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Objective To evaluate the efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. Methods This Phase 2 open-label, single-arm study enrolled Japanese women with homologous recombination deficiency-positive relapsed, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-day cycles until objective progressive disease, unacceptable toxicity, consent withdrawal or discontinuation. The primary endpoint, objective response rate (ORR), was assessed by the investigator using RECIST version 1.1. Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs), including serious TEAEs. Results Twenty women were enrolled and the confirmed ORR in the full analysis set (FAS) was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Disease control rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) were anemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leading to discontinuation of niraparib whereas reductions or interruptions were reported in 14 (70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily) corresponded to a relative dose intensity of 67.6%. Conclusion Efficacy and safety of niraparib in heavily pretreated Japanese women was comparable to that seen in an equivalent population of non-Japanese women. No new safety signals were identified. Trial registration ClinicalTrials.gov Identifier: NCT03759600.

Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

Recent studies in RAS wild-type (WT) metastatic colorectal cancer (mCRC) suggest that the survival benefits of therapy using anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies combined with chemotherapy are maximized when the anti-EGFR antibody is given as first-line, followed by subsequent anti-VEGF antibody therapy. We report reverse-translational research using LIM1215 xenografts of RAS WT mCRC to elucidate the biologic mechanisms underlying this clinical observation. Sequential administration of panitumumab then bevacizumab (PB) demonstrated a stronger tendency to inhibit tumor growth than bevacizumab then panitumumab (BP). Cell proliferation was reduced significantly with PB (P < .01) but not with BP based on Ki-67 index. Phosphoproteomic analysis demonstrated reduced phosphorylation of EGFR and EPHA2 with PB and BP compared with control. Western blotting showed reduced EPHA2 expression and S897-phosphorylation with PB; RSK phosphorylation was largely unaffected by PB but increased significantly with BP. In quantitative real-time PCR analyses, PB significantly reduced the expression of both lipogenic (FASN, MVD) and hypoxia-related (CA9, TGFBI) genes versus control. These results suggest that numerous mechanisms at the levels of gene expression, protein expression, and protein phosphorylation may explain the improved clinical activity of PB over BP in patients with RAS WT mCRC.

85 Background: The optimal choice of monoclonal antibodies (mAbs) for first-line treatment in patients (pts) with RAS ( KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. The meta-analyses of subgroup analyses in phase III studies of pts with KRAS exon 2 wild-type mCRC suggested a longer overall survival (OS) with an anti-EGFR mAb over bevacizumab in pts with RAS wild-type mCRC or with left-sided primary tumors. However, there has been no prospective study comparing the two mAbs in these pt populations. This randomized phase III study was originally designed to demonstrate the superiority of panitumumab versus bevacizumab, both in combination with mFOLFOX6, for RAS wild-type mCRC, but we have revised the protocol to analyze efficacy in pts with a left-sided primary tumor as the primary (final) analysis. Methods: Eligible pts are aged 20-79 years with histologically/cytologically confirmed RAS wild-type chemotherapy-naive mCRC, and ECOG performance status 0-1. Between May 29, 2015 and Jun 8, 2017, 823 pts were randomized 1:1 to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6 by the minimization method and the randomisation was stratified by institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). The primary analysis was revised to adopt a hierarchical testing procedure; we first compare OS between the two arms in left-sided primary tumor population, and only if there is statistically significant difference, then ITT population analysis will be performed. In this revised plan, the expected number of deaths is 420 in the left-sided population to provide 80% power to detect an OS hazard ratio of 0.74 at a one-sided significance level of 0.02101 determined on the alpha spending function approach after one interim analysis. A large-scale exploratory biomarker substudy to identify potential biomarker candidates using tumor tissue and circulating tumor DNA is also underway (Clinical trial no.: NCT02394834). The data cut off for the primary analysis is expected to be during 1Q 2021. Results: Results are expected in 2021. Conclusions: Results are expected in 2021. Clinical trial information: NCT0239475.

