High Incidence Of Liver Metastasis Research Articles

High serum alpha-fetoprotein and positive immunohistochemistry of alpha-fetoprotein are related to poor prognosis of gastric cancer with liver metastasis

Liver metastasis in gastric cancer is incurable. Alpha-fetoprotein-producing gastric cancer has a poor prognosis and is prone to liver metastasis. We investigated the association between preoperative serum alpha-fetoprotein levels, liver metastasis, and expression of primitive enterocyte phenotype markers. We reviewed the medical records of 401 patients with gastric cancer who underwent curative surgical resection and immunohistochemically evaluated the primitive phenotype markers. The preoperative serum alpha-fetoprotein levels were elevated and normal in 8 and 393 patients, respectively. Liver metastasis was more frequent in patients with higher preoperative alpha-fetoprotein levels. The 5-year postoperative recurrence-free survival and overall survival rates were significantly worse in patients with higher preoperative serum alpha-fetoprotein levels. Although alpha-fetoprotein and Glypican3 and Spalt-like transcription factor 4 tended to be stained with high preoperative serum alpha-fetoprotein levels, these markers were also positive in some patients with normal alpha-fetoprotein levels. In summary, patients with gastric cancer and high preoperative serum alpha-fetoprotein levels have a poor prognosis and high incidence of liver metastasis. Alpha-fetoprotein can help detect liver metastasis relating to the primitive enterocyte phenotype.

Clinical features and prognosis of patients with metastatic ocular and orbital melanoma: A bi-institutional study.

Metastatic ocular and orbital melanomas are extremely rare. The clinical characteristics and standard treatments for these patients are not fully established. We retrospectively analyzed patients with metastatic ocular and orbital melanoma from Fudan University Shanghai Cancer Center and Eye & ENT Hospital of Fudan University between January 2012 and May 2022. Overall, 51 patients with metastatic ocular and orbital melanoma were included. The most common primary sites were uvea (73%), followed by conjunctiva (22%), lacrimal sac (4%), and orbit (2%). Patients with uveal melanoma (UM) had a significantly younger age (48 vs. 68 years, p < 0.001), higher incidence of liver metastases (89% vs. 9%, p<0.001), a lower incidence of lymph nodes metastases (16% vs. 46%, p = 0.043) and a lower incidence of BRAF mutation (0% vs. 55%, p<0.001) compared with patients with conjunctival melanoma (CM). The overall response rate of the first-line treatment was 18%. Three of the four patients with BRAF-mutated CM responded to dabrafenib and trametinib treatment. The median progression-free survival (PFS) and overall survival (OS) of first-line treatment were 5.1 and 11.9 months, respectively. Among patients with liver metastases, liver-directed treatment was correlated with better patient PFS (p < 0.001) and OS (p < 0.001) after adjusting for number of metastatic sites and primary sites. CM and UM have different characteristics. Patient with CM had a high incidence of BRAF mutation, and the treatment of BRAF and MEK inhibitors conferred clinical benefit. Liver directed therapies had a potential benefit in disease control in patients with liver metastases.

Liver metastasis in soft tissue sarcoma at initial presentation.

We reviewed all patients with STS diagnosed between 2010 and 2018 in the Surveillance, Epidemiology, and End Resultsdatabase. Incidence of liver metastasis at initial presentation and high incidence of liver metastasis by histological subtype were investigated. In addition, risk factors for liver metastasis were investigated by multiple logistic regression analysis. After excluding patients without information about liver metastasis, cause of death or primary liver tumor, 47 260 patients were included in this study. Of those, 1471 patients (3.2%) showed liver metastasis at initial presentation. The histological subtype showing the highest incidence of liver metastasis was desmoplastic small round cell tumor (30.3%), followed by malignant hemangioendothelioma (11.5%) and angiomyoliposarcoma (10.5%). Deep-rooted tumor, location in the body wall, retroperitoneum, or thorax/peritoneum, high histological grade, and higher T stage were associated with higher incidences of liver metastasis at initial presentation. Risk factors for liver metastasis were deep location, trunk development, larger tumor size, high histological grade, and specific histological subtypes.

