TU-100 Antagonizes the M2 Polarization Phenotype of Macrophages in the Tumor Microenvironment by Suppressing the TLR4/NF-B/STAT3 Axis.

BACKGROUND/AIM: Macrophages are the most abundant immune cells in the tumor stroma, and their polarization states within the tumor microenvironment (TME) exert critical roles in tumorigenesis. TU-100 (Daikenchuto) is a commonly prescribed Japanese herbal medicine that has shown anti-cancer effects by regulating cancer-associated fibroblasts (CAFs) in the TME. However, its effects on tumor-associated macrophages (TAMs) remain unclear. MATERIALS AND METHODS: TAMs were generated by macrophage exposure to tumor-conditioned medium (CM), and their polarization states were evaluated after TU-100 treatment. The underlying mechanism was further studied. RESULTS: TU-100 exhibited little cytotoxicity over a range of doses in M0 macrophages and TAMs. However, it could antagonize the M2-like polarization of macrophages evoked by tumor-CM exposure. These effects might be caused by the inhibition of TLR4/NF-B/STAT3 signaling in the M2-like phenotype of macrophages. Interestingly, TU-100 antagonized the malignancy promoting effects of M2 macrophages on hepatocellular carcinoma cell lines in vitro. Mechanistically, the administration of TU-100 restrained the high expression of MMP-2, COX-2, and VEGF in TAMs. CONCLUSION: TU-100 may alleviate the progression of cancer by regulating the M2 polarization of macrophages within the TME, suggesting a viable therapeutic approach.

Effective in vitro differentiation of adipose-derived stem cells into Schwann-like cells with folic acid supplementation.

Peripheral nerve injury (PNI) after pelvic surgery is a common issue with a significant impact on patients. Autologous nerve grafting is the gold standard treatment for PNI, but this technique cannot be applied to fine nerve fibers in the pelvis. Schwann-like cell (SLC) differentiation is a novel therapeutic strategy for this clinical condition. However, the efficiency of SLC differentiation remains unsatisfactory. We modified an SLC differentiation protocol using adipose-derived stem cells (ADSCs) and folic acid. Morphology, gene expression and secretion of neurotrophic factors were examined to assess the differentiation quality and phenotypic characteristics. Our new modified protocol effectively induced a Schwann cell (SC) phenotype in ADSCs as assessed by morphology and expression of SC markers [S100 calcium-binding protein B (S100B), P < 0.01 ; p75 neurotrophic receptor (p75NTR), P < 0.05]. SLCs produced by the new protocol displayed a repair phenotype with decreased expression of ERBB2 and early growth response protein 2 (EGR2) / KROX20 (P < 0.01). Furthermore, our new protocol enhanced both mRNA expression and secretion of nerve growth factors by SLCs (P < 0.01). This protocol enhanced the SC characteristics and functions of ADSC-derived SLCs. This promising protocol requires further research and may contribute to SC-based nerve regeneration. J. Med. Invest. 68 : 347-353, August, 2021.

Effect of TU-100 on Peyer's patches in a bacterial translocation rat model.

BACKGROUND: Daikenchuto (TU-100), a Japanese herbal medicine, is widely used for various gastrointestinal diseases. We have previously reported that TU-100 suppresses CPT-11-induced bacterial translocation (BT) by maintaining the diversity of the microbiome. In this study we show that TU-100 modulates the immune response during BT by inducing PD-1 expression in Peyer's patches. METHODS: Eighteen male Wistar rats were divided into four groups: a control group; a control + TU-100 group, given TU-100 1000 mg/kg orally for 5 d; a BT group, given CPT-11 250 mg/kg intra-peritoneal for 2 d; and a TU-100 group, given TU-100 1000 mg/kg orally for 5 d with CPT-11 250 mg/kg intra-peritoneal on days 4 and 5. RESULTS: The size of Peyer's patch was significantly bigger in the BT group compared to the control group (9.0 × 104 µm2 vs 29.4 × 104 µm2, P < .05), but improved in the TU-100 group (15.4 × 104 µm2, P < .005). TU-100 significantly induced PD-1 expression in Peyer's patch compared to the control group and the BT group (control vs BT vs TU-100 = 4.3 ± 4.9 vs 5.1 ± 10.3 vs 17.9 ± 17.8). The CD4+ cells were increased in the BT group (P < .05) compared to the control group but decreased in the TU-100 group. The Foxp3+ cells were increased in the BT group compared to the control group (P < .05), and further increased in the TU-100 group compared to the BT group. CPT-11 significantly increased TLR4, NF-κß, TNF-α mRNA expressions in the BT group. TU-100 cotreatment significantly reversed these mRNA expressions. CONCLUSION: TU-100 may have a protective effect against BT through PD-1 expression in Peyer's patch.