Background & Aims: Liver failure is characterized by endothelial dysfunction, which results in hemodynamic disturbances leading to renal failure. Albumin infusion improves hemodynamics and prevents renal dysfunction in advance liver failure. These effects are only partly explained by the oncotic properties of albumin. This study was designed to test the hypothesis that albumin exerts its beneficial effects by stabilising endothelial function. Methods: In vivo: systemic hemodynamics, renal function, markers of endothelial dysfunction (ADMA) and inflammation were studied in analbuminaemic and Sprague–Dawley rats, 6-weeks after sham/bile duct ligation surgery. In vitro: human umbilical vein endothelial cells were stimulated with LPS with or without albumin. We studied protein expression and gene expression of adhesion molecules, intracellular reactive oxygen species, and cell stress markers. Results: Compared to controls, analbuminaemic rats had significantly greater hemodynamic deterioration after bile duct ligation, resulting in worse renal function and shorter survival. This was associated with significantly greater plasma renin activity, worse endothelial function, and disturbed inflammatory response. In vitro studies showed that albumin was actively taken up by endothelial cells. Incubation of albumin pre-treated endothelial cells with LPS was associated with significantly less activation compared with untreated cells, decreased intracellular reactive oxygen species, and markers of cell stress. Conclusions: These results show, for the first time, that absence of albumin is characterised by worse systemic hemodynamics, renal function and higher mortality in a rodent model of chronic liver failure and illustrates the important non-oncotic properties of albumin in protecting against endothelial dysfunction. 2015 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

624 Background: Previous preclinical study reported that a combination of PANI with FTD/TPI demonstrated synergistic antitumor activity (Baba, 2017); however, no clinical study has been reported in this combination yet. Therefore, we conducted a phase I/II study to evaluate the efficacy and safety of this combination in pts with RAS wt mCRC. Here, we report the results of final analysis, including follow-up. Methods: Eligible pts had RAS wt mCRC refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, or angiogenesis inhibitors, and had never been treated with anti-EGFR antibodies, FTD/TPI, or regorafenib (REG).Pts received four-week cycles of PANI (every two weeks) and FTD/TPI (twice daily, days 1 to 5 and 8 to 12). The primary endpoint was frequency of dose-limiting toxicity (DLT) in phase I and progression-free survival (PFS) rate at 6 months (M) in phase II. With a PFS rate at 6 M of 48% deemed promising and 29% judged unacceptable, and assuming a one-sided significance level of 5%, the necessary sample size to achieve a power of 80% was estimated to be 47 pts (target sample size, 52 pts). Results: Since no DLT occurred in phase I, the recommended dose was determined to be 6 mg/kg for PANI and 35 mg/m2 for FTD/TPI. In phase II with a median follow-up of 16.5 M, the PFS rate at 6 M (n = 54) was 33.3% (90% CI: 22.8–45.3; p = 0.24), and median PFS and overall survival were 5.8 M (95% CI: 4.5–6.5) and 14.1 M (95% CI: 12.2–19.3), respectively. The response rate and disease control rate were 37.0% and 81.4%, respectively. The most common grade 3 or higher adverse events (n = 55) were neutropenia (10.9%), febrile neutropenia (9.1%), stomatitis (9.1%), and dermatitis acneiform (9.1%). Subsequent therapy was given to 39 pts (72.2%), including 25 pts (46.3%) treated with REG. Subgroup analyses stratified by age, PS, and primary lesion will be reported at the time of conference presentation. Conclusions: PANI combined with FTD/TPI showed favorable antitumor activity with an acceptable safety profile for previously treated RAS wt mCRC, although the primary endpoint of PFS rate at 6 M did not meet the prespecified threshold. Clinical trial information: NCT02613221.

3523Background: APOLLON is an open-label, single-arm phase I/II study investigating the efficacy and safety of panitumumab (Pmab) in combination with TAS-102 (trifluridine/tipiracil) in pts with RA...

Background. Bone marrow cells (BMCs) are believed to have the ability to generate functional hepatocytes and have some merits as a therapeutic modality for metabolic liver diseases. However, the appearance of BMC-derived hepatocytes (BMDHs) is low. We hypothesized that early BMC injection would be feasible for creating BMDHs for two main reasons: (1) the liver is a hematopoietic organ in neonatal rats and (2) it may allow sufficient time to generate more BMDHs before severe liver injury occurs. Methods. We used Long Evans Cinnamon (LEC) rats as recipients, a model of (1) Wilson disease and (2) liver carcinogenesis. Green fluorescent protein-expressing BMCs were injected into newborn LEC rats through the spleen. The oxidative activity of ceruloplasmin, which is low in LEC rats, was measured to evaluate the treatment. In addition, we performed fluorescence in situ hybridization to clarify the origin of the BMDHs and immunohistochemical analysis to confirm whether these BMDHs had malignant potential. Results. At 18 months after injection, we found some green fluorescent protein-expressing areas macroscopically in the liver of treated LEC rats. The oxidative activity of ceruloplasmin increased in treated LEC rats (n=7) and were much higher than that in untreated LEC rats (P=0.015). Moreover, we confirmed that the BMDHs were generated by cell fusion and was not detected in any of the neoplastic lesions or cholngiofibrotic regions. Conclusion. Our results suggest that this novel strategy for creating BMDHs is effective and safe.

