Clinical implications and optimal extent of lymphadenectomy for intrahepatic cholangiocarcinoma: A multicenter analysis of the therapeutic index.

Aims: Lymph node metastases (LNM) are associated with lethal prognosis in intrahepatic cholangiocarcinoma (ICC). Lymphadenectomy is crucial for accurate staging and hopes of possible oncological treatment. However, the therapeutic implications and optimal extent of lymphadenectomy remain contentious. Methods: To clarify the prognostic value and optimal extent of lymphadenectomy, the therapeutic index (TI) for each lymph node was analyzed for 279 cases that had undergone lymphadenectomy in a multi-institutional database. Tumor localization was divided into hilar lesions (n = 130), right peripheral lesions (n = 60), and left peripheral lesions (n = 89). In addition, the lymph node station was classified as Level 1 (LV1: hepatoduodenal ligament node), Level 2 (LV2: postpancreatic or common hepatic artery nodes), or Level 3 (LV3: gastrocardiac, left gastric artery, or celiac artery nodes). Results: Lymph node metastases were confirmed in 109 patients (39%). Five-y survival rates were 45.3% for N0 disease, 27.1% for LV1-LNM, 22.9% for LV2-LNM, and 7.3% for LV3-LNM (P < 0.001). LV3-LNM were the most frequent and earliest recurrence outcome, including multisite recurrence, followed by LV2, LV1, and N0 disease. The 5-year TI (5year-TI) for lymphadenectomy was 7.2 for LV1, 5.5 for LV2, and 1.9 for LV3. Regarding tumor location, hilar lesions showed 5-year TI >5.0 in LV1 and LV2, whereas bilateral peripheral lesions showed 5-year TI > 5.0 in LV1. Conclusion: The implications and extent of lymphadenectomy for ICC appear to rely on tumor location. In the peripheral type, the benefit of lymphadenectomy would be limited and dissection beyond LV1 should be avoided, while in the hilar type, lymphadenectomy up to LV2 could be recommended.

Impact of lymph node dissection on clinical outcomes of intrahepatic cholangiocarcinoma: Inverse probability of treatment weighting with survival analysis.

BACKGROUND: Lymph node metastasis (LNM) has been established as a critical risk factor for prognosis in intrahepatic cholangiocarcinoma (ICC). The clinical implications of lymph node dissection (LND) have been debated. This study aimed to clarify the prognostic impact of LND by multicenter retrospective analysis. METHODS: A total of 310 ICC patients who had undergone curative resection between 2000 and 2016 were retrospectively analyzed. The prognostic impact of LND was estimated under an inverse probability of treatment weighting (IPTW) approach using propensity scores. RESULTS: LND was performed for 224 patients (72%), with LNM pathologically confirmed in 90 patients (40%). Prognosis was poorer for patients with LNM (median survival, 16.9 months) than for those without (57.2 months; P < .0001). One-, 3-, and 5-year overall survival rates (OS) were comparable among LND+ (81.6%, 48.0%, and 37.5%, respectively) and LND- groups (81.6%, 55.4%, and 44.6%, respectively). However, advanced tumor, as characterized by larger tumor, multinodular lesions, and serosal invasion, was significantly more frequent in the LND+ group than in the LND- group. After IPTW adjusting for imbalances, 1-, 3-, and 5-year OS were better in the LND+ group (83.5%, 52.2%, and 42.8%, respectively) than in the LND- group (71.9%, 32.4%, and 23.4%, respectively; P = .046). LND thus showed significant prognostic impact (hazard ratio = 0.58, 95%CI = |0.39|-|0.84|, P = .005), especially in hilar ICC. However, peripheral ICC displayed no therapeutic benefit from LND. CONCLUSIONS: LND could have a significant role to play in improving oncologic outcomes. Therapeutic LND should be implemented on the basis of tumor location and tumor advancement.

Preoperative prognostic nutritional index predicts postoperative infectious complications and oncological outcomes after hepatectomy in intrahepatic cholangiocarcinoma.

