial cell injury, and hepatocyte apoptosis after excessive liver resection in a rat model. We aimed to examine whether OLP treatment has beneficial effects on SFSS in a rat model of partial liver transplantation (PLT). METHODS: We performed experiments in a rat model of 30% PLT. In the OLP group, we inserted an osmotic pump with OLP into the peritoneal cavity 48 h before liver graft sampling. Recipient rats were not treated with OLP. We examined the liver microstructure by electron microscopy and biochemical examination, and determined the 7-d survival of recipients. RESULTS: In the OLP group 1 h after PLT, the sinusoidal endothelial cells of the liver were well preserved and we observed few vacuolar structures in hepatocytes. The total serum bilirubin level 1 wk after PLT tended to be lower in the OLP group than in the controls, and the liver microstructures were also well preserved in the OLP group. The probability of survival in the OLP group (100%; 14 of 14 rats) was significantly higher than that in the control group (75%; 15 of 20 rats). CONCLUSIONS: Olprinone treatment was demonstrated to have therapeutic potential to overcome SFSS.

Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9.

BACKGROUND & AIMS: Sinusoidal obstruction syndrome (SOS) is a drug-induced liver injury that occurs with oxaliplatin treatment and is associated with postoperative morbidity after hepatectomy. The aim of this study was to investigate the effects of sorafenib in a monocrotaline (MCT)-induced model of SOS in rats. METHODS: Rats were divided into groups treated with sorafenib (2mg/kg) or vehicle, 36 h and 12h before MCT (90 mg/kg) administration by gavage. Liver tissues and blood were sampled 48 h after MCT administration to evaluate SOS. Survival after hepatectomy was examined and immunohistochemistry and electron microscopy were performed to assess sinusoidal injury. RESULTS: In the vehicle group, liver histology showed sinusoidal dilatation, coagulative necrosis of hepatocytes, endothelial damage of the central vein, and sinusoidal hemorrhage. In the sorafenib group, these changes were significantly suppressed, total SOS scores were significantly decreased, and the elevation of serum transaminase levels observed in the vehicle group was significantly reduced. Survival after hepatectomy was significantly higher in the sorafenib group compared to the vehicle group (45% vs. 20%, p=0.0137). Immunohistochemistry and electron microscopy revealed a protective effect of sorafenib on sinusoidal endothelial cells at 6h after MCT treatment. Sorafenib also attenuated the activity of metallopeptidase-9 (MMP-9) and phosphorylation of c-Jun N-terminal kinase (JNK). CONCLUSIONS: Sorafenib reduced the severity of MCT-induced SOS in rats through suppression of MMP-9 and JNK activity, resulting in improvement of survival after hepatectomy.

Downregulation of the Wnt antagonist Dkk2 links the loss of Sept4 and myofibroblastic transformation of hepatic stellate cells.

BACKGROUND/AIMS: Sept4, a subunit of the septin cytoskeleton specifically expressed in quiescent hepatic stellate cells (HSCs), is downregulated through transdifferentiation to fibrogenic and contractile myofibroblastic cells. Since Sept4(-/-)mice are prone to liver fibrosis, we aimed to identify the unknown molecular network underlying liver fibrosis by probing the association between loss of Sept4 and accelerated transdifferentiation of HSCs. METHODS: We compared the transcriptomes of Sept4(+/+) and Sept4(-/-) HSCs undergoing transdifferentiation by DNA microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis. Because Dickkopf2 (Dkk2) gene expression is reduced in Sept4(-/-) HSCs, we tested whether supplementing Dkk2 could suppress myofibroblastic transformation of Sept4(-/-) HSCs. We tested the involvement of the canonical Wnt pathway in this process by using a lymphoid enhancer-binding factor/transcription factor-luciferase reporter assay. RESULTS: We observed consistent upregulation of Dkk2 in primary cultured HSCs and in a carbon tetrachloride liver fibrosis in mice, which was decreased in the absence of Sept4. Supplementation with Dkk2 suppressed the induction of pro-fibrotic genes (α-smooth muscle actin and 2 collagen genes) and induced an anti-fibrotic gene (Smad7) in Sept4(-/-) HSCs. In human liver specimens with inflammation and fibrosis, Dkk2 immunoreactivity appeared to be positively correlated with the degree of fibrotic changes. CONCLUSIONS: Pro-fibrotic transformation of HSCs through the loss of Sept4 is, in part, due to reduced expression of Dkk2 and its homologues, and the resulting disinhibition of the canonical Wnt pathway.