Daikenchuto, a traditional Japanese herbal medicine, promotes colonic transit by inducing a propulsive movement pattern.

BACKGROUND: The traditional Japanese herbal medicine, daikenchuto (DKT), has been used to treat constipation and postoperative ileus. However, the precise mechanisms involved in the pharmacological effects of DKT remain uncertain. The aim of this study was to clarify the effect of DKT on motor patterns and transit activity in the isolated rat colon. METHODS: The entire colon or segments of the proximal colon in rats were isolated and placed in Krebs solution. The motility of the colon was evaluated by analyzing spatiotemporal maps of diameter derived from video imaging and measuring the intraluminal pressure in the anal end of the proximal colon, and the transit time of a plastic bead through the entire isolated colon. KEY RESULTS: Several types of propagating contractions were observed in the isolated entire colon. When DKT was added to Krebs solution, the frequency of large-extent anal propagating contractions increased. DKT treatment increased the intraluminal pressure in the isolated proximal colon, which was related to the propagating contractions. This effect was abolished by treatment with the neural blocker tetrodotoxin. These findings suggest DKT induced peristaltic contractions in the isolated colon. DKT accelerated colonic transit activity, which was related to peristaltic contractions induction in the colon. These effects were also observed in the colons treated with bethanechol and the active ingredient of DKT, hydroxy-α-sanshool. CONCLUSIONS AND INFERENCES: Daikenchuto could enhance colonic transit activity by inducing peristaltic contractions, which may be mediated by the activation of the enteric nervous system in the colon.

Daikenchuto accelerates the recovery from prolonged postoperative ileus after open abdominal surgery: a subgroup analysis of three randomized controlled trials.

PURPOSE: Prolonged postoperative ileus (POI) is a common complication after open abdominal surgery (OAS). Daikenchuto (DKT), a traditional Japanese medicine that peripherally stimulates the neurogenic pathway, is used to treat prolonged POI in Japan. To analyze whether DKT accelerates the recovery from prolonged POI after OAS, we conducted a secondary analysis of three multicenter randomized controlled trials (RCTs). METHODS: A secondary analysis of the three RCTs supported by the Japanese Foundation for Multidisciplinary Treatment of Cancer (project numbers 39-0902, 40-1001, 42-1002) assessing the effect of DKT on prolonged POI in patients who had undergone OAS for colon, liver, or gastric cancer was performed. The subgroup included 410 patients with no bowel movement (BM) before the first diet, a DKT group (n = 214), and a placebo group (n = 196). Patients received either 5 g DKT or a placebo orally, three times a day. The primary endpoint was defined as the time from the end of surgery to the first bowel movement (FBM). A sensitivity analysis was also performed on the age, body mass index and dosage as subgroup analyses. RESULTS: The primary endpoint was significantly accelerated in the DKT group compared with the placebo group (p = 0.004; hazard ratio 1.337). The median time to the FBM was 113.8 h in the placebo group and 99.1 h in the DKT treatment group. CONCLUSIONS: The subgroup analysis showed that DKT significantly accelerated the recovery from prolonged POI following OAS. TRIAL REGISTRATION NUMBER: UMIN000026292.

The Outcome of Sorafenib Therapy on Unresectable Hepatocellular Carcinoma: Experience of Conversion and Salvage Hepatectomy.