BACKGROUND: In the surgical treatment of intrahepatic cholangiocarcinoma (ICC), postoperative complications may be predictive of long-term survival. This study aimed to identify an immune-nutritional index (INI) that can be used for preoperative prediction of complications. PATIENTS AND METHODS: Multi-institutional data from 316 patients with ICC who had undergone surgical resection were retrospectively analysed, with a focus on various preoperative INIs. RESULTS: Severe complications (Clavien-Dindo grade III-V) were identified in 66 patients (20.8%), including Grade V complications in 7 patients (2.2%). Comparison of areas under the receiver operating characteristic curve (AUCs) among various INIs identified the prognostic nutritional index (PNI) as offering the highest predictive value for severe complications (AUC = 0.609, cut-off = 50, P = 0.008). Multivariate analysis revealed PNI <  50 (odds ratio [OR] = 2.22, P = 0.013), hilar lesion (OR = 2.46, P = 0.026), and long operation time (OR = 1.003, P = 0.029) as independent risk factors for severe complications. In comparing a high-PNI group (PNI ≥ 50, n = 142) and a low-PNI group (PNI <  50, n = 174), the low-PNI group showed higher rates of both major complications (27% vs. 13.4%; P = 0.003) and infectious complications (14.9% vs. 3.5%; P = 0.0021). Furthermore, median survival time and 1- and 5-year overall survival rates were 34.2 months and 77.4 and 33.8% in the low-PNI group, respectively, and 52.4 months and 89.3 and 47.5% in the high-PNI group, respectively (P = 0.0017). CONCLUSION: Preoperative PNI appears useful as an INI correlating with postoperative severe complications and as a prognostic indicator for ICC.

Prognostic Utility of the Glasgow Prognostic Score for the Long-Term Outcomes After Liver Resection for Intrahepatic Cholangiocarcinoma: A Multi-institutional Study.

OBJECTIVE: The usefulness of the modified Glasgow prognostic score (GPS) as a prognostic tool remains unclear for patients undergoing curative surgery for intrahepatic cholangiocarcinoma (ICC). Therefore, this study investigated the prognostic usefulness of the GPS for patients who underwent ICC surgery. METHOD: All ICC patients who had a curative-intent hepatectomy at 17 institutions between 2000 and 2016 were included. The correlation was assessed between the preoperative GPS and the baseline characteristics of the patients, histopathological parameters, surgical parameters, and the postresection overall survival (OS). RESULT: There were 273 patients who met the eligibility criteria between the years 2000 and 2016. The postoperative OS rates at 1, 3, and 5 years were 83.8%, 56.3%, and 41.5%, respectively (median OS, 47.7 months). A multivariate analysis revealed the factors that were associated with a worse OS, which included an increased GPS (hazard ratio = 1.62; 95% confidence interval [CI]: 1.01-2.53; P = 0.03), an elevated carcinoembryonic antigen level (hazard ratio = 1.60; 95% CI: 1.06-2.41; P = 0.02), an elevated carbohydrate antigen 19-9 level (hazard ratio = 1.55; 95% CI: 1.05-2.30; P = 0.03), undifferentiated carcinoma (hazard ratio = 2.41; 95% CI: 1.56-3.67; P < 0.01), and positive metastasis to the lymph nodes (hazard ratio = 2.54; 95% CI: 1.76-3.67; P < 0.01). In ICC patients after a hepatectomy, an elevated GPS was associated with poorer OS, even if the tumour factors that affected GPS were eliminated by propensity-score matching. CONCLUSION: Preoperative GPS can be useful to predict the postoperative outcomes of ICC patients. Therefore, this relatively simple and inexpensive scoring system can be utilized to further refine patient stratification as well as to predict survival.

Efficacy of surgical management for recurrent intrahepatic cholangiocarcinoma: A multi-institutional study by the Okayama Study Group of HBP surgery.

