[A case of large cell neuroendocrine carcinoma of the stomach with liver metastasis effectively treated with S-1 and CDDP combination therapy].

A 73-year-old man was referred to our hospital because of appetite loss and weight loss in January 2009. Endoscopy showed an advanced type II gastric tumor at the middle of the gastric wall, and computed tomography showed multiple liver metastases. Immunohistological examination confirmed a diagnosis of large cell neuroendocrine carcinoma which was chromogranin A(+), CD56(+), and synaptophysin(+). Oral administration of S-1(100mg/body)was given 5 days on and 2 days off, while cisplatin(CDDP 40 mg/body)was administered intravenously once every 2 weeks. The patient achieved a partial response(PR), and no serious adverse effects were observed. This case suggests that S-1/CDDP chemotherapy may be an effective treatment in patients with large cell neuroendocrine carcinoma of the stomach.

Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts.

Knowledge of tumor-stromal interactions is essential for understanding tumor development. We focused on the interaction between cholangiocarcinoma and cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma and reported their positive interaction in vitro and in vivo. The aim of this study is to identify the key protein involved in the interaction between cholangiocarcinoma cells and CAFs and its role on cholangiocarcinoma progression. Using the conditioning medium from cholangiocarcinoma cells, hepatic stellate cells and coculture of them, Protein-Chip analysis with SELDI-TOF-MS showed that the peak of an 8,360-Da protein remarkably increased in the coculture medium. This protein was identified as CXCL5/ENA78, epithelial cell-derived neutrophil-activating peptide-78, by q-TOF/MS/MS analysis. Two cholangiocarcinoma cell lines, HuCCT1 and RBE, produced CXCL5 that promoted their invasion and migration in an autocrine fashion. These effects of CXCL5 significantly decreased by inhibition of CXC-receptor 2, which is the receptor for CXCL5. In addition, IL-1ß produced by hepatic stellate cells induced the expression of CXCL5 in cholangiocarcinoma cells. In human tissue samples, a significant correlation was observed between CAFs and CXCL5 produced by cholangiocarcinoma cells in intrahepatic cholangiocarcinoma (p = 0.0044). Furthermore, the high-CXCL5-expression group exhibited poor overall survival after curative hepatic resection (p = 0.027). The presence of tumor-infiltrating neutrophils expressing CD66b was associated with CXCL5 expression in tumor cells (p < 0.0001). These data suggest that CXCL5 is important for the interaction between cholangiocarcinoma and CAFs, and inhibition of tumor-stromal interactions may be a useful therapeutic approach for cholangiocarcinoma.

Hybrid ablation using percutaneous and endoscopic approach for multi-nodular hepatocellular carcinomas.

BACKGROUND/AIMS: To investigate the efficacy and the safety of a hybrid ablation combining a percutaneous and endoscopic approach for multi-nodular hepatocellular carcinomas. METHODOLOGY: Hybrid ablation consists of a percutaneous approach for deep-sited tumors and an endoscopic approach for superficial ones. Between January 1991 and December 2007, forty eight patients with 139 nodules were treated with hybrid ablation. The perioperative clinical data and prognosis of the hybrid approach group were compared with 15 patients with superficial and deep-sited multinodular HCCs treated by the pure endoscopic ablation. RESULTS: With regard to the deep-site of the liver tumors, the complete disappearance of tumor enhancement was observed in 76 of 77 tumors (98.7%) in the hybrid ablation group and 15 of 18 tumors (83.3%) in the pure endoscopic ablation group (p=0.02). The mean operation time (236.5min), the mean amount of intraoperative bleeding (20.3g), the median days of postoperative hospital stay (14 days), major complication rates (10.4%) and the 5-year overall survival (42%) in the hybrid ablation group were similar to the pure endoscopic group. CONCLUSIONS: Hybrid ablation is a clinically useful treatment for multi-nodular hepatocellular carcinomas located in both the superficial and deep-site of the liver.

Amount of operative blood loss affects the long-term outcome after liver resection for hepatocellular carcinoma.

