A patient who underwent conversion surgery after atezolizumab plus bevacizumab for hepatocellular carcinoma with portal vein thrombosis and perihepatic lymph node metastases achieved a pathological complete response.

Here, we present a patient with hepatocellular carcinoma complicated by tumor thrombosis into the main portal trunk and perihepatic lymph node metastases who was treated with atezolizumab plus bevacizumab. Shrinkage of the main tumor, portal vein thrombosis, and lymph node metastases were achieved; therefore, hepatectomy with lymphadenectomy could be performed. Final pathology indicated a complete pathological response in the main tumor, portal vein thrombosis, and perihepatic lymph nodes. The patient is currently alive with no evidence of recurrence on radiological assessment at 3 months after surgery.

Preoperative diagnosis of adhesion severity between the abdominal wall and intestinal tract with novel abdominal ultrasound methodology to enhance surgical safety.

BACKGROUND: Adhesions between the abdominal wall and intestinal tract from previous surgeries can complicate reoperations; however, predicting the extent of adhesions preoperatively is difficult. This study aimed to develop a straightforward approach for predicting adhesion severity using a novel abdominal ultrasound technique that quantifies the displacement of motion vectors of two organs to enhance surgical safety. The efficacy of this methodology was assessed experimentally and clinically. METHODS: Using Aplio500T, a system we developed, we measured the displacement of the upper peritoneum and intestinal tract as a vector difference and computed the motion difference ratio. Twenty-five rats were randomized into surgery and nonsurgery groups. The motion difference ratio was assessed 7 days after laparotomy to classify adhesions. In a clinical trial, 51 patients undergoing hepatobiliary pancreatic surgery were evaluated for the motion difference ratio within 3 days preoperatively. Intraoperatively, adhesion severity was rated and compared with the motion difference ratio. A receiver operating characteristic curve was used to appraise the diagnostic value of the motion difference ratio. RESULTS: In the animal experiment, the adhesion group exhibited a significantly higher motion difference ratio than the no-adhesion group (0.006 ± 0.141 vs 0.435 ± 0.220, P < .001). In the clinical trial, the no-adhesion or no-laparotomy group had a motion difference ratio of 0.128 ± 0.074; mild-adhesion group, 0.143 ± 0.170; moderate-adhesion group, 0.326 ± 0.153; and high-adhesion group, 0.427 ± 0.152. The motion difference ratio receiver operating characteristic curve to diagnose the adhesion level (≥moderate) was 0.938, indicating its high diagnostic value (cut-off 0.204). CONCLUSION: This methodology may preoperatively predict moderate-to-high adhesions.

Surgical Intervention After Lenvatinib Treatment in Patients With Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: The survival and prognostic factors in patients with advanced hepatocellular carcinoma (HCC) who underwent surgical intervention after lenvatinib treatment is not well-understood. PATIENTS AND METHODS: Seventy-six patients with advanced HCC who had lenvatinib treatment were retrospectively analyzed. RESULTS: Of 70 patients who were treated with lenvatinib, 14 patients underwent surgical intervention after lenvatinib treatment for 4-28 weeks. Progression-free survival (PFS) was significantly longer in patients who underwent surgical intervention than in patients with non-surgical treatment (median, 8.6 vs. 5.1 months, p=0.019). Non-significantly longer overall survival (OS) was also observed in patients with surgical intervention compared to patients with non-surgical treatment (median, unreached vs. 21.0 months, p=0.206). In patients who underwent surgical intervention, two patients had a partial response, and 12 had stable disease according to RECIST ver. 1.1 criteria. The serum alpha-fetoprotein (AFP) level was significantly lower after lenvatinib treatment than before lenvatinib treatment (median, 19.2 vs. 196.5 ng/ml, p=0.0081). Eleven patients underwent curative surgery with a 14% major postoperative complication (Clavien-Dindo ≥IIIa) rate. Patients who exhibited decreases in AFP levels or maintained AFP levels within the normal range during lenvatinib treatment had significantly longer PFS (median, 8.6 vs. 3.0 months, p=0.0009) and OS (median, unreached vs. 12.4 months, p=0.012) compared to those with persistently elevated AFP levels beyond the normal range. CONCLUSION: Surgical intervention after lenvatinib treatment for advanced HCC was associated with longer PFS. Patients exhibiting decreased AFP levels or maintaining AFP levels within the normal limit may be suitable candidates for surgical intervention after lenvatinib treatment for advanced HCC.