BACKGROUND/AIM: We report the outcomes of sorafenib therapy for advanced hepatocellular carcinoma (HCC) in our Department. PATIENTS AND METHODS: Thirty-eight patients with unresectable HCC who were administrated sorafenib from 2009 to 2015 were investigated retrospectively. RESULTS: The 1-year overall survival rate was 59.3%. The macroscopic vascular invasion and response rate were independent prognostic factors of survival. Surgical resection after sorafenib achieved long-term survival in two cases. Case 1: A patient with locally unresectable HCC showed significant response induced by sorafenib, which allowed complete surgical resection. This tumor tested positive for FGF4. Case 2: A patient with a history of hepatectomy for HCC had multiple distant metastases. Most lesions were reduced in size after sorafenib therapy and new lesions in the remnant liver and residual lung metastases were resected. The sorafenib-resistant lesions were negative for FGF4. CONCLUSION: Sorafenib combined with surgical resection is a feasible option in advanced HCC patients, if sorafenib has been effective.

Effect of Adjuvant Gemcitabine Combined with Low-dose 5-Fluorouracil and Cisplatin Chemotherapy for Advanced Biliary Carcinoma.

BACKGROUND/AIM: The aim of this retrospective study was to clarify the effectiveness of chemotherapy with gemcitabine combined with low-dose 5-fluorouracil and cisplatin (GFP) for advanced biliary carcinoma after hepatectomy. PATIENTS AND METHODS: Sixty-two patients had biliary carcinoma with lymph node metastasis, intrahepatic metastasis or positive surgical margins, including intrahepatic cholangiocarcinoma (IHC, n=25), hilar cholangiocarcinoma (HC, n=14), and gallbladder cancer (GBC, n=23). Twenty-eight patients (IHC; n=9, HC; n=8, GBC; n=11) received adjuvant GFP chemotherapy. RESULTS: We found no significant difference in clinicopathological factors in patients treated with or without adjuvant GFP chemotherapy. Overall, survival in the adjuvant GFP group was significantly better than that in the non-adjuvant GFP group (3-year survival: 61.9% vs. 8.8%, p<0.001), as was relapse-free survival. CONCLUSION: Adjuvant GFP chemotherapy after hepatectomy may be a promising option for improving surgical outcomes in patients with advanced biliary carcinoma.

The Kampo medicine "Daikenchuto (TU-100)" prevents bacterial translocation and hepatic fibrosis in a rat model of biliary atresia.

BACKGROUND: Biliary atresia is the most common cause of end-stage liver disease in children. It is known that bile duct ligation contributes to liver fibrosis via bacterial translocation (BT) and toll-like receptor 4 (TLR4) signaling of hepatic stellate cells (HSCs). We have reported previously that the traditional Japanese medicine, "Dai-kenchu-to (TU-100)," a form of "Kampo medicine" prevents BT in rats exposed to the stress of fasting. The aim of this study was to clarify the effect of TU-100 on a rat model of biliary atresia using bile duct ligation. METHODS: Bile duct ligation and subsequent daily oral administration of TU-100 was performed in 6-week-old rats. The rats were killed at 3, 7, or 14 days after bile duct ligation to evaluate the liver injury, occurrence of BT, and hepatic fibrosis. As an in vitro experiment, we isolated fresh HSCs from the rats undergoing bile duct ligation. After cell attachment, TU-100 and its 3 component herbs (eg, processed ginger, ginseng radix, and Japanese pepper) were added, and the expressions of Alpha actin2 (acta2), Alpha-1 type I collagen (colIa1), and tissue inhibitor of metalloproteinase 1 (timp1) were analyzed. RESULTS: In vivo experiments demonstrated that oral administration of TU-100 decreased liver injury and atrophy of intestinal mucosa BT, hepatic fibrosis, and hepatic expression of alpha smooth muscle actin (αSMA) and TLR4, compared with rats that underwent bile duct ligation only. In vitro experiments showed that administration of TU-100 or the component herbs inhibited the expressions of acta2, colIa1, and timp1 in the HSCs. CONCLUSION: TU-100 prevented BT, activation of HSCs, and subsequent hepatic fibrosis. TU-100 may prevent progression of hepatic fibrosis in children with biliary atresia and improve prognosis.

Epigallocatechin gallate hinders human hepatoma and colon cancer sphere formation.