BACKGROUND/AIMS: Numerous prognostic factors for HCC have been reported. Few literatures have reported clinical significance of amount of intraoperative blood loss (ABL) for the outcome after surgery for HCC. The aim of this study is to analyze the significance of ABL for outcome after surgery for HCC. METHODOLOGY: A total of 301 patients who underwent liver resection for HCC between January 1998 and June 2007 were included. Clinical and surgical characteristics were collected and prognostic factors were identified using univariate and multivariate analysis. RESULTS: Impaired liver function (liver damage B), large tumor (>36mm), multiple tumors, existence of macroscopic vessel invasion, large ABL (=700mL) and replacement of red blood cells were identified as independent prognostic factors for overall survival (OS). For disease free survival (DFS), old age (>66), male gender, impaired liver function, large tumor, multiple tumors, existence of macroscopic vessel invasion and large ABL were extracted. Limited to the patients without blood transfusion, large ABL is associated with poor OS and DFS. CONCLUSIONS: Large ABL could result in poor OS and DFS after liver resection of HCC in patients without blood transfusion. Surgeons have to make the best effort to reduce ABL.

Liver hanging maneuver decreases blood loss and operative time in a right-side hepatectomy.

BACKGROUND/AIMS: To clarify the clinical benefits of the maneuver in right-side hepatectomy. METHODOLOGY: Eighty-one patients with liver tumor (54 hepatocellular carcinoma, 17 metastatic liver tumor and 10 other tumors) treated with a right-side hepatectomy were prospectively analyzed. The patients were divided into the following three groups: a conventional approach (group A, n=21); liver dissection under the hanging maneuver after liver mobilization (group B, n=19) and liver dissection under the hanging maneuver prior to liver mobilization (group C, n=41). RESULTS: The liver hanging maneuver was safely performed in all the patients in groups B and C. Tumor size had a significantly positive correlation with the amount of intraoperative blood loss (R=0.52, p<0.05) in group A only. The patients in groups B and C had a significantly lower intraoperative use of blood loss (both p<0.01), operation time (p<0.05 and p<0.01) and the frequency of blood product (both p<0.05), in comparison to group A, respectively. The postoperative morbidity and the mortality rates were similar in the three groups. CONCLUSIONS: Liver hanging maneuver is a safe procedure, which can decrease intraoperative blood loss and administration of blood product in right-side hepatectomy.

Hepatic resection using a liver-hanging maneuver and Glissonean pedicle transection for hepatocellular carcinoma in a patient with situs inversus totalis: report of a case.

Situs inversus totalis is a rare congenital anomaly in which the major abdominal organs are located as a mirror image of their normal positions. This poses much difficulty for surgeons. We describe how we performed the liver-hanging maneuver (LHM) for hepatocellular carcinoma (HCC) in a 59-year-old man with situs inversus totalis, to resolve the difficulty of the mirror-image location of his liver. The HCC was located in the right lateral sector. Although segmentectomy of segment 7 would normally be considered minimal for a curative treatment of HCC, this was relatively complicated in this patient. Thus, we performed an extended right lateral sectionectomy using the LHM to achieve a simple transection. The hepatic hilum was dissected using the Glissonean pedicle transection method. The operation time and intraoperative blood loss were 6 h 45 min and 471 ml, respectively. No blood product transfusion was required. The LHM and the hilar Glissonean pedicle approach proved effective for resolving the difficulties of performing surgery in a mirror image for HCC in a patient with situs inversus totalis.

Hepatic stellate cells accelerate the malignant behavior of cholangiocarcinoma cells.

BACKGROUND: Although tumor-stromal interaction has been discussed, the role of hepatic stellate (HS) cells against cancer, especially cholangiocarcinoma (CC), has not been clarified. The aim of this study is to investigate the effect of HS cells on CC cell progression in vitro and in vivo. METHODS: The effects of CC conditioned medium (CC-CM) on activation and proliferation of HS cells (LI90 and LX-2), the influences of HS cell CM (HS-CM) on proliferation and invasion of CC cells (HuCCT-1 and RBE), and the effects of their interaction on HUVEC tube formation were assessed using each CM. The effect of HS cells on tumor growth was examined in vivo by subcutaneous co-injection. Cytokine array was performed to assess the secreted proteins induced by their coculture. RESULTS: CC-CM activated HS cells and increased their proliferation. HS-CM dose-dependently increased CC cell proliferation and invasion. Chemotherapy of CC cells was less effective when treated with HS-CM. HS-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. The indirect interaction of CC and HS cells promotes tube formation of human umbilical venous endothelial cells. Subcutaneous co-injection of tumor cells with HS cells in nude mouse resulted in increased tumor size. Several proteins were found in the culture medium induced by their coculture, thought to be key proteins which regulated tumor-stromal interaction. CONCLUSIONS: This study indicates that HS cells play an important role in accelerating cholangiocarcinoma progression and may be a therapeutic target in cholangiocarcinoma.