According to Farrar's criteria, a tumor restricted to the cystic duct is defined as cystic duct carcinoma, but this definition excludes advanced carcinoma originating from the cystic duct.For the purpose of this study, primary cystic duct carcinoma was defined as a tumor originating from the cystic duct. We investigated the clinicopathological features of 15 cystic duct carcinomas, including 13 that did not fit Farrar's criteria, and compared them with those of 52 cases of gallbladder carcinoma and 161 cases of extrahepatic bile duct carcinoma.The incidence of primary cystic duct carcinoma was 6.6% among all malignant biliary tumors. The main symptom was jaundice in 67% of cases. The operative procedures employed ranged from cholecystectomy to hepatopancreatoduodenectomy. The cases of cystic duct carcinoma and bile duct carcinoma showed a high frequency of perineural infiltration. The overall 5-year survival rate of the 15 patients was 40%.Patients with advanced cystic duct carcinoma show a high frequency of jaundice and perineural infiltration. Our data suggest that cystic duct carcinoma may be considered a distinct subgroup of gallbladder carcinoma. Radical surgery is necessary for potentially curative resection in patients with advanced cystic duct carcinoma.

We examined whether the expression of thioredoxin-1 (Trx-1) was associated with patient prognosis after liver resection for metastatic colorectal cancer. Eighty-four patients underwent resection of liver metastases from colorectal cancer, leaving no macroscopic evidence of residual tumor. Immunohistochemical study was performed to evaluate the relation among Trx-1, vascular endothelial growth factor (VEGF), and redox factor-1 (Ref-1) expression and the clinicopathologic characteristics and patient survival. Thirty-seven patients (44.0%) with Trx-1-positive metastases had shorter survival after primary liver resection (P = .0003) than the 47 patients (56.0%) with Trx-1-negative metastases. The percentage VEGF-positive and Ref-1-positive metastases was significantly higher in patients with Trx-1 expression (P = .0009 and .0002, respectively). Multivariate analysis revealed that Trx-1 expression was an independent prognostic factor. Expression of VEGF and Ref-1 is associated with Trx-1 overexpression, which is related to a poor prognosis in patients with liver metastases from colorectal cancer.

The importance of gallbladder carcinoma spread to the cystic duct has not yet been described. Although the cystic duct is contiguous with the gallbladder, it is located in the hepatoduodenal ligament and differs in structure from the gallbladder. The incidence and prognostic significance of cancer spread to the cystic duct in patients with gallbladder cancer is unclear. Surgical specimens from 42 patients who underwent resection for advanced gallbladder carcinoma were examined retrospectively. Altogether, 13 (31%) of the patients had cancer spread to the cystic duct. The incidences of perineural invasion, lymph node metastasis, and venous invasion were significantly higher in these patients than in the other 29 patients without cancer spread to the cystic duct (P = 0.027, 0.034, and 0.034, respectively). The 3- and 5-year survival rates of these 13 patients were significantly lower than those of the other 29 patients (15.4% vs. 51.0% and 7.7% vs. 46.6%, respectively, P

Although dendritic cells (DCs) play an important role in tumor immunity, there have been no reports on their role in cholangiocellular carcinoma (CCC). In 26 formalin-fixed, paraffin-embedded tissue sections from patients with CCC, cells positive for CD83 (a marker of mature DCs), CD1a (a marker of immature DCs), and CD8 and CD4 (T cell markers) were counted, and expression of glucose-regulated protein (grp) 94, which is considered to participate in the maturation of DCs, was evaluated by immunohistochemistry and Western blot analysis to study the relationship between their expression and patients' disease outcome. The number of CD83-positive DCs at the invasive margin of CCCs correlated significantly with the number of CD8-positive or CD4-positive T cells in the cancerous region and was significantly higher in grp94-positive cancer than in grp94-negative cancer (P = 0.0006). CD83-positive patients (positive cells in invasive margin > 12.4/field) had both a significantly lower incidence of lymph node metastasis (23.1% vs 69.2%; P = 0.0206) and a better outcome than CD83-negative patients (P