BACKGROUND: The prognosis of intrahepatic cholangiocarcinoma (ICC) has been poor, because of the high recurrence rate even after curative surgery. This study aimed to evaluate the prognostic impact of surgical resection of recurrent ICC. PATIENTS AND METHODS: A total of 345 cases of ICC who underwent hepatectomy with curative intent in 17 institutions were retrospectively analyzed, focusing on recurrence patterns and treatment modalities for recurrent ICC. RESULTS: Median survival time and overall 5-year recurrence-free survival rate were 17.8 months and 28.5%, respectively. Recurrences (n = 223) were classified as early (recurrence at ≤1 year, n = 131) or late (recurrence at >1 year, n = 92). Median survival time was poorer for early recurrence (16.3 months) than for late recurrence (47.7 months, p<0.0001). Treatment modalities for recurrence comprised surgical resection (n = 28), non-surgical treatment (n = 134), and best supportive care (BSC) (n = 61). Median and overall 1-/5-year survival rates after recurrence were 39.5 months and 84.6%/36.3% for surgical resection, 14.3 months and 62.5%/2.9% for non-surgical treatment, and 3 months and 4.8%/0% for BSC, respectively (p<0.0001). Multivariate analysis identified early recurrence, simultaneous intra- and extrahepatic recurrence, and surgical resection of recurrence as significant prognostic factors. In subgroup analyses, surgical resection may have positive prognostic impacts on intra- and extrahepatic recurrences, and even on early recurrence. However, simultaneous intra- and extrahepatic recurrence may not see any survival benefit from surgical management. CONCLUSION: Surgical resection of recurrent ICC could improve survival after recurrence, especially for patients with intra- or extrahepatic recurrence as resectable oligo-metastases.

Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report.

Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.

[Efficacy of chemotherapy combined with bevacizumab for unresectable advanced or recurrent colorectal cancer].

Systemic treatment for metastatic or advanced colorectal cancer(mCRC)has remarkably progressed during recent years. All previously untreated mCRC patients at our institution between November, 2007 and June, 2010 were retrospectively evaluated. Of 72 patients, 39 were treated with chemotherapy alone, and 33 were treated with chemotherapy plus bevacizumab(BV). The median progression-free survival(mPFS)was 329 days in the group given chemotherapy plus BV, compared with 209 days in the group given chemotherapy alone(p=0. 0189). In sub-group analysis of those treated with chemotherapy plus BV, mPFS between 70 y/o

[A case of advanced hepatocellular carcinoma with portal vein invasion successfully treated by sorafenib].

A 73-year-old man was followed up for HCV-associated chronic hepatitis and hepatocellular carcinoma (HCC), developed in segment 8 of the liver. Radiofrequency ablation (P-RFA) was used to treat the tumor in June 2004. Afterwards, the patient underwent repetitive transcatheter arterial chemoembolization (TACE) against recurrent tumors 5 times. An abdominal computed tomogram (CT) showed an infiltrative mass in the left liver with tumor thrombus invading into the umbilical portion. Transarterial infusion (TAI) therapy of cisplatin (CDDP) was performed 2 times, in January and June of 2010. The size of the main tumor was decreased according to CT, and tumor marker levels such as AFP and PIVKA-II also decreased, but tumor thrombus of the portal vein developed into the main trunk (Vp4). We started therapy with sorafenib in July, 2010. Two months later, an abdominal CT revelaed further reduction of the main tumor and a shrunken tumor thrombus of the portal vein back to the left lobe. The therapeutic effect of sorafenib against HCC with tumor thrombus of the portal vein continued for 9 months.

Evaluation of cholecystic venous flow using indocyanine green fluorescence angiography.