Preoperative portal vein embolization (PVE) for patients with hepatocellular carcinoma can improve resectability and may improve disease-free survival.

BACKGROUND: The aim of this study is to identify the efficacy of portal vein embolization (PVE) before right hepatectomy in patients with hepatocellular carcinoma (HCC) with regard to hepatic function, surgical stress, and survival benefit. METHODS: Fifty-five patients with HCC underwent right hepatectomy between 1999 and 2009. Preoperative PVE was performed in 19 patients (PVE group) and was not applied in 36 patients (non-PVE group). Changes in liver function and volume were investigated in PVE group. Short and long clinical outcomes after the surgeries were compared between the two groups. RESULTS: The percentage of future liver remnant (%FLR) before PVE was significantly lower (37.8%) in PVE group than in non-PVE group (58.1%) but increased remarkably after PVE (from 37.8% to 55.0%, P < 0.0001). Cumulative disease-free survival and overall survival rates in PVE group were significantly superior to those in non-PVE group (P = 0.010 and 0.049, respectively). Although surgical stress estimated by E-PASS scores and CRP value was not different between the groups, the postoperative value of PT on postoperative day 3 in PVE group was significantly better than in non-PVE group. CONCLUSIONS: Preoperative PVE improves resectability and may improve disease-free survival for patients with HCC requiring right hepatectomy.

Pigmented hepatocellular adenoma: report of a case.

Hepatocellular adenoma is a rare, benign neoplasm that is related to the use of contraceptives or androgenic-anabolic steroids. A 51-year-old man with no history of steroid use was found to have a liver tumor. Plain computed tomography showed a high-density tumor that was enhanced in the arterial phase, and the enhancement was prolonged in the delayed phase. Magnetic resonance imaging showed that the tumor was hyperintense on in- and opposed-phase T1-weighted gradient recalled echo images and hyperintense on T1-weighted spin echo images. A partial hepatic resection was performed. A histological examination revealed normal hepatocyte-like tumor cells, composed of abundant dark brown granules of Dubin-Johnson-like pigment, which stained positively for Masson-Fontana stain. The tumor was diagnosed to be a very rare hepatocellular adenoma with the deposition of Dubin-Johnson-like pigment.

Primary neuroendocrine tumor in the liver treated by hepatectomy: report of a case.

A 49-year-old woman was admitted to our hospital under suspicion of an enlarging hepatic tumor, which had been previously diagnosed to be a cavernous hemangioma. Computed tomography revealed three enhanced tumors, one measuring 15 cm in diameter within the right lobe of the liver and two intrahepatic metastases in Couinaud's hepatic segments 3 and 5. We diagnosed the patient to have primary liver cancer, and suspected a combined liver tumor preoperatively. We performed a right trisectionectomy with radiofrequency ablation of the intrahepatic metastasis in S3. According to the immunohistochemical findings of the resected specimen and the findings of postoperative imaging studies, the tumor was diagnosed to be a primary neuroendocrine tumor in the liver. The patient is presently alive without recurrence at 33 months after the operation.

Preoperative tumor marker doubling time is a useful predictor of recurrence and prognosis after hepatic resection of hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: It is important to identify prognostic factors in patients with hepatocellular carcinoma (HCC) before hepatectomy. No previous studies have addressed the predictive efficacy of the preoperative doubling times of alpha-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKA-II). METHODS: A total of 210 HCC patients who underwent a hepatic resection between 1998 and 2006 were prospectively evaluated. Serum AFP and PIVKA-II levels were measured at least twice before surgery to calculate the doubling times. Nineteen clinical factors that can be examined preoperatively, including the doubling times of AFP and PIVKA-II were investigated to identify prognostic factors for disease-free and overall survival after hepatectomy. RESULTS: There was no relationship between preoperative levels and doubling times of AFP and PIVKA-II. In a multivariate analysis, patients with a doubling time of AFP ≤30 days and PIVKA-II ≤16 days showed a significantly worse disease-free (P = 0.02, P = 0.03, respectively) and overall survival (P < 0.0001, P = 0.03, respectively). CONCLUSIONS: In HCC patients, the doubling times of preoperative serum AFP or PIVKA-II levels are useful tools to predict early postoperative recurrence and a poor prognosis.