Liver stiffness measured by virtual touch quantification predicts the occurrence of posthepatectomy refractory ascites in patients with hepatocellular carcinoma.

PURPOSE: This study assessed the significance of measuring liver stiffness using virtual touch quantification before hepatectomy to predict posthepatectomy refractory ascites. METHODS: A total of 267 patients with hepatocellular carcinoma who underwent hepatectomy were prospectively analyzed. Liver stiffness was defined as the median value of the virtual touch quantification (Vs; m/s) by acoustic radio-force-impulse-based virtual touch. RESULTS: A multivariate analysis showed that Vs and the aspartate aminotransferase-to-platelet ratio index were independent risk factors for postoperative refractory ascites (odds ratio = 3.27 and 3.08, respectively). The cutoff value for Vs was 1.52 m/s (sensitivity: 59.5%, specificity: 88.6%) as determined by the analysis of the receiver-operating characteristic curve, and the area under the receiver-operating characteristic curve was 0.79. The cutoff value for the aspartate aminotransferase-to-platelet ratio was 0.952 (sensitivity: 65.5%, specificity: 82.9%), and the area under the receiver-operating characteristic curve was 0.75. CONCLUSIONS: Vs is an independent risk factor for refractory ascites after hepatectomy. The measurement of liver stiffness by virtual touch quantification before hepatectomy can help estimate the risk of postoperative refractory ascites. Nonsurgical treatments should be considered for the management of patients who are at high risk for refractory ascites.

Enhanced patterns on intraoperative contrast-enhanced ultrasonography predict outcomes after curative liver resection in patients with hepatocellular carcinoma.

PURPOSE: This study aimed to clarify what hepatocellular carcinoma (HCC) phenotype, as categorized by intraoperative contrast-enhanced ultrasonography (CEUS), showed a high risk of recurrence after hepatic resection. METHODS: Patients who underwent initial curative hepatectomy with intraoperative CEUS for a single HCC nodule were retrospectively assigned to three patterns of fine (FI), vascular (VA), and irregular (IR) according to the maximum intensity projection pattern based on intraoperative CEUS. Staining was performed for Ki-67, pyruvate kinase type M2 (PKM2), and vascular endothelial growth factor (VEGF) to assess the tumor proliferative activity, tumor glucose metabolism, and angiogenesis, respectively. RESULTS: Of 116 patients, 18, 50, and 48 were assigned to the FI, VA and IR patterns, respectively. IR patients demonstrated a significantly worse prognosis for both the recurrence-free survival (RFS) and overall survival (OS) (P = 0.0002, 0.0262, respectively) than did patients with other patterns. A multivariate analysis revealed an IR pattern in intraoperative CEUS to be an independent predictive factor for a poor RFS, and major hepatectomy and an IR pattern were independent predictive factors for a poor OS. An IR pattern was closely related to the tumor size (≥ 3.3 cm) and poor histological differentiation and showed a high Ki-67 index, low VEGF expression, and high PKM2 expression. CONCLUSION: IR-pattern HCCs as classified by intraoperative CEUS may be associated with a higher risk of recurrence and worse outcomes in HCC patients after hepatic resection than other patterns.

Hepatectomy using a novel cart-based indocyanine green fluorescence imaging system.

Indocyanine green (ICG) fluorescence has been used effectively in imaging for locating hepatic tumors and evaluating hepatic segmentation. We report our initial experience of performing hepatic resection using the novel cart-based ICG fluorescence device LIGHTVISION®. This device has several promising features, including the fact that there is no need to switch off the room light, it has hands-free operability, and it can be located away from the workspace to facilitate a good field of vision. We used the LIGHTVISION® for 15 patients and detected 59 nodules (86.8%) in a total of 68 tumors in the resected specimens during surgery. The LIGHTVISION® was used to identify the hepatic segments in ten patients, and the boundaries of the segment were clearly visualized on the liver surface on fluorescent images in all patients. All tumors were resected with surgical margins. Thus, the LIGHTVISION® appears to be very useful for navigation in liver surgery.

Difficulty Achieving a Preoperative Diagnosis of IgG4-Related Sclerosing Cholangitis.