BACKGROUND AND AIM: The long-term survival of patients with hepatocellular carcinoma remains unsatisfactory because of the presence of cancer stem cells (CSCs), which are responsible for tumor recurrence and chemoresistance after hepatectomy. Drugs that selectively target CSCs thus offer great promise for cancer treatment. Although the antitumor effects of epigallocatechin gallate (EGCG) have been reported in some cancer cells, its effects on CSCs remain poorly studied. In this study, we investigated the effects of EGCG on human hepatoma and colon CSCs. METHODS: HepG2 and HCT-116 cell lines were enriched by sphere formation, and their gene-expression profiles were analyzed by quantitative real-time polymerase chain reaction. EGCG-induced growth inhibition in the parental cells was determined by WST-8 assay, and protein expression was assessed by western blotting. Cell cycle profile and apoptosis analysis was performed using flow cytometer. RESULTS: Sphere-derived cells grown in serum-free, nonadherent cultures showed increased expression of stem cell markers, Nek2, and ATP-binding cassette transporter genes, compared with parental cells grown in conventional culture. EGCG induced growth inhibition in the parental cells in a dose-dependent manner. EGCG also inhibited self-renewal in hepatoma and colon CSCs, attenuated the expression of stem cell markers and ATP-binding cassette transporter genes, which are putative molecules associated with treatment resistance in CSCs, and decreased the transcription of Nek2 and p-Akt, resulting in the inhibition of Akt signaling. EGCG also altered cell cycle profile and apoptosis, which may in part play an important role in EGCG-induced cancer cell death. CONCLUSIONS: Overall, these results suggest that EGCG could be a useful chemopreventive agent for targeting hepatocellular carcinoma and colon CSCs, in combination with standard chemotherapies.

Effect of TU-100, a traditional Japanese medicine, administered after hepatic resection in patients with liver cancer: a multi-center, phase III trial (JFMC40-1001).

BACKGROUND: This multi-center, phase III trial assesses the efficacy of daikenchuto (TU-100) on gastrointestinal disorders after hepatic resection (UMIN Registration No. 000003103). MATERIALS AND METHODS: A total of 231 patients, who underwent hepatic resection at 26 Japanese centers, were enrolled. Patients were randomly assigned to receive either oral doses (15 g/day, three times a day) of TU-100 or placebo control from preoperative day 3 to postoperative day 10, except on the day of surgery. Primary end points were the time from extubation until the first postoperative bowel movement (FBM-T), serum C-reactive protein (CRP) and ammonia levels. RESULTS: Finally, 209 patients (TU-100: n = 108, placebo: n = 101) were included in the statistical analysis. The median FBM-T was 88.2 h (95 % CI 74.0-94.1) in the TU-100 group and 93.1 h (95 % CI 83.3-99.4) in the placebo group, demonstrating that TU-100 accelerated the time to first bowel movement significantly more than placebo control. Serum CRP levels did not differ significantly during the study period, although serum CRP levels in the TU-100 group tended to be lower than those in the placebo group in patients with grade B liver damage. Meanwhile, the two groups had similar serum ammonia levels. TU-100-related serious adverse events did not occur during the study. CONCLUSIONS: TU-100 appears to improve gastrointestinal dysmotility and reduce serum CRP levels in patients with grade B liver damage after hepatectomy. TU-100 is an effective treatment option after hepatic resection in patients with liver cancer.

Branched chain amino acid suppressed insulin-initiated proliferation of human cancer cells through induction of autophagy.

BACKGROUND: Branched chain amino acid (BCAA) dietary supplementation inhibits activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis in diabetic animal models. However, the in vitro effect of BCAA on human cancer cell lines under hyper-insulinemic conditions remains unclear. MATERIALS AND METHODS: Colon (HCT-116) and hepatic (HepG2) tumor cells were treated with varying concentrations of BCAA with or without fluorouracil (5-FU). The effect of BCAA on insulin-initiated proliferation was determined. Gene and protein expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. RESULTS: BCAA supplementation had no significant effect on cell proliferation and did not show significant synergistic or antagonistic effects with 5-FU. However, BCAA significantly decreased insulin-initiated proliferation of human colon and hepatic cancer cell lines in vitro. BCAA supplementation caused a marked decrease in activated IGF-IR expression and significantly enhanced both mRNA and protein expression of LC3-II and BECN1 (BECLIN-1). CONCLUSION: BCAA could be a useful chemopreventive modality for cancer in hyperinsulinemic conditions.

Gene profile in the spleen under massive partial hepatectomy using complementary DNA microarray and pathway analysis.