Proliferative activity in hepatocellular carcinoma is closely correlated with glucose metabolism but not angiogenesis.

BACKGROUND & AIMS: This study investigated the relationship between tumor proliferative activity and the grade of tumor glucose metabolism or angiogenesis in hepatocellular carcinoma (HCC). METHODS: The study was performed as a retrospective analysis of 63 patients with HCC who underwent fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) as a preoperative examination prior to liver resection. Tumor proliferative activity was evaluated by the Ki-67 labeling index (LI). The grade of tumor glucose metabolism was evaluated by measuring the protein expression level of glucose transporter (GLUT)-1, expression level of pyruvate kinase type M2 (PKM2) mRNA, and FDG uptake. The grade of tumor angiogenesis was evaluated by the protein expression level of vascular endothelial growth factor (VEGF) and tumor microvessel density. RESULTS: All patients were divided into tertiles according to the Ki-67 LI: the low LI group (n = 21), the intermediate LI group (n = 21), and the high LI group (n = 21). The high LI group showed a tendency to have advanced tumor stage, and lower disease-free survival and overall survival rates than the low LI and the intermediate LI groups. The expression grade of GLUT-1, PKM2 mRNA, and FDG uptake gradually increased with the Ki-67 LI. On the other hand, the protein expression grade of VEGF and microvessel density was paradoxically decreased with the Ki-67 LI. CONCLUSIONS: These data suggest that (1) the proliferative activity of a resected specimen predicted the prognosis in patients with HCC; (2) the proliferative activity was closely correlated with the glucose metabolism, but not with angiogenesis.

Olprinone attenuates excessive shear stress through up-regulation of endothelial nitric oxide synthase in a rat excessive hepatectomy model.

After extended hepatectomy, excessive shear stress in the remnant liver causes postoperative liver failure. Olprinone (OLP), a selective phosphodiesterase inhibitor, has been reported to improve microcirculation and attenuate inflammation. The aim of this study was to investigate the effects of OLP on shear stress in rats with an excessive hepatectomy (EHx) model. In this study, EHx comprised 90% hepatectomy with ligation of the left and right Glisson's sheaths in Lewis rats. OLP or saline was intraperitoneally administered with an osmotic pump 48 hours before EHx. To evaluate the shear stress, we measured the portal vein (PV) pressure. We also assessed sinusoidal endothelial cell injury by immunohistochemistry and electron microscopy. Furthermore, we assessed apoptosis in the liver with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. Treatment with OLP up-regulated hepatic endothelial nitric oxide synthase (eNOS) expression. The increase in the PV pressure due to Glisson's sheath ligation was attenuated in OLP-treated rats during a 30-minute period after ligation. Treatment with OLP preserved sinusoidal endothelial cells and reduced apoptosis in the remnant liver. The probability of survival in the OLP-treated rats was significantly better than that in the controls (33.3% versus 13.3%). Furthermore, the postoperative eNOS activity in the OLP-treated rats was higher than that in the controls. The administration of Nω-nitro-l-arginine methyl ester to OLP-treated rats eliminated the effects of OLP on PV pressure and survival after EHx. Therefore, we concluded that OLP attenuates excessive shear stress through the up-regulation of eNOS and improves the survival rate after EHx.