A 75-year-old male was admitted to our hospital because of bile duct stenosis. He had no medical history of autoimmune disease. The level of tumor markers, serum IgG, and IgG4 were within normal ranges. Computed tomography showed perihilar and distal bile duct stenosis and wall thickening without swelling or abnormal enhancement of the pancreas. Endoscopic retrograde cholangiopancreatography showed perihilar and distal bile duct stenosis. A biopsy and cytology from the distal bile duct stenosis suggested adenocarcinoma, and cytology from the perihilar bile duct also suggested adenocarcinoma. A preoperative diagnosis of perihilar and distal bile duct cancer was made, and the patient underwent left hepatectomy and pancreaticoduodenectomy. Resected specimens showed wall thickening in the perihilar and distal bile duct; however, tumors were unclear. A histopathological examination revealed lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis in the perihilar and distal bile ducts. Immunohistochemistry revealed diffuse infiltration of IgG4-positive plasma cells in the perihilar and distal bile ducts. Lymphoplasmacytic infiltration, inflammatory change, storiform fibrosis, and obliterative phlebitis were shown in the pancreas. A final diagnosis of IgG4-related sclerosing cholangitis (IgG4-SC) with autoimmune pancreatitis was made. We herein report a case in which a preoperative diagnosis of IgG4-SC was difficult due to normal serum IgG4 levels and no obvious pancreatic lesion.

[A Case of Malignant Lymphoma of the Jejunum That Developed Stenosis and Perforation after a Complete Response to Chemotherapy].

A 57-year-old woman was admitted owing to epigastric pain.Abdominal computed tomography demonstrated a tumor in the origin of the jejunum.After an endoscopic biopsy, we diagnosed diffuse large B-cell lymphoma.We treated her with CHOP chemotherapy because pancreaticoduodenectomy is highly invasive.After 1 course of chemotherapy, the tumor was reduced.However, she developed a jejunal stenosis; therefore, we performed laparoscopic gastrojejunostomy.Furthermore, she developed perforated peritonitis on the sixth day after the surgery, and therefore, an emergency partial jejunum resection was performed.Histopathologically, viable lymphoma cells were not found in the resected intestine.She had a complete response 10 months after the surgery.Chemotherapy may cause intestinal stenosis and perforation requiring surgery; therefore, decisions about surgical procedures must be made carefully.

Multi-institutional phase II study on the feasibility of liver resection following preoperative mFOLFOX6 therapy for resectable liver metastases from colorectal cancers.

BACKGROUND: Although liver resection combined with preoperative chemotherapy is expected to improve outcomes of patients with resectable colorectal liver metastasis (CRLM), there is as yet insufficient clinical evidence supporting the efficacy of preoperative systemic chemotherapy. The aim of this phase II study was to assess the feasibility and efficacy of preoperative FOLFOX systemic chemotherapy for patients with initially resectable CRLM. METHODS: A prospective multi-institutional phase II study was conducted to evaluate the feasibility and efficacy of preoperative chemotherapy for resectable CRLM (ClinicalTrials.gov identifier number NCT00594529). Patients were scheduled to receive 6 cycles of mFOLFOX6 therapy before liver surgery. The primary endpoint was the macroscopic curative resection rate. RESULTS: A total of 30 patients were included in this study. Two patients who were diagnosed with hepatocellular and intrahepatic cholangiocellular carcinoma based on pathology were excluded from the analysis. More than half of the patients (57 %) had solitary liver metastasis. The completion rate of preoperative chemotherapy was 64.3 % and the response rate was 53.6 %. Two patients were unable to proceed to liver resections due to disease progression and severe postoperative complications following primary tumor resection. Macroscopic curative resection was obtained in 89.3 % of eligible patients. Postoperative mortality and severe complication (≥Gr. 3) rates were 0 and 11 %, respectively. The 3-year overall and progression-free survival rates were 81.9 and 47.4 %, respectively. CONCLUSION: Our phase II study demonstrated the feasibility of liver resection combined with preoperative mFOLFOX6 therapy in patients with initially resectable CRLM. Further study is warranted to address the oncological effects of preoperative chemotherapy.

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.

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.

P-glycoprotein expression affects 18F-fluorodeoxyglucose accumulation in hepatocellular carcinoma in vivo and in vitro.

