Rate Of Liver Metastasis Research Articles

Variations in Metastasis Site by Primary Location in Colon Cancer

ObjectiveThe purpose of this paper is to determine whether sites of distant recurrence are associated with specific locations of primary disease in colon cancer. MethodsA cohort including all patients (n = 947) undergoing a segmental colonic resection for colon cancer at our center (2004–2011) comparing site-specific metastatic presentation and recurrence rates, as well as their respective multivariable American Joint Committee on Cancer (AJCC) stage-adjusted hazard ratios (mHR). ResultsRight-sided colectomies (n = 557) had a lower overall metastasis rate (24.8 % vs. 31.8 %; P = 0.017; mHR = 1.24 [95% CI: 0.96–1.60]; P = 0.011) due to significantly lower pulmonary metastasis in follow-up (2.7 % vs. 9 %; P < 0.001; mHR = 0.32 [95% CI: 0.17–0.58]; P = 0.001) and lower overall liver metastasis rate (15.6 vs. 22.1 %; P = 0.012; mHR = 0.74 [95% CI: 0.55–0.99];P = 0.050). Left colectomies (n = 127) had higher rates of liver metastasis during follow-up (9.4 % vs. 4.8 %; P = 0.029; mHR = 1.64 [95% CI: 0.86–3.15]; P = 0.134). Sigmoid resections (n = 238) had higher baseline rates of liver metastasis (17.1 % vs. 11.3 %; P = 0.015) and higher cumulative rates of lung (12.2 % vs. 5.4 %; P < 0.001; mHR = 2.26 [95 % CI: 1.41–3.63]; P = 0.001) and brain metastases (2.3 % vs. 0.6 %; P = 0.033; mHR = 4.03 [95% CI: 1.14–14.3]; P = 0.031). Other sites of metastasis, including the (retro) peritoneum, omentum, ovary, and bone, did not yield significant differences. ConclusionsImportant variations in site-specific rates of metastatic disease exist within major resection regions of colon cancer. These variations may be important to consider when evaluating options for adjuvant treatment and surveillance after resection of the primary disease.

Risk factors of liver metastasis in patients after radical resection of pancreatic cancer

To analyze the risk factors of liver metastasis in patients after radical resection of pancreatic cancer. One hundred and twenty-four patients with non-metastatic, resectable pancreatic cancer treated in our department between 2006 and 2012 were included in this study. All of these patients underwent resection of the primary tumor combined with extensive lymph node dissection. The development of postoperative liver metastases was carefully followed up, and the clinicopathological factors and molecular characteristics were evaluated by univariate analysis and multivariate logistic regression using SPSS 16.0 software. Forty-eight cases of liver metastases were found among the 124 cases of pancreatic cancer after radical surgery (38.7%). The rate of liver metastasis of pancreatic cancer after radical surgery in the age groups < 40, 40-60, and > 60 were 68.8%, 33.3% and 35.1%, respectively. The rate of liver metastasis in the body mass index (BMI) group < 20 kg/m2, 20-25 kg/m2, and > 25 kg/m2 were 21.6%, 44.1% and 52.6%, and the rate of liver metastasis in the time between the onset and diagnosis groups ≥ 3 months and < 3 months were 59.4% and 31.5%, respectively. The rate of liver metastasis in patients with preoperative fatty liver was 14.3% and it was 43.7% in patients without preoperative fatty liver. The rate of liver metastasis in patients of histological high, medium and low grade was 10.0%, 35.4% and 49.0%, respectively. The rate of liver metastasis in patients with venous tumor thrombus was 68.8% and it was 34.3% in patients without venous tumor embolus. The rate of liver metastasis in patients with postoperative chemotherapy was 31.2% and it was 51.1% in patients without postoperative chemotherapy. All those differences had statistical significance (P < 0.05). Univariate analysis revealed that age, body mass index (BMI), time between the onset and diagnosis, preoperative fatty liver, histological grading, tumor invasion depth, venous tumor embolus, and postoperative chemotherapy were significantly related to postoperative liver metastasis. Multivariate analysis revealed five statistically independent risk factors for postoperative liver metastasis: BMI, time between onset and diagnosis, preoperative fatty liver, histological grading, and venous tumor embolus. Our data suggest that patient's BMI, time between onset and diagnosis, histological grade, and venous tumor embolus are significantly correlated with postoperative liver metastases in patients with pancreatic cancer. Pancreatic cancer patients with preoperative fatty liver have less postoperative liver metastasis.

Beneficial effects of perioperative chemotherapy for pancreatic cancer.