Alpha-fetoprotein can promote gastric cancer progression via upregulation of metastasis-associated colon cancer 1.

High serum alpha-fetoprotein (AFP) level is a predictor of poor prognosis in patients with gastric cancer (GC). AFP-producing GC (AFP-GC) is an aggressive subtype of GC characterized by a high incidence of liver metastasis and high c-Met expression. High expression of metastasis-associated colon cancer 1 (MACC1), which is the transcription activator of c-Met, also predicts a poor prognosis of GC. c-Met is known to be involved in tumor progression into malignant invasive phenotypes. Considering that high c-Met expression is simultaneously positively correlated with high AFP and MACC1 expression levels and that high expression of AFP or MACC1 predicts poor prognosis in GC, we hypothesized that an interaction may exist between AFP and MACC1. In the present study, GC cell lines with AFP-overexpression, MACC1-downregulation and the combination of both transfections were used as experimental models. The relative mRNA and protein expression of c-Met, AFP and MACC1 were analyzed using reverse transcription quantitative PCR and western blotting, respectively. Cell viability was evaluated using Cell Counting Kit-8 assay. Cell invasion and cell migration were examined using Transwell migration assay with and without Matrigel, respectively. The results demonstrated that, compared with the control group, the mRNA and protein expression of MACC1was significantly elevated in the AFP-overexpressed group and in the group with AFP overexpressed and MACC1 downregulated. Furthermore, a significantly enhanced cell viability, migration and invasion were observed in the AFP-overexpressing group, whereas opposite effects were found in the MACC1-downregulating group. In summary, the results from this study indicated that AFP may promote GC progression by stimulating MACC1. This finding may help illustrating the aggressive behaviors of GC in patients with high AFP serum level and AFP-GC.

Targeting the IGF-Axis Potentiates Immunotherapy for Pancreatic Ductal Adenocarcinoma Liver Metastases by Altering the Immunosuppressive Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, resistant to chemotherapy and associated with high incidence of liver metastases and poor prognosis. Using murine models of aggressive PDAC, we show here that in mice bearing hepatic metastases, treatment with the IGF-Trap, an inhibitor of type I insulin-like growth factor receptor (IGF-IR) signaling, profoundly altered the local, immunosuppressive tumor microenvironment in the liver, curtailing the recruitment of myeloid-derived suppressor cells, reversing innate immune cell polarization and inhibiting metastatic expansion. Significantly, we found that immunotherapy with anti-PD-1 antibodies also reduced the growth of experimental PDAC liver metastases, and this effect was enhanced when combined with IGF-Trap treatment, resulting in further potentiation of a T-cell response. Our results show that a combinatorial immunotherapy based on dual targeting of the prometastatic immune microenvironment of the liver via IGF blockade, on one hand, and reversing T-cell exhaustion on the other, can provide a significant therapeutic benefit in the management of PDAC metastases.

Association of Epstein-Barr virus infection with peripheral immune parameters and clinical outcome in advanced nasopharyngeal carcinoma

The purpose of this study was to investigate the association of Epstein-Barr virus (EBV) with peripheral blood immune cell counts and clinical outcomes in advanced nasopharyngeal carcinoma (NPC) patients. In a retrospective design, 146 patients with NPC at stage IV were enrolled in this study. The association of EBV status with peripheral blood immune cell counts, distant metastases, and long-term survival in patients with advanced NPC were determined. Eighty-seven (59.6%) of all patients were positive for EBV. Compared with patients with normal NK cell count, patients with lower NK cell count showed a significantly lower EBV viral load (median: 614.0 vs. 2190.0 copies/mL, P = 0.024). EBV-positive patients showed a significantly higher incidence of liver metastasis than EBV-negative patients (32.6% vs. 23.7%, P = 0.021). Multi-variant regression analysis showed that EBV infection was independently associated with liver metastasis (OR: 2.33, P = 0.043). EBV positive patients showed a significantly worse PFS (P = 0.001) and OS (P = 0.001) than EBV negative patients. Multivariate Cox regression analysis revealed that EBV infection was independently associated with a worse PFS (HR: 1.94, P = 0.003), and OS (HR: 2.12, P = 0.014) in advanced NPC. In conclusion, EBV infection is associated with a high risk of liver metastasis and is also an independent negative predictor for PFS and OS in patients with advanced NPC. EBV infection is associated with lower CD8% and higher NK%, while lower NK cell count is associated with lower EBV viral load.