18F-fluorodeoxyglucose (FDG) uptake in hepatocellular carcinoma (HCC) is associated with tumor differentiation and expression of P-glycoprotein (P-gp), a drug efflux pump that plays an important role in chemoresistance. The aim of the study was to clarify the factors that affects FDG uptake in HCC in vivo and in vitro. The standardized uptake value (SUV) and the tumor to non-tumor SUV ratio (TNR) for FDG uptake in HCC in vivo was determined by FDG-PET in 28 patients. Expression levels of glucose transporter-1 (GLUT-1), GLUT-2 and type II hexokinase (HK-II) were examined immunohistochemically in resected specimens. The glucose-6-phosphatase (G-6-Pase) activity was determined in tissue homogenates. In vitro, PLC/PRF/5 cells and doxorubicin-resistant PLC/DOR cells were used to examine the effect of P-gp on FDG uptake. The effects of two P-gp inhibitors, verapamil and cepharanthine, on accumulation of FDG were also examined. in vivo, GLUT-1 expression was low in HCCs, but was significantly higher in poorly differentiated HCCs than in moderately differentiated HCCs (P=0.043) and was positively correlated with SUV (r=0.75, P<0.0001) and TNR (r=0.7, P<0.0001). GLUT-2 and HK-II expression and G-6-Pase activity were not correlated with tumor differentiation, SUV or TNR. P-gp was over-expressed in PLC/DOR cells, and accumulation of FDG was significantly higher in PLC/PRF/5 cells than in PLC/DOR cells (P=0.04). Verapamil and cepharanthine restored FDG uptake in PLC/DOR cells, but not in PLC/PRF/5 cells. Collectively, our results show that FDG uptake in HCC is weakly correlated with GLUT-1 expression, and that FDG could be a substrate of P-gp, which may act as an efflux pump to reduce FDG accumulation.

[Case report of gastric cancer patient who suffered life-threatening adverse events including severe myelosuppression during neoadjuvant chemotherapy with S-1 and CDDP combination].

Neoadjuvant chemotherapy has been a recent focus in the treatment for advanced gastric cancer. Although the preoperative chemotherapeutic regimen of S-1 and CDDP is regarded as effective, safe and well tolerable according to previous clinical study, we experienced a 74-year-old woman who suffered from life-threatening adverse events including severe myelosuppression during the neoadjuvant chemotherapy. Although the patient did not experience any severe adverse events during the first course of treatment, on day 18 of the second course of chemotherapy, she was hospitalized because of anorexia and severe dehydration, leading to following grade 4 leukopenia/neutropenia, bacteremia, and disseminated intravascular coagulation (DIC). She finally recovered from the life-threatening adverse events with intensive therapy and eventually had a distal gastrectomy. Clinicians need to be alert especially to renal dysfunction that induces severe myelosuppression during chemotherapy with S-1, which contains 5-chloro-2,4-dihydroxypyridine (CDHP), a renal excretory inhibitor of dihydropyrimidine dehydrogenase (DPD).

Fluorine-18 fluorodeoxyglucose positron emission tomography predicts lymph node metastasis, P-glycoprotein expression, and recurrence after resection in mass-forming intrahepatic cholangiocarcinoma.

BACKGROUND: Patients with intrahepatic cholangiocarcinoma (ICC) have a poor prognosis, and lymph node metastasis is an important prognostic factor. In this study, we investigated the usefulness of fluorodeoxyglucose positron emission tomography (FDG-PET) as a marker for lymph node metastasis, P-glycoprotein (P-gp) expression, and recurrence in ICC. METHODS: The subjects were 35 patients who underwent FDG-PET. Detectability of lymph node metastasis using FDG-PET was compared with that using computed tomography (CT) or magnetic resonance imaging (MRI). In patients who underwent resection, expression of P-gp was examined immunohistochemically, and the relationship between P-gp expression and the standardized uptake value (SUV) in FDG-PET was investigated. Survival rates were analyzed using clinical and pathologic factors. RESULTS: Of the 35 patients, 5 did not undergo surgery based on FDG-PET findings (2 with extrahepatic metastasis, and 3 with para-aortic lymph node metastasis) and 3 underwent laparotomy only (2 with peritoneal dissemination and 1 with para-aortic lymph node metastasis). The diagnostic accuracies of FDG-PET, CT, and MRI for detection of lymph node metastasis were 86%, 68%, and 57%, the sensitivities were 43%, 43% and 43%, and the specificities were 100%, 76%, and 64%, respectively. A negative correlation was found between SUV and P-gp expression (P = .002; r = -0.62). The disease-free survival rates in the high SUV group (>or=8.5) were significantly lower than in the low SUV group (<8.5; P = .04), and a high SUV was an independent predictor of postoperative recurrence in multivariate analysis (risk ratio, 1.3; P = .03). CONCLUSIONS: FDG-PET is useful for prediction of lymph node metastasis, P-gp expression and recurrence in ICC.

Influence of coexisting cirrhosis on outcomes after partial hepatic resection for hepatocellular carcinoma fulfilling the Milan criteria: an analysis of 293 patients.