448 Background: We retrospectively assessed the benefits of 5-fluorouracil (5-FU)- and heparin-based portal infusion chemotherapy (PI) combined with systemic administration of mitomycin C (MMC) and cisplatin (CDDP) for 4 weeks following surgery (PI4W). The goal was to determine if this treatment prevented liver metastasis and improved survival for patients with potentially curative resection of pancreatic cancer. Methods: 263 patients who underwent pancreatectomy from January 1985 to December 2013 were treated. Of these cases, 50 patients received portal infusion with 5-FU (250 mg/day) for 2 weeks (PI2W) following surgery (1985 `2001 Group A), while 94 patients received PI4W therapy (250 mg/day of 5-FU with 2,000 IU/day of heparin for 4 weeks, 4 mg MMC on days 6, 13, 20, 27, and 10 mg CDDP on days 7, 14, 21, 28)(2001 `2013 Group B). The remaining 119 patients (Ct) without adjuvant therapy during the perioperative period divided Group A (n=58) and Group B (n=61). Results: The cumulative overall survival rate in the PI2W was significantly higher than those in Ct of Group A. The cumulative overall survival rate in the PI4W also was significantly higher than those in Ct of Group B. Furthermore, in the PI4W group, the rate of liver metastasis is lower than Ct. Conclusions: PI therapy after surgery, especially PI4W, could become a promising adjuvant therapy in patients with potentially curative resection of pancreatic cancer. Clinical trial information: 000002976.

Effect of preoperative hepatic and regional arterial chemotherapy on metachronous liver metastasis after curative colorectal cancer resection: A prospective, multicenter, randomized controlled trial.

511 Background: To evaluate the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis for stage II and III colorectal cancer in a multicenter setting. Methods: Patients with clinical stage II or stage III colorectal cancer (CRC) were randomly assigned to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary end point was disease free survival (DFS). Second end points were incidence of metachronous liver metastasis, overall survival (OS) and safety. Results: A total of 688 patients from 5 centers of China were randomly assigned to each arm. Five-year DFS were 75% for PHRAC arm and 61% for control arm (HR 0.60; 95% CI, 0.45 to 0.80; p&lt;0.001). Five-year liver-metastasis rate was 8% and 18% in PHRAC arm and control arm, respectively (HR 0.39; 95% CI, 0.24 to 0.64; p&lt;0.001). Five-year OS was 81% in PHRAC arm and 72% in control arm (HR 0.59; 95% CI, 0.42 to 0.84; p=0.003). There were no significant differences in morbidity or mortality between two arms. The results of eligible patients were barely changed. Subgroup analysis shows differences of DFS, liver-metastasis rate and OS were significant in stage III patients, but not in stage II patients. Conclusions: Additional PHRAC could reduce the incidence of metachronous liver metastasis and improve DFS and OS in patients with stage III CRC, without compromising patient safety. Clinical trial information: NCT00643877.

Research of shRNAmir inhibitory effects towards focal adhesion kinase expression in the treatment of gastric cancer.

Gastric cancer is the fourth most common type of malignant tumor, with a poor prognosis. Focal adhesion kinase (FAK) mediates the crosslink of intracellular signaling networks, playing a key role in cell migration and invasion. The aim of the present study was to investigate the effects of FAK interference on the proliferation ability, invasion and metastasis of gastric cancer cells. The FAK-RNAi lentiviral vector was infected into SGC7901 gastric cancer cells in order to observe the in vivo situations of tumor growth and metastasis before and after the FAK interference. The growth of SGC7901 gastric cancer cells in the interference group was significantly inhibited compared with that of the negative control (P<0.05) and the blank control groups (P<0.05), and the FAK expression significantly decreased (P<0.05). The in vitro invasion and metastasis experiments showed that the cell invasion and metastasis abilities of the interference group significantly decreased when compared with those of the negative control (P<0.05) and blank control groups (P<0.05). In the nude mouse subcutaneous tumor transplantation model, the mean ± standard deviation tumor weight of the interference group (1.474±0.9840 g) was lower than that of the negative control (3.134±0.3299 g) and blank control (2.68±0.12 g) groups (P<0.05). In the nude mice, the liver and peritoneal metastasis rates of the interference group were significantly lower than those of the negative control (P<0.05) and the blank control groups (P<0.05), and the FAK mRNA of the interference group significantly reduced (P<0.05). In conclusion, FAK interference could effectively suppress the proliferation, invasion and metastasis of transfected SGC7901 gastric cancer cells, and could inhibit the growth and distant metastasis of gastric cancer in nude mice.