Treatment efficacy of ramucirumab-based chemotherapy in patients with alpha-fetoprotein producing gastric cancer (AFPGC).

389 Background: AFPGC is an aggressive subgroup of gastric cancer and is associated with a worsened survival because of a high incidence of liver metastasis. Ramucirumab-based chemotherapy is the standard treatment as a second line in advanced gastric cancer. Recently ramucirumab has showed survival benefit in hepatocellular carcinoma, but only those with higher AFP levels. However, the efficacy of ramucirumab in AFPGC is unknown. Methods: We retrospectively assessed 283 patients who received paclitaxel or nab-paclitaxel combined with ramucirumab between July 2015 and December 2018. AFPGC was defined when serum AFP levels were elevated and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal when diagnosed. Other patients were excluded. Patients’ demographics, progression-free survival (PFS), overall survival (OS) and objective response rates (ORR) were compared between the two groups. Results: Among the 283 patients, 24 patients were AFPGC and 189 patients were non-AFPGC. AFPGC was associated with high incidences of intestinal histology (46%) and liver metastasis (63%), while AFPGC was associated with a low incidence of peritoneal metastasis (21%), compared with non-AFPGC. There was no significant difference in PFS and OS between the two groups. Median PFS were 5.4 (95%CI 3.6-6.7) months in AFPGC and 4.1 (3.7-5.1) months in non-AFPGC (HR 0.93 95%CI 0.60-1.46, p = 0.788), respectively. Median OS were 19.0 (95%CI 13.2-NA) months in AFPGC and 19.3 (17.9-20.1) months in non-AFPGC (HR 1.21 95%CI 0.70-2.10, p = 0.494), respectively. Regarding with ORR, AFPGC showed higher ORR with 52.6% (95%CI 30.2-75.1), while 37.3% (95%CI 26.4-48.3) in non-AFPGC (p = 0.296), although this was not statistically significant. Conclusions: Ramucirumab showed comparable survival and higher ORR in AFPGC than in non-AFPGC. Considering the generally poor prognosis of AFPGC, it is speculated that ramucirumab may have compensated for disadvantage in survival.

Evaluation of [18F]FDG/[18F]FLT/[18F]FMISO-based micro-positron emission tomography in detection of liver metastasis in human colorectal cancer

IntroductionPositron emission tomography (PET) is extensively used in clinical oncology for tumor detection. This study aimed to explore the application of the radiotracers [18F]fluorodeoxyglucose ([18F]FDG), 3′-deoxy-3′- [18F]fluorothymidine ([18F]FLT), and [18F]fluoromisonidazole ([18F]FMISO) in the diagnosis and monitoring of hepatic metastasis in human colorectal cancer (CRC). MethodsA mouse model of human CRC with hepatic metastasis was established by intrasplenic implantation of human CRC cell lines LoVo or HCT8. Metastatic potential of these two cell lines was evaluated by wound healing assay in vitro and survival analysis. Uptake of radiotracers between LoVo and HCT8 cells and uptake of radiotracers in the resulting mouse tumor models were examined by in vivo and in vitro experiments. Uptake of each radiotracer in hepatic metastatic lesions was quantified and expressed as standard uptake value (SUV). Protein expression of multiple tumor biomarkers was determined in metastatic lesions. The correlation between tracer uptake and tumor marker expression was evaluated using linear regression. ResultsLoVo cells exhibited a stronger metastatic potential and a higher radiotracer uptake ability than HCT8 cells, as evidenced by significantly greater wound closure percentage, shorter survival, higher incidence of liver metastases, and higher cellular radiotracer levels in LoVo cells or LoVo cell-xenografted mice. SUV values of [18F]FLT and [18F]FMISO, but not [18F]FDG, in LoVo cell-derived metastatic lesions were significantly greater than those in HCT8 lesions. Mechanistically, the expression of MACC1, HIF-1α, and GLUT-1(metastasis associated in colon cancer 1, MACC1; hypoxia-inducible factor 1-alpha, HIF-1α; and glucose transporter 1, GLUT-1, respectively) in LoVo cell-derived metastatic lesions was more effectively induced than in HCT8-derived ones. A linear regression analysis demonstrated significant positive correlations between [18F]FLT/[18F]FMISO uptake and tumor biomarker expression in metastatic tissues. Conclusions[18F]FLT and [18F]FMISO-based PET imaging may serve as a promising method for early detection and monitoring of hepatic metastasis in patients with CRC.