BACKGROUND: For patients with liver cirrhosis and hepatocellular carcinoma (HCC) satisfying the Milan criteria (single tumor < or =5 cm or 2 or 3 tumors < or =3 cm), orthotopic liver transplantation (OLT) is an effective treatment. Nevertheless, it remains controversial whether OLT is the best treatment strategy for patients with resectable HCC. METHODS: This study included 293 HCC patients (both with and without cirrhosis) oncologically satisfying the Milan criteria who underwent primary and curative liver resection between 1990 and 2003. RESULTS: There were 127 noncirrhotic, 129 Child-Pugh A cirrhotic, and 37 Child-Pugh B cirrhotic patients. Five-year survival rates in each population were 81%, 54%, and 28%, respectively. Coexisting cirrhosis, Child-Pugh classification, alpha-fetoprotein value, tumor burden, and vascular invasion by the tumor were identified as significant prognostic factors. Among these factors, coexisting cirrhosis was the most crucial variable by multivariate analysis. During the initial 3 postoperative years, yearly tumor recurrence rate was 22% in cirrhotic patients and 15% in noncirrhotic patients. In cirrhotic patients, the recurrence rate did not decrease even after three years of tumor-free survival post-resection, whereas in noncirrhotic patients the recurrence rate decreased to 9%. Cirrhosis was associated with a higher probability of recurrence exceeding the Milan criteria. CONCLUSIONS: Hepatic resection offers an acceptable survival result for HCC patients fulfilling the Milan criteria. Coexisting cirrhosis is associated with higher mortality and recurrence rate, possibly due to multicentric carcinogenesis which limits the efficacy of hepatic resection.

Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma.

PURPOSE: To investigate the diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for prediction of tumor differentiation, P-glycoprotein (P-gp) expression, and outcome in hepatocellular carcinoma (HCC) patients. EXPERIMENTAL DESIGN: Seventy HCC patients who underwent curative resection were prospectively enrolled in the study. FDG-PET was done 2 weeks preoperatively, and the standardized uptake value (SUV) and the tumor to nontumor SUV ratio (TNR) were calculated from FDG uptake. Tumor differentiation and P-gp expression were examined with H&E and immunohistochemical staining, respectively. RESULTS: SUV and TNR were significantly higher in poorly differentiated HCCs than in well-differentiated (P = 0.001 and 0.002) and moderately differentiated HCCs (P < 0.0001 and P < 0.0001). The percentage P-gp-positive area was significantly higher in well-differentiated HCCs than in poorly differentiated (P < 0.0001) and moderately differentiated HCCs (P = 0.0001). Inverse correlations were found between SUV and P-gp expression (r = -0.44; P < 0.0001) and between TNR and P-gp expression (r = -0.47; P = 0.01). Forty-three (61.4%) patients had postoperative recurrence. The overall and disease-free survival rates in the high TNR (> or =2.0) group were significantly lower than in the low TNR (<2.0) group (P = 0.0001 and 0.0002). In multivariate analysis, a high alpha-fetoprotein level (risk ratio, 5.46; P = 0.003; risk ratio, 8.78; P = 0.006) and high TNR (risk ratio, 1.3; P = 0.03; risk ratio, 1.6; P = 0.02) were independent predictors of postoperative recurrence and overall survival. CONCLUSIONS: The results suggest that preoperative FDG-PET reflects tumor differentiation and P-gp expression and may be a good predictor of outcome in HCC.

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.

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.

[Postoperative adjuvant immunochemotherapy using Lentinan for advanced gastric carcinoma patients with metastasis in the regional lymph nodes and serosal invasion].

Six patients with gastric cancer, stage IIIA to IV, received intraabdominal cisplatin (CDDP) at laporotomy. This was followed by postoperative intravenous infusion of mitomycin C (MMC), CDDP or fluorouracil (5-FU). When these patients recovered to the extent that permitted oral medication, an immunochemotherapeutic regimen containing either oral UFT (uracil and tegafur) or 5'-deoxy-5-fluorouridine (5'-DFUR), plus intravenous Lentinan (LNT) was administered for a period ranging from one and a half to two years. This postoperative immunochemotherapy was successful in all 6 patients. No relapse has been observed in any of them for at least 4 years. These findings indicate that the chemotherapeutic strategy of administering intraabdominal CDDP immediately after surgery, followed by postoperative immunochemotherapy with pyrimidine-fluoride products plus Lentinan on an outpatient basis may be useful in the treatment of T3 or T4 gastric carcinoma with metastasis in the regional lymph nodes.