BACKGROUND/PURPOSE: The cholecystic veins are thought to be an important metastatic route of gallbladder carcinoma to the liver. In the present study we evaluated the cholecystic venous drainage area, utilizing a novel method, indocyanine green (ICG) fluorescence angiography after superselective catheterization of the cholecystic artery, to detect and elucidate cholecystic venous flow. METHODS: Cannulation of the cholecystic artery was performed under laparotomy in nine patients who required a cholecystectomy. After ICG injection into the cholecystic artery, the cholecystic venous flow images were visualized with a near-infrared camera system and were analyzed according to site, shape, and time of fluorescence. RESULTS: Fluorescence images of the cholecystic venous flow could be viewed as real-time images in all patients. We demonstrated that the route of the cholecystic venous flow could be classified into two patterns: type 1, in which the cholecystic veins flowed directly into the hepatic parenchyma adjacent to the gallbladder; and type 2, in which the veins flowed into sites separate from the gallbladder. In the type 1 pattern, fluorescence was observed in segment (S; defined according to Couinaud's nomenclature) 4a or S5 adjacent to the gallbladder in all cases. On the other hand, in the type-2 pattern, fluorescence was observed in S4a (6/9), S5 (8/9), S4b (2/9), S3 (2/9), S1 (1/9), S2 (1/9), and S8 (1/9) distant from the gallbladder. Overall, two-thirds of the cases showed fluorescence in segments other than S4a or S5. CONCLUSIONS: Indocyanine green (ICG) fluorescence angiography is considered to be a useful method to detect and elucidate cholecystic venous flow in real time. This study showed that the cholecystic venous flow spread to the liver through two different pathways, one that flowed directly into the hepatic parenchyma adjacent to the gallbladder, while the other flowed into sites separate from the gallbladder. Taking these findings into consideration, we may therefore need to reconsider the preventive effects of a hepatic resection.

A novel antiangiogenic effect for telomerase-specific virotherapy through host immune system.

Soluble factors in the tumor microenvironment may influence the process of angiogenesis; a process essential for the growth and progression of malignant tumors. In this study, we describe a novel antiangiogenic effect of conditional replication-selective adenovirus through the stimulation of host immune reaction. An attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1 genes, could replicate in and cause selective lysis of cancer cells. Mixed lymphocyte-tumor cell culture demonstrated that OBP-301-infected cancer cells stimulated PBMC to produce IFN-gamma into the supernatants. When the supernatants were subjected to the assay of in vitro angiogenesis, the tube formation of HUVECs was inhibited more efficiently than recombinant IFN-gamma. Moreover, in vivo angiogenic assay using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice showed that tumor cell-induced neovascularization was markedly reduced when the chambers contained the mixed lymphocyte-tumor cell culture supernatants. The growth of s.c. murine colon tumors in syngenic mice was significantly inhibited due to the reduced vascularity by intratumoral injection of OBP-301. The antitumor as well as antiangiogenic effects, however, were less apparent in SCID mice due to the lack of host immune responses. Our data suggest that OBP-301 seems to have antiangiogenic properties through the stimulation of host immune cells to produce endogenous antiangiogenic factors such as IFN-gamma.

[A case of dihydropyrimidine dehydrogenase (DPD) deficiency with severe side effects from UFT/Uzel administration].

5-FU is among the drugs most frequently used in the treatment of gastrointestinal malignancies. Also, it has been reported to reveal severe side effects in the case of a dihydropyrimidine dehydrogenase (DPD) deficiency. A 75-year-old man showed severe nausea and vomiting after administration of UFT/Uzel as adjuvant chemotherapy. Because of severe thrombocytopenia and grade 4 neutropenia, platelet transfusion and G-CSF administration were performed. With time, the leukocyte, neutrophil and platelet count recovered to normal level. We strongly suspected a DPD deficiency from the result of urinary pyrimidine analysis.

[A case of advanced breast cancer leading to DIC after chemotherapy].

We reported a case of DIC who was administered FEC90 (5-FU 1,000 mg/body, epirubicin 170 mg/body, cyclophosphamide 1,000 mg/body) for advanced breast cancer. A 55-year-old woman was referred to our hospital with lumbago. There was a huge tumor in her left breast (10x10 cm) and bone scintigraphy showed multiple bone metastasis, so she was treated with FEC90. Before the third course, DIC occurred. The patient was then treated with FOY and heparin, and the DIC was resolved. We think the DIC of this case was related with tumor lysis syndrome. Febrile neutropenia has been occasionally emphasized during chemotherapy, but due care must be taken for lymphocyte depletion during treatment.