Resistance to cisplatin-induced apoptosis via PI3K-dependent survivin expression in a rat hepatoma cell line.

Hepatocellular carcinoma (HCC) is known to be resistant to chemotherapy. Survivin, a member of the inhibitor of apoptosis proteins, is overexpressed in most cancers but is absent in most normal adult tissue. The aim of this study was to investigate whether expression of survivin contributes to resistance to cisplatin-induced apoptosis. We confirmed induction of survivin expression in hepatoma in the N-diethylnitrosamine (DEN) induced rat and in the rat hepatoma cell line (K-251). We examined cell proliferation after treatment with cisplatin (CDDP) in the presence and absence of siRNA or the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 to suppress survivin or PI3K/Akt, respectively. Survivin was expressed in DEN-induced rat HCC with RT-PCR and Western blotting. Expression of survivin was observed primary in the nuclei and in the cytoplasm with immunohistochemistry. However, survivin was not detected in non-tumor tissues. Expression of survivin was also observed primarily in the nuclei and in the cytoplasm of the K-251 rat hepatoma cell line. CDDP induced survivin expression, which was blocked by siRNA. LY294002 also attenuated survivin expression induced by CDDP. Our results indicate that survivin expression via PI3K contributes to resistance to CDDP-induced apoptosis in a rat hepatoma cell line.

Dai-kenchu-to attenuates rat sinusoidal obstruction syndrome by inhibiting the accumulation of neutrophils in the liver.

BACKGROUND AND AIM: Sinusoidal obstruction syndrome (SOS) is drug-induced liver injury that occurs in patients who receive hematopoietic cell transplantation and oxaliplatin-contained chemotherapy. The aim of study was to investigate the pharmacological treatment of SOS using a traditional Japanese medicine, Dai-kenchu-to (DKT). METHODS: Male Sprague-Dawley rats were treated with monocrotaline (MCT) to induce SOS. The rats were divided into three groups: control, MCT and MCT+DKT groups. In the MCT+DKT group, DKT was gavaged at 12 h after MCT treatment and given every 12 h until the end of the protocol. The rats of MCT group were treated with water instead of DKT. At 48 h after MCT treatment, blood and liver samples were collected. RESULTS: In the MCT+DKT group, the macroscopic and histological findings revealed liver congestion, sinusoidal alteration and the destruction of sinusoidal lining, which were comparable with those of the MCT group. However, the area of hepatic necrosis and serum AST levels significantly decreased in the MCT+DKT group compared with those of the MCT group. Treatment with DKT resulted in the reduction of neutrophil accumulation, myeloperoxidase activity and the expression of cytokine-induced neutrophil chemoattractant (CINC) and intracellular adhesion molecule-1 (ICAM-1) mRNA in the liver compared with those of the MCT group. Treatment with processed ginger, one of the ingredients in DKT, resulted in similar effects to those shown by DKT. CONCLUSIONS: Dai-kenchu-to attenuates MCT-induced liver injury by preventing neutrophil-induced liver injury through blockage of upregulation of CINC and ICAM-1 mRNA level.

Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma.

UNLABELLED: Transforming growth factor beta (TGF-beta) signaling involves both tumor-suppression and oncogenesis. TGF-beta activates the TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TbetaRI-dependent pSmad3C transmits a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7.9 +/- 0.8 versus 17.7 +/- 0.9: P < 0.001; 6.3 +/- 1.2 versus 7.1 +/- 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DEN-induced HCC (113 versus 97 days: log-rank P = 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, TbetaRI/pSmad3C/p21(WAF1) was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21(WAF1), acting as a tumor suppressor in normal hepatocytes. CONCLUSION: Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression.

A phosphodiesterase III inhibitor protects rat liver from sinusoidal obstruction syndrome through heme oxygenase-1 induction.