We report a case of a primary abscess of the omentum without any obvious etiology. A 62-year-old man was referred to our clinic with lower abdominal pain, and computed tomography showed an intra-abdominal abscess in the left pelvic area. Laparotomy revealed that the abscess adhered to the urinary bladder and abdominal wall, but no perforation of the alimentary tract was identified and there was no foreign body in the abscess cavity. A culture of the abscess fluid grew Clostridium perfringens. The patient was discharged on the 16th hospital day after an uneventful postoperative course without any complications.

We investigated the chronological profile of graft damage and recovery after liver cold ischemia-reperfusion (I/R) injury, with particular attention to the role of apoptosis on hepatocyte and sinusoidal endothelial cell (SEC) damage. Male Lewis rats underwent rearterialized orthotopic liver transplantation using grafts subjected to a short (University of Wisconsin [UW] solution for 1 hour [UW1h]) and prolonged period (UW16h) of cold preservation. Experiments were performed immediately after preservation and 4 hours, 24 hours, 3 days, and 7 days after reperfusion. At each time, graft function, incidence of apoptotic cells, expression of the epitope recognized by a monoclonal antibody specific to rat SECs (SE-1), and incidence of proliferating cells were estimated. In the UW16h group, the proportion of apoptotic SECs was markedly elevated at 4 hours. The incidence of hepatocyte apoptosis was very low, although massive hepatocyte necrosis was evident at 24 hours. The incidence of proliferating hepatocytes and SECs peaked at 3 days, then returned to normal by 7 days. SE-1 expression was reduced immediately after preservation, followed by a marked reduction at 4 and 24 hours after reperfusion, and expression returned to normal by 7 days. Although SEC apoptosis was induced in the early phase of cold I/R injury, hepatocyte damage developed without the occurrence of apoptosis. Regeneration of both hepatocytes and SECs after cold I/R injury peaked at 3 days and was complete by 7 days, whereas functional recovery of these cell populations was complete 3 days after reperfusion.

Kupffer cells, residential liver macrophages, have binding sites for carcinoembryonic antigen (CEA), but their role in metastatic liver tumor progression has not been well addressed clinically. Liver macrophages were analyzed morphometrically and their relationship with CEA and tumor microvessel density (MVD) was examined in 71 patients who underwent macroscopic curative hepatectomy for metastatic liver tumors from colorectal cancer. In paraffin-embedded sections, MVD was evaluated by CD34-positive cell counts, liver macrophages visualized using anti PG-M1 (CD68) antibody were analyzed, and membrane-bound CEA was assessed by immunoreactivity of tumor cells for CEA. The area of liver macrophages in peritumoral regions (43.0±11.6 μm2) was significantly larger than that in non-tumor regions (25.2±24.2 μm2) (P

Background: Staged hepatectomy after emergency transcatheter arterial embolization (TAE) has been advocated in ruptured hepatocellular carcinoma (HCC). However, there have been no reports of clinical series of this strategy. The purpose of this study was to evaluate the protocol of this therapeutic strategy. Methods: Sixteen patients with suspected rupture of HCC were included in the study. After emergency TAE, tumor resectability was assessed, followed by staged hepatectomy or repeated TAE. The patients were reevaluated with regard to rupture of HCCs. Results: Primary hemostasis was achieved successfully in all patients. Eleven patients were finally judged to have experienced HCC rupture. Seven of them underwent staged hepatectomy; the other four underwent repeated TAE because their tumors were considered unresectable. Survival time tended to be longer, but not to a significant extent, in patients who underwent hepatectomy (range, 139 to 1527 days; median, 375 days) than in those treated by TAE alone (range, 43 to 1317 days; median, 158 days). Conclusions: Staged hepatectomy after TAE is a rational treatment for patients with ruptured HCC. Although TAE is highly effective for initial hemostasis, hepatectomy appears to provide better long-term survival. (Surgery 1998;124:526-35.)