Enhanced antitumor efficacy of telomerase-selective oncolytic adenoviral agent OBP-401 with docetaxel: preclinical evaluation of chemovirotherapy.

Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemotherapeutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers.

Histone deacetylase inhibitor FR901228 enhances the antitumor effect of telomerase-specific replication-selective adenoviral agent OBP-301 in human lung cancer cells.

Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus OBP-301 (Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, could replicate in and causes selective lysis of human cancer cells. Infection efficiency in target cancer cells is the most important factor that predicts the antitumor effects of OBP-301. The objectives of this study are to examine the effects of the histone deacetylase inhibitor FR901228 on the level of coxsackie and adenovirus receptor (CAR) expression and OBP-301-mediated oncolysis in human non-small cell lung cancer cell lines. Flow cytometric analysis revealed up-regulated CAR expression in A549 and H460 cells following treatment with 1 ng/ml of FR901228, which was associated with increased infection efficiency as confirmed by replication-deficient beta-galactosidase-expressing adenovirus vector. In contrast, neither CAR expression nor infection efficiency was affected by FR901228 in H1299 cells. To visualize and quantify viral replication in the presence of FR901228, we used OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region. Fluorescence microscopy and flow cytometry showed that FR901228 increased GFP expression in A549 and H460 cells following OBP-401 infection in a dose-dependent manner, but this effect did not occur in H1299 cells. In addition, OBP-301 and FR901228 demonstrated a synergistic antitumor effect in A549 cells in vitro, as confirmed by isobologram analysis. Our data indicate that FR901228 preferentially increases adenovirus infectivity via up-regulation of CAR expression, leading to a profound oncolytic effect, which may have a significant impact on the outcome of adenovirus-based oncolytic virotherapy.

Human monocyte-derived dendritic cells pulsed with wild-type p53 protein efficiently induce CTLs against p53 overexpressing human cancer cells.

PURPOSE: Dendritic cells are the most potent antigen-presenting cells for initiating cellular immune responses. Dendritic cells are attractive immunoregulatory cells for cancer immunotherapy, and their efficacy has been investigated in clinical trials. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and p53-based immunization is an attractive approach to cancer immunotherapy because of the accumulation of p53 protein in malignant but not in normal cells. It has been shown that dendritic cells transduced with an adenoviral wild-type p53 (wt-p53) construct mediate the antitumor immune responses against p53-overexpressing tumor cells. We examined whether monocyte-derived human dendritic cells pulsed with the purified full-length wt-p53 protein were also capable of inducing the specific antitumor responses against p53-overexpressing tumors in vitro. EXPERIMENTAL DESIGN: Immature dendritic cells generated in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor from monocytes of HLA-A2- or HLA-A24-positive healthy individuals were pulsed with the purified p53 protein. Uptake of p53 protein by human dendritic cells was assessed by Western blotting and immunohistochemical staining using anti-p53 antibody. Induction of p53-specific CTL response was also evaluated by the cytotoxic assay against p53-overexpressing human tumor cells. RESULTS: Both Western blot and immunohistochemical analysis showed the accumulation of p53 protein in human immature dendritic cells. T cells obtained from HLA-A2- or HLA-A24-positive healthy donors were stimulated twice with p53 protein-pulsed dendritic cells and then applied to the cytotoxicity assay against p53-overexpressing target cells. The CTL activity was specific for p53-overexpressing tumor cells and MHC class I restricted. Moreover, the CTL activity generated by p53 protein-pulsed dendritic cells was nearly identical with that induced by adenoviral wt-p53-transduced dendritic cells. CONCLUSIONS: Our results indicate that monocyte-derived human dendritic cells pulsed with the wt-p53 protein could induce the specific antitumor effect against p53-overexpressing tumors and that this in vitro model offers a new and more simple approach to the development of p53-based immunotherapy.