BACKGROUND AND AIM: In general, the spleen is one of the abdominal organs connected by the portal system, and a splenectomy improves hepatic functions in the settings of partial hepatectomy (Hx) for portal hypertensive cases or living donor liver transplantation with excessive portal vein flow. Those precise mechanisms remain still unclear; therefore, we investigated the DNA expression profile in the spleen after 90% Hx in rats using complementary DNA microarray and pathway analysis. METHODS: Messenger RNAs (mRNAs) were prepared from three rat spleens at each time point (0, 3, and 6 h after 90% Hx). Using the gene chip, mRNA was hybridized to Affymetrix GeneChip Rat Genome 230 2.0 Array (Affymetrix®) and pathway analysis was done with Ingenuity Pathway Analysis (IPA®). RESULTS: We determined the 3-h or 6-h/0-h ratio to assess the influence of Hx, and cut-off values were set at more than 2.0-fold or less than 1/2 (0.5)-fold. Chemokine activity-related genes including Cxcl1 (GRO1) and Cxcl2 (MIP-2) related pathway were upregulated in the spleen. Also, immediate early response genes including early growth response-1 (EGR1), FBJ murine osteosarcoma (FOS) and activating transcription factor 3 (ATF3) related pathway were upregulated in the spleen. CONCLUSIONS: We concluded that in the spleen the expression of numerous inflammatory-related genes would occur after 90% Hx. The spleen could take a harmful role and provide a negative impact during post Hx phase due to the induction of chemokine and transcription factors including GRO1 and EGR1.

Changes of immunological parameters with administration of Japanese Kampo medicine (Juzen-Taihoto/TJ-48) in patients with advanced pancreatic cancer.

BACKGROUND: The prognosis of pancreatic cancer is extremely poor regardless of various combination therapies. Immunoaugumentation against tumor cells was recently A focus. We reported that the population of Foxp3(+)CD25(+)CD4(+) regulatory T cells (Foxp3(+)Treg) was the new parameter for the estimation of host immunity and had correlation with tumor aggressiveness. Here we show the immunoaugumentation effects of Japanese Kampo medicine, Juzen-Taihoto/TJ-48, empirically considered as an immunoaugumentation drug, with investigation of Treg and other immunological parameters. PATIENTS AND METHOD: Peripheral Foxp3(+) Treg populations, CD4/CD8 ratio, and CD57(+) cells (NK cells) populations in advanced pancreatic cancer patients (n = 30, stage VI A and B according to TNM classification) were estimated after TJ-48 administration for 14 days before the anti-cancer therapy. RESULTS: Treg populations were significantly increased compared to healthy donors (Mann-Whitney U test, P < 0.001). Administration of Juzen-Taihoto/TJ-48 significantly decreased Treg populations (Mann-Whitney U test, P < 0.001) and increased the CD4/CD8 ratio (Mann-Whitney U test, P < 0.01), even though CD57(+) cell populations did not change significantly. CONCLUSIONS: Juzen-Taihoto/TJ-48 increased regulatory activities in T cells through decreasing Foxp3(+) Treg populations in advanced pancreatic cancer patients. This effect can lead to immunoaugumentation for various combination therapies.

Beneficial effects of green tea catechin on massive hepatectomy model in rats.

BACKGROUND: Green tea catechin, especially epigallocatechin gallate (EGCG), is a well-known scavenger of reactive oxygen species and it may also function as an antioxidant through modulation of transcriptional factors and enzyme activities. METHODS: Green tea extract (GTE®) which contained numerous EGCG was used. Wistar rats were performed 90 % hepatectomy and classified into 2 groups with (GTEHx, n = 25) or without GTE treatment (Hx, n = 25) and sacrificed at 1, 3, 7 and 14 days after operations. All rats had free access to drinking water supplemented with or without GTE from the 7th pre-operative day. Liver regeneration, hepatic inducible nitric oxide synthase (iNOS), anti-oxidative enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px)] and inflammatory markers [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NFκB), tumor necrosis factor-α (TNF-α)] were investigated. RESULTS: The liver weight to body weight ratio (p < 0.01), proliferating cell nuclear antigen labeling index (p < 0.05) and phosphorylated extracellular signal-regulated kinase 1/2 (p < 0.05) at day 1 in the GTEHx group significantly increased compared to the Hx group. Hepatic iNOS levels at day 1 significantly decreased (p < 0.01) in the GTEHx group. Hepatic SOD, CAT and GSH-Px levels at day 1 significantly increased (SOD: p < 0.01, CAT and GSH-Px: p < 0.05) in the GTEHx group. In contrast, COX-2, NFκB and TNF-α levels at day 1 significantly decreased (COX-2: p < 0.01, NFκB and TNF-α: p < 0.05) in the GTEHx group. CONCLUSIONS: GTE pretreatment stimulated liver regeneration and improved liver damage after massive hepatectomy through anti-oxidative and anti-inflammatory effects. Green tea catechin might have the potential to attenuate liver dysfunction in early stage after massive hepatectomy.