Abstract CT318: FOLFOXIRI+B-mab showed powerful effect as preoperative chemotherapy for multiple liver metastases of colorectal cancer

Abstract Background; R0 resection for liver metastases of colorectal cancer is one of the promising treatment to improve prognosis of advanced colorectal cancer. Powerful regimen FOLFOXIRI including 3 cytotoxic drugs; 5FU, irinotecan and oxaliplatin was reported as promising treatment for advanced colorectal cancer (J Clin Oncol 2007; 25: 1670-76). In our department Phase I/II study of FOLFOXIRI+B-mab including fluoroiuracil/oxaliplatin/irinotecan/bevacizumab for advanced liver metastases of colorectal cancer as pre-operative chemotherapy has been conducted now, and Phase II was on going. In this study, we report effect and safety of FOLFOXIRI+B-mab. Methods: The study was designed as a single-arm, open-label phase I/II trial. Phase I was conducted to decide tolerated dose (MTD) of irinotecan and 150 mg/m2 was decided as recommended dose. Patients who are colorectal cancer with 4 or more liver metastases and no other distant metastases are included. The regimen includes bevacizumab; 5 mg/kg, irinotecan; 150 mg/m2, oxaliplatin; 85 mg/m2, l-LV; 200 mg/m2, 5FU; 400 mg/m2 administered on day 1, followed by 5FU; 2400 mg/m2 continuously administered for 46 hours. R0 resection rate of liver metastases as primary endpoint will be evaluated. Results: Currently, 16 patients were enrolled. Two patients dropped out because of grade 3 diarrhea and grade 3 thromboembolism. One patient is waiting for liver resection and R0 resection of liver metastases was performed for 9 patients. In the 14 patients excluding 2 drop out, 13 showed PR and average of reduction rate was 51%. There was no pathological CR in the 9 patients who was performed R0 resection. There was no severe postoperative complication in them. Conclusion: This regimen is safe and shows high PR rate. So, the regimen is effective and improve R0 resection rate for multiple liver metastases of colorectal cancer. Further investigation of this study is still ongoing now. Citation Format: Yasushi Ichikawa, Ayumu Goto, Noritoshi Kobayashi, Motohiko Tokuhisa, Takashi Ishikawa, Atsushi Ishibe, Kazuteru Watanabe, Kazunori Nojiri, Yoshibumi Kumamoto, kazuhisa Takeda, Mitsuyoshi Ota, Hirotoshi Akiyama, Kuniya Tanaka, Itaru Endo. FOLFOXIRI+B-mab showed powerful effect as preoperative chemotherapy for multiple liver metastases of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT318. doi:10.1158/1538-7445.AM2014-CT318

Patterns and risk factors of recurrence in triple-negative breast cancer

To analyze the recurrence characteristics of triple-negative breast cancer (TNBC) and explore their clinicopathological correlations in northern China. Regression analyses were performed for 4 579 breast cancer patients from September 2002 to September 2007. Among them, there were 787 TNBC patients. The median follow-up period was 72 (9-116) months. And 187 (23.8%) TNBC patients recurred and it was significantly different from the recurrence rate of non-TNBC group (17.4%, P = 0.024). The median time to recurrence was 30.2 (4-110) months and 36.3% recurred 2 years while 27.8% did within 2-3 years. The rates of lung, liver and brain metastases to other sites were higher in TNBC patients than those in non-TNBC patients. TNBC patients had higher local recurrence rates than non-TNBC counterparts (2.92% vs 1.56%) (P = 0.009). Age, regional lymph node infiltration, tumor size and pathological stage were all independent prognostic factors of TNBC. TNBC has unique recurrence characteristics. It is prone to recur shortly with a high local recurrence rate. Metastatic rate is higher in visceral organ than bone.

Inhibitory effect of gene combination in a mouse model of colon cancer with liver metastasis.

The aim of the present study was to establish an animal liver metastasis model with human colon cancer and investigate the inhibitory effect of the wild type (WT) p53 gene combined with thymidine kinase/ganciclovir (TK/GCV) and cytosine deaminase/5-fluorocytosine (CD/5-FC) systems on liver metastasis of colon cancer. A nude mouse liver metastasis model with human colon cancer was established via a spleen cultivation method. A total of 32 nude mice were randomly divided into four groups, each group with eight mice. Group 1 mice received splenic injections of SW480 cells (control group), while group 2 mice were injected with SW480/p53 cells in the spleen. Group 3 mice were administered splenic injections of SW480/TK-CD cells, and GCV and 5-FC were injected into the abdominal cavity. Finally, group 4 mice received splenic injections of SW480/p53 cells mixed in equal proportion with SW480/TK-CD cells, as well as GCV and 5-FC injections in the abdominal cavity. These cells described were constructed in our laboratory and other laboratories. The number of liver metastatic tumors, the liver metastasis rate, conventional pathology, electron microscopy and other indicators in the nude mice of each group were compared and observed. The nude mouse liver metastasis model with human colon cancer was successfully established; the liver metastasis rate of the control group was 100%. The results demonstrated that the rate of liver metastasis in the nude mice in each treatment group decreased, as well as the average number of liver metastatic tumors. Furthermore, the effect of the treatment group with genetic combination (group 4) was the most effective, demonstrating that WTp53 had a synergistic effect with TK/GCV and CD/5-FC. Therefore, the present study successfully established a mouse model of liver metastasis with colon cancer by injecting human colon cancer cells in the spleen. Combined gene therapy was shown to have a synergistic effect, which effectively inhibited the formation of liver metastasis from colon cancer.