Identifying the key genes and microRNAs in colorectal cancer liver metastasis by bioinformatics analysis and invitro experiments.

Colorectal cancer (CRC) is one of the principal causes of cancer-associated mortality worldwide. The high incidence of liver metastasis is the leading risk factor of mortality in patients with CRC, and the mechanisms of CRC liver metastasis are poorly understood. In the present study, 7 datasets, including 3 gene expression profile datasets and 4 microRNA (miRNA) expression profile datasets were downloaded from the NCBI Gene Expression Omnibus (GEO) database to identify potential key genes and miRNAs, which may be candidate biomarkers for CRC liver metastasis. Differentially expressed (DE) genes (DEGs) and DE miRNAs of primary CRC tumor tissues and liver metastatic CRC tumor tissues were selected using the GEO2R tool. Gene Ontology and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery online database. Furthermore, Cytoscape with cytoHubba and the Molecular Complex Detection (MCODE) plug-in were used to visualize a protein-protein interaction (PPI) network for these DEGs, and to screen hub genes and gene modules in the PPI network. In addition, the online databases, TargetScan, miRanda, PITA, miRWalk and miRDB, were used to identify the target genes of the DE miRNAs. In the present study, 141 DEGs (97 upregulated and 44 downregulated) and 3 DE miRNAs (2 upregulated and 1 downregulated) were screened from the 3 gene expression microarray datasets and 4 miRNA expression microarray datasets, respectively. In total, 10 hub genes with a high degree of connectivity were selected from the PPI network, including albumin (ALB), coagulation factor II (F2), thrombin, apolipoprotein H (APOH), serpin family C member 1 (SERPINC1), apolipoprotein A1 (APOA1), α-1-microglobulin/bikunin precursor (AMBP), apolipoprotein C3 (APOC3), plasminogen (PLG), α-2 HS glycoprotein (AHSG) and apolipoprotein B (APOB). The most important module was detected in the PPI network using the MCODE plug-in. A total of 20 DEGs were identified to be potential target genes of these DE miRNAs, and novel miRNA-DEGs regulatory axes were constructed. In vitro experiments were performed to demonstrate that miR-885 promoted CRC cell migration by, at least partially, decreasing the expression of von Willebrand factor (vWF) and insulin-like growth factor binding protein 5 (IGFBP5). In conclusion, by using integrated bioinformatics analysis and in vitro experiments, key candidate genes were identified and novel miRNA-mRNA regulatory axes in CRC liver metastasis were constructed, which may improve understanding of the molecular mechanisms underlying CRC liver metastasis.

Phase I/II Study of Hepatic Arterial Infusion of Nab-paclitaxel in Patients With Metastatic Melanoma to the Liver.

Hepatic arterial infusion (HAI) of cytotoxic chemotherapy is a strategy to deliver high dose of anticancer therapy to liver metastases that derive their blood supply from the hepatic artery. Metastatic melanoma (MM) has a high incidence of liver metastases, with uveal subtype in particular exhibiting a predilection for liver dissemination. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated efficacy in MM and first-pass hepatic metabolism. Therefore, we hypothesized that HAI of nab-paclitaxel would deliver an effective dose of drug to the end organ of interest, with minimal systemic exposure. We performed a single-institution open-label phase I/II study of HAI of nab-paclitaxel in MM patients with liver metastasis. Patients received treatment every 21 days at 4 different dose levels. The primary objective of the phase I portion of the study was safety and determination of the maximum-tolerated dose. The primary objective of the phase II portion of the study was overall response rate per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0. A total of 30 patients were treated between 2009 and 2013, 16 of whom had uveal melanoma. The maximum-tolerated dose was 220 mg/m and 19 patients were treated at this dose. There was 1 patient (5%) with a partial response at this dose, and 8 patients (42%) with stable disease at this dose. HAI nab-paclitaxel demonstrates rare objective responses in melanoma patients with liver metastases. This treatment should be studied in combination with checkpoint blockade or other novel treatments to enhance meaningful responses but should not be considered effective monotherapy.