The beneficial effects of Kampo medicine Dai-ken-chu-to after hepatic resection: a prospective randomized control study.

BACKGROUND/AIMS: After hepatic resection, delayed flatus and impaired bowel movement often cause problematic postoperative ileus. Kampo medicine, Dai-kenchu-to (DKT), is reported to have a various beneficial effects on bowel systems. The aim of this study was to prospectively evaluate effects of DKT after hepatic resection. METHODOLOGY: Thirty-two patients who underwent hepatic resection between July 2007 and August 2008 in Tokushima University Hospital were prospectively divided into DKT group (n=16) and control group (n=16). In DKT group, 2.5 g of DKT was administered orally three times a day from postoperative day (POD) 1. Blood was examined on POD 1, 3, 5 and 7. Postoperative first flatus, bowel movement and full recovery of oral intake, hospital stays and complications were checked. RESULTS: In DKT group, levels of c-reactive protein and beta-(1-3)-D-glucan on POD 3 were significantly decreased (p<0.05). Moreover, postoperative periods for the first flatus, bowel movement and the full recovery of oral intake were significantly shortened in DKT group (p<0.05). CONCLUSIONS: DKT suppressed inflammatory reaction, stimulated bowel movement and improved oral intake after hepatic resection, which may decrease serious morbidity after hepatic resection.

Influence of Dai-kenchu-to (DKT) on human portal blood flow.

BACKGROUND/AIMS: Dai-kenchu-to (DKT) is known as an herbal medicine used for postoperative ileus. However, no report exists about the effect of DKT on portal blood flow. The aim of this study is to clarify the influence of DKT on portal blood flow. METHODOLOGY: To healthy volunteers (Healthy; n = 6), cirrhotic patients (Cirrhosis; n = 7) and liver-transplant patients (LTx; n = 3), DKT (2.5g) with 100mL of warm water was orally administrated in the DKT group, and only warm water was administrated in the control group. The portal blood flow rate (M-VEL: cm/sec.) and portal blood flow (Flow volume: mL/min.) was measured each time after administration using an ultrasonic Doppler method. Furthermore, the arterial blood pressure and heart rate was measured at the same time points. RESULTS: In the DKT group, a significant increase of M-VEL (120%) and flow volume (150%) 30 minutes after administration was observed in both Healthy and Cirrhosis in comparison with the control group. In LTx, there was also a significant increase of flow volume (128%) 30 minutes after administration. However, there was no change in average blood pressure and heart rate in all groups. CONCLUSIONS: DKT increases portal blood flow in early phase after oral administration without any significant changes in the blood pressure and heart rate.

Effect of a new adjuvant systemic interferon alpha, 5-fluorouracil and cisplatin on advanced hepatocellular carcinoma with macroscopic portal invasion.

BACKGROUND/AIMS: Despite an adequate hepatic resection, theprognosis of the patients with hepatocellular carcinoma (HCC) that have macroscopic tumor thrombus in the portal vein has still been poor. The prognosis of those patients and was investigated the significance of postoperative adjuvant therapy was discussed in this study. METHODOLOGY: Twenty five patients who had Vp2 or more portal invasion were included in this study. Those patients were retrospectively divided into 2 groups: the systemic interferon alpha, 5-Fluorouracil (FU) and cisplatin group (n = 10, IFN+ chemo group); and the no adjuvant therapy group (n = 15, control group). RESULTS: The overall survival rate was significantly higher in the IFN+chemo group compared with the control group. There was no significant difference between the 2 groups in regard to the disease-free survival rate. However, a difference in the recurrence pattern was observed between the 2 groups. In the IFN+chemo group, 3 of 6 patients with a recurrence had a single tumor in the remnant liver. While in the control group, 10 of 11 recurrent patients had either distant metastasis or multiple recurrences in the residual liver. CONCLUSIONS: Our new adjuvant systemic therapy including interferon alpha, 5FU and cisplatin for advanced HCC with macroscopic portal invasion is promising.