OBJECTIVE: The aim of study was to investigate pharmacological treatment for sinusoidal obstruction syndrome (SOS). BACKGROUND: SOS is associated with oxaliplatin-based chemotherapy in patients with hepatic colorectal metastases. Patients with SOS have increased postoperative morbidity after major hepatectomy, but a method for effective prevention of SOS has not been established. METHODS: Male Sprague-Dawley rats were treated with cobalt protoporphyrin IX (CoPP) or olprinone (OLP), a phosphodiesterase III inhibitor, and hepatic HO-1 expression and HO enzymatic activity were determined. Monocrotaline (MCT) was given to rats to induce SOS, and blockage of SOS by CoPP or OLP-induced hepatic HO-1 was examined in these rats. Zinc protoporphyrin IX (ZnPP), a competitive HO inhibitor, was given to MCT-treated rats together with OLP to clarify the mechanism of protection against SOS. We also examined if OLP preserved remnant liver function after 70% hepatectomy in MCT-treated rats. RESULTS: OLP up-regulated hepatic HO-1 protein expression and HO enzymatic activity, and activated Akt protein. Administration of ZnPP to OLP-treated rats resulted in inhibition of HO activity and inactivation of Akt. Induction of HO-1 by pretreatment with CoPP led to amelioration of SOS in histologic findings and blockage of elevation of serum liver enzymes. Pretreatment with OLP gave a similar result and preserved remnant liver function, as indicated by improved survival after hepatectomy. ZnPP completely abolished the protective effects of OLP. CONCLUSIONS: Protection of the liver from drug-induced injury by prior up-regulation of HO-1 using OLP may have potential as a therapeutic strategy for prevention of SOS.

Prophylactic respiratory management after liver resection with bilevel positive airway pressure ventilation: Report of three cases.

Pulmonary complications after hepatectomy occur with relative frequency and are associated with increased morbidity and mortality. Moreover, their prevention is often difficult. We report using prophylactic bilevel positive airway pressure ventilation, initiated just after the operation, for the successful postoperative respiratory management of three patients predisposed to the development of pulmonary complications. One patient had insufficient pulmonary function (forced expiratory volume in 1 s (FEV(1)) 0.95 l; FEV(1)/forced vital capacity 40.8%) caused by previous thoracoplasty. The other two patients were obese and had obstructive sleep apnea syndrome (OSAS). None of the patients required endotracheal intubation after hepatectomy, although the two with severe OSAS suffered pulmonary thromboembolism postoperatively. Bilevel positive airway pressure ventilation was well tolerated and there were no adverse effects, suggesting its effectiveness for preventing pulmonary complications after hepatectomy.

[Retrospective analysis of clinical results in eight patients with advanced hepatocellular carcinoma with lung metastases treated by TS-1].

Advanced hepatocellular carcinoma (HCC) with distant metastases, in particular to the lung, has a poor prognosis. This study was undertaken to evaluate the effectiveness of TS-1 as chemotherapy in advanced HCC with lung metastases. Between January 2004 and October 2005, 8 patients with advanced HCC with lung metastasis were enrolled. All patients received systemic chemotherapy with TS-1. The drug was administered at a dose of 80 mg/m(2)/day for four weeks, followed by a two-week rest, repeated every six weeks until disease progression, unacceptable toxicity, or the patient's refusal. Median age of the patients was 59 years (range, 44 to 79 years). All patients were in Child-Pugh class A. A total of 22 cycles were administered to each patient (range, 1 to 5). No complete or partial responses were observed. There were two patients (25%) with decreasing tumor marker. Median progression-free survival was 79.5 days (range, 29 to 225). The median overall survival was 257 days (95% confidence interval, 191 to 323 days). TS-1 as chemotherapy was well tolerated when administered in the schedule used in this study. Some patients achieved stable disease and clinical benefits, though this regimen has limited activity in HCC with lung metastases. Randomized controlled trials are necessary to clarify survival benefits in patients with advanced HCC with lung metastasis.