Colorectal cancer liver metastases \u2013 a population-based study on incidence, management and survival

BackgroundColorectal cancer (CRC) is a leading cause of cancer-associated deaths with liver metastases developing in 25–30% of those affected. Previous data suggest a survival difference between right- and left-sided liver metastatic CRC, even though left-sided cancer has a higher incidence of liver metastases. The aim of the study was to describe the liver metastatic patterns and survival as a function of the characteristics of the primary tumour and different combinations of metastatic disease.MethodsA retrospective population-based study was performed on a cohort of patients diagnosed with CRC in the region of Stockholm, Sweden during 2008. Patients were identified through the Swedish National Quality Registry for Colorectal Cancer Treatment (SCRCR) and additional information on intra- and extra-hepatic metastatic pattern and treatment were retrieved from electronic patient records. Patients were followed for 5 years or until death. Factors influencing overall survival (OS) were investigated by means of Cox regression. OS was compared using Kaplan-Meier estimations and the log-rank test.ResultsLiver metastases were diagnosed in 272/1026 (26.5%) patients within five years of diagnosis of the primary. Liver and lung metastases were more often diagnosed in left-sided colon cancer compared to right-sided cancer (28.4% versus 22.1%, p = 0.029 and 19.7% versus 13.2%, p = 0.010, respectively) but the extent of liver metastases were more extensive for right-sided cancer as compared to left-sided (p = 0.001). Liver metastatic left-sided cancer, including rectal cancer, was associated with a 44% decreased mortality risk compared to right-sided cancer (HR = 0.56, 95% CI: 0.39–0.79) with a 5-year OS of 16.6% versus 4.3% (p < 0.001). In liver metastatic CRC, the presence of lung metastases did not significantly influence OS as assessed by multivariate analysis (HR = 1.11, 95% CI: 0.80–1.53).ConclusionThe worse survival in liver metastatic right-sided colon cancer could possibly be explained by the higher number of metastases, as well as more extensive segmental involvement compared with left-sided colon and rectal cancer, even though the latter had a higher incidence of liver metastases. Detailed population-based data on the metastatic pattern of CRC and survival could assist in more structured and individualized guidelines for follow-up of patients with CRC.

The Differences of c-Met Expression Between AFP-Producing Gastric Cancer and Common Gastric Cancer

BackgroundAlpha-fetoprotein (AFP)–producing gastric cancer is a distinct type of gastric cancer with a high incidence of liver metastasis. c-Met is considered to play an important role in liver metastasis of gastric cancer.ObjectiveThe purpose of this study was to compare the expression of c-Met in AFP-producing gastric cancer and gastric cancers not producing AFP.MethodsWe evaluated 23 patients with AFP-producing gastric cancer (AFP+) and 18 patients with common gastric cancer (AFP–) were evaluated for c-Met expression using immunohistochemical analysis.ResultsThe incidence of c-Met expression in 2 groups was the same (P &amp;gt; 0.05), but the AFP+ group had a higher strong positive rate of c-Met expression than the AFP– group (P &amp;lt; 0.01).ConclusionThe higher expression of c-Met might be the reason for the high incidence of liver metastasis in AFP-producing gastric cancer.

Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations.