Beneficial effects of Kampo medicine Inchin-ko-to on liver function and regeneration after hepatectomy in rats.

AIM: Inchin-ko-to (ICKT), Kampo medicine, is known to inhibit hepatocyte apoptosis as well as promote the secretion and excretion of bile. The aim of this study is to clarify the effects of ICKT on liver function and hepatic regeneration after massive hepatectomy in rats. METHODS: Male Wistar rats received 2 g/kg ICKT from 3 days preoperatively and underwent 90% hepatectomy. Liver sections were stained using immunohistochemistry (hemeoxygenase-1 [HO-1], alpha-smooth muscle actin [SMA], and proliferating cell nuclear antigen [PCNA]). RESULTS: The survival period was significantly prolonged, and the remnant liver/body weight ratio was significantly increased postoperatively in the ICKT group. The values of transaminase, total bile acid, and total bilirubin were significantly improved in the ICKT group. In the ICKT group, PCNA and HO-1 were strongly expressed early postoperatively, but the expression of alpha-SMA was weak. CONCLUSION: The preoperative administration of ICKT has been suggested to provide beneficial effects in promoting hepatic regeneration and preventing postoperative hepatic failure. The reduced activation of stellate cells may be involved in their mechanisms.

Nutritional treatment of a patient with hepatic cirrhosis with the novel low glycemic index liquid food (Inslow).

A sixty-six year-old patient with liver cirrhosis and diabetes was nutritionally treated by administration of the low glycemic index liquid food (Inslow) as a late evening sack (LES) for 6 weeks. The mean energy intake increased from 825+/-48 kcal/d to 1567+/-66 kcal/d after the 6-week treatment period. The fasting glucose level did not change, remaining at about 100 mg/dl throughout this period. Interestingly, the amount of insulin administered was reduced from 38 units before treatment to 28 units in the fifth week of treatment without a change in the fasting glucose level. This indicates a marked improvement in insulin sensitivity due to Inslow administration in this patient. In conclusion, the long-term administration of Inslow as an LES may be an effective treatment for cirrhotic patients.

Beneficial effects of hyperbaric oxygen pretreatment on massive hepatectomy model in rats.

BACKGROUND: The purpose of this study was to investigate the impact of hyperbaric oxygen (HBO) pretreatment in massive hepatectomy model, a surrogate model of small-for-size graft, using rats. METHODS: (Experiment I) Rats were divided into the following four groups: HBO (-), HBO-1D (day), HBO-3D, and HBO-5D. Samples were taken after the completion of HBO pretreatment, and the following parameters were evaluated: reverse transcription polymerase chain reaction and immunohistochemical staining for HSP 70 and HO-1; biochemical parameters; and liver weight to body weight ratio (Lw/Bw ratio). (Experiment II) Rats were divided into four groups as follows; 70% hepatectomy (Hx), 70% Hx-HBO, 90% Hx, and 90% Hx-HBO group. Samples were taken 12, 24, 48, and 72 hr after hepatectomy and the following parameters were investigated: biochemical analysis; Lw/Bw ratio; PCNA labeling index; and survival. RESULTS: (Experiment I) The expression of HSP70 mRNA was significantly increased in the HBO-3D group compared with the HBO (-) group (P<0.05). HSP70- and HO-1-positive hepatocytes were significantly increased in the HBO-3D group compared with the HBO (-) group (P<0.05). (Experiment II) Transaminases were significantly decreased in both 70% and 90% Hx-HBO groups compared with Hx alone group (P<0.05). The Lw/Bw ratio and PCNA labeling index of the 90% Hx-HBO group were significantly increased compared with the 90% Hx group, 24, 48 and 72 hr after hepatectomy (P<0.05). The survival rate in the 90% Hx-HBO group was significantly higher than that in the 90% Hx group (P=0.01). CONCLUSIONS: HBO pretreatment had beneficial effects in a massive hepatectomy model in rats via the induction of HSP70 and HO-1.