[Utility of arterial infusion chemotherapy and radiation therapy for the pelvic local recurrence of rectal cancer].

We treated 3 cases of local pelvic recurrence due to a rectal cancer post operation by arterial infusion chemotherapy with 5-FU and levofolinate calcium and also by radiation therapy. The result of imaging analysis showed that a recurrent tumor was decreased effectively in 2 cases by chemo-radiation therapy. We confirmed the cancer pain and tumor bleeding were gone for all of the 3 cases. As for side effects of arterial infusion chemotherapy and radiation therapy, we confirmed a paralysis of the pelvic nerve in 1 case and dermatopathy in 1 case. This therapy seemed to be an effective treatment for elderly patients with inoperable cases.

Assessment of safety in hepatic resection for hepatocellular carcinoma focusing on indirect hyperbilirubinemia.

BACKGROUND/PURPOSE: The indications for hepatic resection for hepatocellular carcinoma (HCC) patients with total bilirubin (T-Bil) equal to or higher than 1.2 mg/dl remain controversial. The aim of this study was to investigate the safety of hepatic resection for HCC patients who showed high T-Bil (≥1.2 mg/dl) with low direct bilirubin (D-Bil ≤ 0.5 mg/dl). METHODS: Thirty-four HCC patients showing high T-Bil with low D-Bil were treated with mono- to tri-segmentectomy between January 2000 and December 2010. The perioperative clinical parameters and prognosis of the high T-Bil/low D-Bil patients were compared with those of 253 HCC patients showing normal T-Bil. In addition, complication rates of the patients with high T-Bil/high D-Bil (n = 4) were analyzed. RESULTS: The prothrombin time activity, indocyanine green clearance test, asialo-scintigraphy, and platelet count were similar in the two groups. The mean serum albumin in high T-Bil/low D-Bil patients was significantly higher than that of normal T-Bil patients (4.2 ± 0.5 vs. 4.0 ± 0.4 g/dl, P = 0.004). There were no significant differences in operation time, intraoperative bleeding, red cell concentrate transfusion rate, postoperative complication rate, and disease-free and overall survivals between the two groups. Postoperative hyperbilirubinemia (T-Bil >5 mg/dl) with ascites was observed in one of four high T-Bil/high D-Bil patients (25 %). CONCLUSIONS: Mono- to tri-segmentectomy can be performed in patients with low D-Bil (≤0.5 mg/dl) similarly to patients with low T-Bil (<1.2 mg/dl), even in HCC patients showing high T-Bil (≥1.2 mg/dl).

Liver functional volumetry for portal vein embolization using a newly developed 99mTc-galactosyl human serum albumin scintigraphy SPECT-computed tomography fusion system.

BACKGROUND: We developed a new combined (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy single-photon emission computed tomography (SPECT)/CT system to evaluate the changes in functional liver volume with portal vein embolization (PVE). METHODS: We performed a prospective analysis of 25 patients treated with right PVE, and evaluated their functional liver volume perioperatively with a (99m)Tc-GSA scintigraphy SPECT-CT fusion system. The percentage of the non-tumorous remnant liver volume (%LV) and the percentage of functional remnant liver volume (%FLV) were estimated by using the following calculations: (future remnant volume - tumor volume)/(total liver volume - tumor volume) and functional future remnant liver volume/functional total liver volume, respectively. RESULTS: Before PVE, the correlation was strongly significant between %LV and %FLV of the non-embolized liver, and the data were nearly equal (the regression coefficient was 1.005, P < 0.0001). In contrast, after PVE, there was a significant correlation between %LV and %FLV (P < 0.0001), but the regression coefficient was 1.192. The % LV increased significantly, from 38.1 to 52.0%, and the increment was 13.9% (P < 0.0005). The %FLV was also increased significantly, from 36.6 to 58.0%, and the increment was 21.4% (P < 0.0001). The increment was 7.5% greater for the %FLV compared to that of the %LV (P < 0.001). CONCLUSIONS: The (99m)Tc-GSA scintigraphy SPECT-CT fusion system can estimate the correct functional liver volume and is useful in comparison with conventional CT volumetry.