Background MM is one of the most common hematologic malignancies in Japan and deaths due to MM represent 1.1% of all cancer deaths in 2014. Proteasome inhibitors and immunomodulatory drugs have led to improvements in overall survival (Kumar et al. Blood 2008); a trend that was confirmed in a large retrospective analysis of Japanese patients across the years 2001-2012 (Ozaki, et al, Blood Cancer Journal, 2015). The Japan Society of Hematology guideline for MM and guidelines for diagnosis and management of MM by the Japanese Myeloma Study Group recommend bortezomib (approved 2006), thalidomide (approved 2008) and lenalidomide (approved 2010) along with other anti-MM agents for treatment of RRMM. The objective of this study is to describe patient characteristics, contemporary treatment patterns, and outcomes in patients with RRMM using real world data. Method Patients with MM diagnoses based on ICD-10-CM (C900) codes, during the study period of April 2008 to January 2016, were followed using Japanese health insurance claims data provided by Medical Data Vision (MDV) in this retrospective cohort study. Index date was defined as the first observed claim for MM treatment after at least 90 days of washout period from enrollment. Progression to a subsequent line of therapy was defined as switch to another drug combination > 60 days from index date or retreatment following a treatment gap of > 90 days. Time to next treatment (TTNT) was used as a disease progression proxy and was measured as the time from the start date of the line of therapy to the start date of a subsequent line of therapy. Descriptive analyses were carried out to examine patient characteristics, treatment patterns and outcomes. Observations were censored at time of loss to follow up/end of study period. Results Among a total of 12,348 patients with a diagnostic code of MM between April 2008 and January 2016, 358 patients who received at least one treatment episode were identified with RRMM. Median follow-up was 34.0 months. Median age was 71.0 years; 34% were aged 65-74 years and 35% were 75 years or older. Male patients constituted 56%, however female patients over 80 years outnumbered male patients. Cytogenetic testing was performed in 70%. Thirteen percent of patients received stem cell transplant and 22% of those were over 65 years. Across the lines of therapy for RRMM, the regimens were: bortezomib (V) ± dexamethasone (d) (V ± d, 27.7%), melphalan (M) + prednisone (P) (MP, 20.9%), lenalidomide (R) ± d (10.9%), VM ± P (4.2%), V-cyclophosphamide (C) ± d (VC ± d, 3.1%), V + other (2%), R + other (0.3%), and others (50.0%). Among patients treated with others, a corticosteroid alone such as dexamethasone or prednisone was commonly used and alkylating agents or thalidomide were also used. Among patients treated with V-based regimen, 75% had at least one medical claim for acyclovir or valacyclovir for prophylaxis against risk of infection. Among patients treated with R-based regimen, 69% had at least one medical claim for aspirin, enoxaparin or warfarin for thromboembolism prophylaxis. Median duration of treatment was 5.1 months for patients with V ± d, 5.2 months for patients with MP and 5. 3 months for patients with R ± d. Median daily dose of R was 13.3 mg. Median TTNT for patients treated with V ± d, MP and R ± d was 11.5 months, 8.4 months and 12.5 months, respectively. Conclusion This is the first database analysis based on health insurance claims data of MM in Japan. This analysis of treatment patterns found that doublet regimens were used mainly in Japanese patients with RRMM, with V ± d and MP regimens being the most common. The duration of each regimen was relatively short and the majority of patients discontinued therapy prior to disease progression. Recent evidence has shown triplet regimens have better efficacy than doublet regimens among RRMM patients. Triplet regimens containing novel agents with sustainable efficacy, and a manageable safety and tolerability may increase the likelihood of prolonged therapy which has been correlated with better outcomes over fixed duration therapy in MM. This study may underestimate the duration of each treatment since the data were not censored. Disclosures Jun: Takeda Pharmaceutical Company Limited: Employment. Luptakova:Takeda Oncology: Employment. Koizumi:Takeda Pharmaceutical Company Limited: Consultancy. Iwasaki:Takeda Pharmaceutical Company Limited: Consultancy. Hiroi:Takeda Pharmaceutical Company Limited: Employment. Soeda:Takeda Pharmaceutical Company: Employment.