In the present study, we examined the pattern of metastatic spread in patients with advanced non-small-cell lung cancer (nsclc) and the effect of EGFR mutations. Patients were identified from a provincial cancer registry, and individual medical records were reviewed. Patients were included if they had stage iv nsclc and underwent diagnostic EGFR mutation testing. Patients were divided into EGFR mutation-positive (EGFR+) and EGFR wild type (wt) cohorts. The primary endpoint was the cumulative incidence for each metastatic site: lung, bone, brain, liver, adrenal glands, distant nodes, and other. Cumulative incidence curves were estimated using a competing-risks method. The secondary outcome was survival. Of the 543 identified patients, 121 (22.3%) tested as EGFR+, and 422 (77.7%) tested as EGFR wt. The incidence of brain (39.2% vs. 28.2%, p = 0.038) and lung (61.2% vs. 51.0%, p = 0.048) metastasis was higher in the EGFR+ cohort than in the EGFR wt cohort. In the EGFR+ cohort, a higher incidence of liver metastasis was associated with the exon 21 mutation subtype than with the exon 19 deletion subtype [23% vs. 7%, p < 0.01; hazard ratio (hr): 3.47]. Median survival was significantly longer for the EGFR+ cohort than for the EGFR wt cohort (22.4 months vs. 7.9 months, p < 0.001). In multivariable analysis, brain (hr: 1.73), liver (hr: 1.69), and bone (hr: 1.89) metastases were associated with worse survival. Rates of lung and brain metastases are higher in EGFR mutation carriers, even when adjusted for differences in survival. Brain, liver, and bone metastases are independent negative prognostic factors for survival.

Influence of high serum alpha fetoprotein on patients with gastric cancer

SummaryBackgroundsPatients with alphafetoprotein (AFP)‐producing gastric cancer (AFPGC) have a high incidence of liver metastasis and poor prognosis. However, the clinical manifestation of AFPGC remains controversial.MethodsWe enrolled patients who, before surgery, had gastric cancer with serum AFP levels of &gt; 100 ng/mL (n = 30) and of ≦ 20 ng/mL (n = 1236). Clinical manifestations were compared between these two groups.ResultsCompared with in the AFP &gt; 100 group, early gastric cancer was more frequent (30.1% vs. 0%) and advanced gastric cancer was less frequent (69.9% vs. 100%) in the AFP ≦ 20 ng/mL group (p &lt; 0.001). Moreover, the incidence of liver and lymph node metastases was lower in the AFP ≦ 20 ng/mL group than in the AFP &gt; 100 ng/mL group (4.4% vs. 43.3%, p &lt; 0.001 and 60.7% vs. 93.3%, p &lt; 0.001, respectively). More patients had stage IV AFPGC in the AFP &gt; 100 ng/mL group than in the ≦ 20 ng/mL group (66.7% vs 27.1%, p &lt; 0.001). Furthermore, fewer patients underwent curative surgery in the AFP &gt; 100 ng/mL group (6.7% vs 37.9%, p &lt; 0.001). More patients in the AFP &gt; 100 ng/mL group died because of gastric cancer (66.7% vs 27.1%, p &lt; 0.0001).ConclusionsPatients with very high serum AFP levels have a high incidence of liver and lymph node metastases and extremely poor prognosis.Copyright © 2017, The Gastroenterological Society of Taiwan, The Digestive Endoscopy Society of Taiwan and Taiwan Association for the Study of the Liver.

Phase II multicenter, single arm, open label study of nivolumab (NIVO) in combination with ipilimumab (IPI) as first line in adult patients (pts) with metastatic uveal melanoma (MUM): GEM1402 NCT02626962.