TPS776 Background: Optimal combination of monoclonal antibody (anti-VEGF vs. anti-EGFR antibody) with standard chemotherapy as first-line treatment in patients (pts) with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. FIRE-3 study demonstrated a significant improvement in overall survival (OS) with anti-EGFR over bevacizumab in pts with KRAS exon 2 wild type mCRC, while CALGB 80405 study did not. PARADIGM study is designed to compare panitumumab vs. bevacizumab combined with mFOLFOX6 in pts with RAS wild-type chemotherapy-naive mCRC. Methods: Eligible pts are aged 20-79 years with ECOG performance status (PS) 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. 800 pts will be randomly assigned in a 1:1 ratio to mFOLFOX6 plus panitumumab or bevacizumab, and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil (5-FU) iv 400 mg/m2 at day 1, 5-FU civ 2400 mg/m2 at day 1-3, and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg at day 1 every two weeks. The primary endpoint is the OS; the study was designed to detect the OS hazard ratio of 0.76, with a one-sided type I error of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. One interim analysis is planned for the OS when approximately 70% of the targeted 570 events has been observed. Exploratory endpoint is to investigate possible biomarkers including oncogenic mutations using tumor tissue and circulating tumor DNA (Study ID: NCT02394834). As of August 2015, 21 pts have been randomized and recruitment is ongoing. Clinical trial information: NCT02394795.

We report a 50-year-old male patient with primary liver carcinoma exhibiting dual hepatocellular and biliary epithelial differentiations associated with citrin deficiency (asymptomatic adult-onset type II citrullinemia, CTLN2). Although so far 14 CTLN2 patients with hepatocellular carcinoma have been reported, this report describes a unique case of liver carcinoma showing the features of both hepatocellular and cholangiocellular carcinoma. In addition to the clinical data of the 14 patients reported previously, the findings in our patient suggest that the citrin deficiency might be one of the key disorders causing hepatocellular carcinoma especially at younger ages and can also play an important role in hepatocarcinogenesis of the hepatic progenitor cells, which have the bipotential to differentiate into both hepatocytes and cholangiocytes.

We performed hepatectomy without lymph node (LN) dissection for intrahepatic cholangiocarcinoma (ICC) limited to the peripheral region of the liver, and hepatectomy with extrahepatic bile duct resection and regional LN dissection for any types of ICC extending to the hepatic hilum. Surgical outcomes were evaluated to elucidate the prognostic factors that influence patient survival with respect to intrahepatic recurrence.Forty-one patients underwent resection of ICC with no macroscopic evidence of residual cancer.Significant risk factors for poorer survival included preoperative jaundice (P = 0.0115), serum CA19-9 levels37 U/ml (P = 0.0089), tumor diameter4.5 cm (P = 0.017), ICC extending to the hepatic hilum (P = 0.0065), mass-forming with periductal-infiltrating type (P = 0.003), poorly differentiated adenocarcinoma, portal vein involvement (P = 0.0785), LN metastasis at initial hepatectomy (P0.0001), and positive surgical margin (P = 0.023). Intrahepatic recurrence, which was the predominant manner of recurrence, was detected in 20 patients (74.1%). Patients with intrahepatic recurrence had a significantly high incidence of high serum CA19-9 levels (37 U/ml; P = 0.0006), preoperative jaundice (P = 0.0262), ICC extended to the hepatic hilum (P = 0.0349), large tumors (4.5 cm; P = 0.0351), portal vein involvement (P = 0.0423), and LN metastasis at initial hepatectomy (P = 0.009) compared with disease-free patients. The multiple logistic regression analysis revealed that preoperative CA19-9 elevation and obstructive jaundice influenced intrahepatic recurrence of ICC.Although LN metastasis is a significant prognostic factor, the most obvious recurrence pattern after surgery was intrahepatic recurrence, which could be predicted preoperatively by a combination of elevated serum CA19-9 levels and manifestation of obstructive jaundice.