9533 Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall Survival (OS) at 5 years(y) is 62% due high incidence of liver metastasis, fatal within 4-9 months(m) from diagnosis. No standard treatment exists for MUM. NIVO+IPI combination has shown efficacy in metastatic cutaneous melanoma. However, MUM pts were excluded in these trials. Methods: GEM1402 is a phase-2 trial evaluating NIVO+IPI in untreated adult pts with MUM; is being conducted in 10 centers in Spain, leading by the Spanish Melanoma Group. Eligible pts had histologically-confirmed MUM, ECOG-PS 0/1, and no prior systemic treatment for MUM. Treatment consisted in NIVO (1mg/kg, iv, q3 weeks [wk]) and 4 doses of IPI (3mg/kg iv q3wk) followed by NIVO (3mg/kg q2wk) until progressive disease (PD), toxicity or withdrawal. Primary endpoint is OS and secondary progression free survival (PFS), Overall Response Rate (ORR) (per RECIST 1.1) and safety. Radiologic evaluations q6wk. Interim analysis (n = 19) was planned per protocol to assess safety and ORR. Intention to treat analysis includes pts with PD at first radiological evaluation. Safety population includes all pts receiving at least one dose of study treatment. Results:19 pts enrolled from April to July 2016: Median age 62y (43y-82y), 63% male, liver M1 84% pts and extra-liver M1 42% pts, 31% elevated baseline LDH. 11 pts completed cycle 2 and 8 pts stopped after 1 dose (6 PD, 2 toxicity). Treatment-related adverse events were reported in 12 pts and lead to end of treatment in 2 pts. Grade ≥3 toxicities were seen in 7 pts (36.8%): diarrhea, transaminitis, dermatological events, anemia, acute thyroiditis. All G3/4 were resolved following the toxicity guideline. One G5 acute thyroiditis related to NIVO+IPI was reported. ORR was observed in 15.8% and disease stabilization in 47.4%. With a median follow-up of 4.6m, PFS was 4.99m. Median OS was not reached at time of this analysis. Conclusions: Combination of NIVO+IPI is feasible for MUM. In this INTERIM ANALYSIS, ORR did not reach yet 20%, but PFS seems promising. The clinical trial is ongoing. Final results will be updated. Clinical trial information: 2015-004429-15.

Prognostic impact of type of preoperative biliary drainage in patients with distal cholangiocarcinoma

BackgroundSurgical results of patients with resected distal cholangiocarcinoma (DCC) were evaluated to elucidate prognostic impact of the type of preoperative biliary drainage (PBD). MethodsEighty-eight patients with resected DCC were stratified into two groups according to the type of PBD: the percutaneous transhepatic biliary drainage (PTBD) group (n = 25) and the endoscopic biliary drainage (EBD) group (n = 63). ResultsOverall 5-year survival rate of the patients in the PTBD group was poorer than in the EBD group (24% vs. 52%, P = 0.020). On univariate analysis, PTBD, pancreatic invasion, perineural invasion, and lymph node involvement were significant prognostic factors for poor overall survival. On multivariate analysis, PTBD was the only significantly independent prognostic factor for poor overall survival. The incidence of liver metastasis was significantly higher in the PTBD group than in the EBD group (32.0% vs. 13.3%, P = 0.034). ConclusionsPTBD should be avoided as much as possible in patients with DCC since the patients who underwent PTBD had poorer overall survival and higher incidence of liver metastasis than those who underwent EBD.

Multimodality Treatment Including Triplet Regimen as First-Line Chemotherapy May Improve Prognosis of Serum AFP-Elevated Gastric Cancer with Liver Metastasis

Serum α-fetoprotein- (AFP-) elevated gastric cancer is a rare tumor that has a poor prognosis due to high incidence of liver metastasis. This study sought to investigate the optimal treatment modality. A total of 319 gastric cancer patients with liver metastasis (GCLM) whose serum AFP levels were tested before treatment were enrolled in this study. They were classified as the serum AFP ≥ 20 ng/ml group (n = 74) and the AFP < 20 ng/ml group (n = 245). Median OS of the AFP < 20 ng/ml group was significantly longer than that of the AFP ≥ 20 ng/ml group (15.7 m versus 10.9 m, P = 0.004). ORR of first-line chemotherapy was 43.3% and 56.1% of the two groups, respectively (P = 0.024). Of patients who received doublet regimen, ORR of the AFP ≥ 20 ng/ml group was significantly lower (38.2 versus 56.9%, P = 0.013), while in those received triplet regimens, ORR between two groups was similar (66.7% versus 66.7%, P = 0.676). Moreover, for patients of the AFP ≥ 20 ng/ml group, those who reached PR had a longer survival period (15.4 m versus 9.4 m, P = 0.017), and combined with local treatment for liver metastasis also seemed to improve prognosis (19.2 m versus 8.4 m, P = 0.003). In conclusion, serum AFP-elevated GCLM had a poorer prognosis. Multimodality treatment including aggressive first-line chemotherapy with triplet regimen may be needed when treating them.