Major hepatectomy with concomitant pancreatoduodenectomy (M-HPD) is usually indicated for the resection of diffuse bile duct cancer or advanced gallbladder cancer. This is the only procedure that can potentially cure such advanced cancers, so both a low mortality rate and long-term survival could potentially justify performing this procedure.Between 1990 and 2005, the morbidity, mortality, and long-term survival of 26 patients with advanced biliary tract carcinoma 14 with diffuse bile duct cancer, 9 with advanced gallbladder cancer, and 3 with hilar bile duct cancer, who underwent hepatopancreatoduodectomy (HPD) were reviewed and analyzed.The overall morbidity and mortality rates were 30.8% and 0%, respectively. Postoperative infectious complications occurred in 6 patients (23.0%). The 5-year survival rate of the 14 patients with diffuse bile duct cancer who underwent HPD was 51.9%, while the 5-year survival rate in the 12 of these patients who underwent M-HPD was 61.4%. Patients with diffuse bile duct cancer without residual tumor and those without lymph node metastasis had 5-year survival rates of 68.6% and 80%, respectively. Thirty-three percent (2 of 6) of the patients who underwent M-HPD for advanced gallbladder cancer survived for more than 5 years.Preoperative biliary drainage, portal embolization, complete external drainage of pancreatic juice, reduction of intraoperative bleeding, and prevention of bacterial colonization of bile may enable the incidence of mortality and hepatic failure to approach zero in patients who undergo HPD. Surgeons should strive for complete clearance of the tumor with a negative surgical margin to achieve long-term survival when performing M-HPD.

Although dendritic cells (DCs) play an important role in tumor immunity, their prognostic significance and factors related to mature DCs have not been addressed in metastatic liver tumors. In surgically resected, paraffin-embedded tissue sections from 70 patients with colorectal liver metastasis, CD83 (a marker of mature DCs) positive cells and cancer cells positive for the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay were counted. Expression of gp96, which is considered to participate in the maturation of DCs, was also evaluated. CD83-positive cells were observed predominantly in the cancer invasive margin. Patients with CD83-positive cell counts of2 per field had a significantly poorer prognosis (5-year survival rate 47.5% vs 23.1%; P=0.0184). Patients with0.83% apoptotic cancer cells had significantly higher numbers of CD83-positive cells (7.3 +/- 7.3 vs 4.0 +/- 5.1; P=0.039). Patients with immunohistochemically positive gp96 expression in tumors had significantly higher numbers of CD83-positive cells than those with negative gp96 expression (6.0 +/- 6.5 vs 1.4 +/- 2.3; P=0.0108). Patients with metachronous occurrence of liver metastasis had significantly higher numbers of CD83 positive cells than those with synchronous detection (6.3 +/- 6.5 vs 3.9 +/- 5.9; P=0.0313). Although the number of apoptotic cancer cells, degree of tumor gp96 expression, and synchronous or metachronous occurrence of liver metastasis did not directly influence patient outcome, they did influence the number of CD83-positive cells in the cancer invasive margin, which was a significant prognostic factor in patients with colorectal liver metastasis.

BACKGROUND Matrix metalloproteinase-7 (MMP-7) recently has been reported to play a role in tumor cell invasion. The objective of the current study was to examine the expression of MMP-7 in patients with cholangiocellular carcinoma. METHODS Twenty-six patients underwent resection of cholangiocellular carcinoma, leaving no macroscopic evidence of residual tumor. Immunostaining was performed to evaluate the relation between MMP-7 expression and clinicopathologic features and patient prognosis. The immunostaining pattern of the tumor cells for MMP-7 was classified as negative (−) (n = 9), positive (+) (n = 11), or strongly positive (++) (n = 6). Western blot analysis was performed to investigate the expression of active or latent forms in cancerous and noncancerous lesions in four patients. RESULTS The survival rates in patients with MMP-7 expression judged to be (−), (+), and (++) were 75%, 80%, and 0%, respectively, at 1 year, and 47%, 24%, and 0%, respectively, at 3 years. The survival rate of MMP-7 (++) patients was significantly lower than that of MMP-7 (+) patients (P = 0.003) and MMP (−) patients (P = 0.008). At last follow-up, 3 patients in the MMP-7 (−) group had survived for > 5 years. Western blot analysis demonstrated that there were two types of cholangiocellular carcinoma: those producing both latent and active MMP-7 and those producing only the latent form. CONCLUSIONS Although the results of the current study are based on a small number of patients, they suggest that MMP-7 expression is a significant prognostic factor in patients with cholangiocellular carcinoma and that cholangiocellular carcinoma demonstrating strongly positive expression of MMP-7 on immunostaining may have a higher malignant potential compared with that showing negative or positive expression of MMP-7. Cancer 2002;94:428–34. © 2002 American Cancer Society.