Different Efficiency of Liposomal Forms with Hydrophilic and Hydrophobic Antitumor Agents in Relation to Solid Transplants of Mouse Tumor and Its Metastases in the Liver

Experiments were performed on the model of transplanted mouse tumor with high incidence of liver metastases. Hydrophilic drug cycloplatam (injected intravenously in liposomes) was more potent than "free cycloplatam" (injected intravenously or intraperitoneally in physiological saline) in inhibiting the growth of natural and experimental metastases in the liver. By contrast, liposomal cycloplatam had lower efficiency than free cycloplatam in suppressing the growth of solid tumor. Liposomal and free cortifen (hydrophobic hormonal cytostatic) produced nearly the same effects on solid tumor growth. Our results suggest that liposomal forms of hydrophobic compounds producing nonselective effect on tumor cells (e.g., actinomycin D or Cosmegen), should not have advantages over free forms.

Suppression of pancreatic cancer growth and metastasis by HMP19 identified through genome-wide shRNA screen.

Therapeutic effectiveness against metastatic or even locally advanced pancreatic ductal adenocarcinoma (PDAC) is dismal, with 5‐year survival less than 5%. Even in patients who undergo potentially curative resection, most patients' tumors recur in the liver. Improving therapies targeting or preventing liver metastases is crucial for improving prognosis. To identify genes suppressing metastasis, a genome‐wide shRNA screen was done using the human non‐metastatic PDAC cell line, S2‐028. After identification of candidates, functional validation was done using intrasplenic and orthotopic injections in athymic mice. HMP19 strongly inhibited metastasis but also partially attenuated tumor growth in the pancreas. Knockdown of HMP19 increased localization of activated ERK1/2 in the nucleus, corresponding to facilitated cell proliferation, decreased p27Kip1 and increased cyclin E1. Over‐expression of HMP19 exerted the opposite effects. Using a tissue microarray of 84 human PDAC, patients with low expression of HMP19 showed significantly higher incidence of liver metastasis (p = 0.0175) and worse prognosis (p = 0.018) after surgery. HMP19, a new metastasis/tumor suppressor in PDAC, appears to alter signaling that leads to cell proliferation and appears to offer prognostic value in human PDAC.

Abstract 3264: Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC)

Abstract Background: PDAC is a leading cause of cancer-related death worldwide, and most patients have incurable disease at diagnosis. Life expectancy is only 3-6 months post-diagnosis, ostensibly due to early dissemination to liver and other vital organs. Results: By transfecting a shRNA library into non-metastatic PDAC line S2-028 followed by experimental metastasis assay, ITIH5 was identified. Metastatic PDAC cell lines (e.g., S2-007, MIAPaCa-2, Panc-1) had significantly lower ITIH5 protein expression compared to immortalized pancreatic ductal epithelial cells and non-/poorly-metastatic PDAC cell lines (e.g., S2-028 and BxPC3). By manipulating expression in different PDAC cell lines (over-expression in S2-007 and MIAPaCa-2, knockdown in non-metastatic S2-028 with two different shRNA) functional and selective regulation of metastasis was observed. Orthotopic tumor growth of PDAC cells was not blocked. Thus ITIH5 qualifies as a metastasis suppressor. Overexpression of ITIH5 significantly inhibited invasion and migration, while down-regulation increased these cellular properties. Immunohistochemistry of a human PDAC tissue microarray (n = 81) revealed that negative expression of ITIH5 showed significantly higher incidence of liver metastasis (P = 0.0482) corresponding with worse prognosis after surgery (P = 0.0299). Conclusions: ITIH5 is a potent metastasis suppressor with suggestive prognostic value in PDAC. Future studies will continue to characterize biochemical properties of ITIH5, identify interaction partners, and investigate the molecular mechanism(s) of action. Support: National Foundation for Cancer Research, Steiner Family Fund and CA168524. Citation Format: Ken Sasaki, Hiroshi Kurahara, S Natsugoe, Tomoo Iwakuma, Danny R. Welch. Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3264. doi:10.1158/1538-7445.AM2015-3264