Baseline staging tests based on molecular subtype is necessary for newly diagnosed breast cancer

BackgroundBone scanning (BS), liver ultrasonography (LUS), and chest radiography (CXR) are commonly recommended for baseline staging in patients with newly diagnosed breast cancer. The purpose of this study is to demonstrate whether these tests are indicated for specific patient subpopulation based on clinical staging and molecular subtype.MethodsA retrospective study on 5406 patients with newly diagnosed breast cancer was conducted to identify differences in occurrence of metastasis based on clinical staging and molecular subtypes. All patients had been evaluated by BS, LUS and CXR at diagnosis.ResultsComplete information on clinical staging was available in 5184 patients. For stage I, II, and III, bone metastasis rate was 0%, 0.6% and 2.7%, respectively (P < 0.01); liver metastasis rate was 0%, 0.1%, and 1.0%, respectively (P < 0.01); lung metastasis rate was 0.1%, 0.1%, and 0.7%, respectively (P < 0.01). Complete information on molecular subtype was available in 3411 patients. For Luminal A, Luminal B (HER2-), Luminal BH (HER2+), HER2+ overexpression, and Basal-like, bone metastasis rate was 1.4%, 0.7%, 2.5%, 2.7%, and 0.9%, respectively (P < 0.05); liver metastasis rate was 0.1%, 0.1%, 1.0%, 1.1%, and 0.9%, respectively (P < 0.01); lung metastasis rate was 0.20%, 0%, 0%, 0.27%, and 0.9%, respectively (P < 0.05). cT (tumor size), cN (lymph node), PR (progesterone receptor), and HER2 status predicted bone metastasis (P < 0.05). cT, cN, ER (estrogen receptor), PR, and HER2 status predicted liver metastasis (P < 0.05). cT, cN, and PR status predicted lung metastasis (P < 0.05).ConclusionThese data indicate that based on clinical staging and molecular subtypes, BS, LUS and CXR are necessary for patients with newly diagnosed breast cancer.

Clinical characteristics and prognosis of hepatoid adenocarcinoma of the stomach

Hepatoid adenocarcinoma of the stomach (HAS) is a special type of gastric cancer characterized with hepatoid differentiation and the production of large amounts of α-fetoprotein (AFP). The pathogenesis of HAS is still not clear. Most of the relative studies are single case reports, and studies with large sample are absent. The prognosis of HAS is poor. HAS has a high rate of liver metastasis. The biology behaviors of HAS differ from common gastric cancers. Radical resection of the gastric cancer is considered to be the main treatment when no liver metastasis is found, while the treatment regimens of the metastasis lesions are still in debate. The serum AFP test is important for the early detection and diagnosis of HAS, and it is crucial for monitoring the therapeutic effect and the relapse and metastasis of the tumor.

MiRNA27a Is a Biomarker for Predicting Chemosensitivity and Prognosis in Metastatic or Recurrent Gastric Cancer

We previously identified five miRNAs (miR-1, miR-20a, miR-27a, miR-34a, and miR-423-5p) that are up-regulated in gastric cancer. The goal of this study was to investigate the value of these miRNAs as potential biomarkers for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer patients who received first-line chemotherapy. A total of 82 patients with metastatic or recurrent GC receiving first-line chemotherapy were included in our study. The expression levels of the five miRNAs were evaluated using hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in individual samples before first-line chemotherapy. Patients receiving first-line chemotherapy with fluoropyrimidine combined with oxaliplatin or paclitaxel were chosen for the chemosensitivity analysis. The relationships between expression of the five-miRNAs and clinicopathological parameters, response to chemotherapy and prognosis were analyzed statistically. Patients with higher miRNA1 expression levels tended to have a higher rate of liver metastasis, and higher miRNA34a expression levels occurred more frequently in males (P = 0.022). The expression of the remaining three miRNAs showed no obvious relationship to any of the clinicopathological features. The partial response rates of the patients with high miRNA1 expression and low miRNA1 expression were 11.1% and 23.1%, respectively (P = 0.048). Similar results were observed for miRNA27a (the partial response rate was 7.7% vs. 25.9%, P = 0.018). Patients with up-regulated miRNA27a expression had a significantly worse overall survival (OS) than patients with lower miRNA27a expression (P = 0.024). In patients with MRGC, miRNA27a is a potential biomarker for predicting resistance to fluoropyrimidine-based chemotherapy and a novel prognostic marker for gastric cancer.

Is prostate cancer changing?: evolving patterns of metastatic castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) most commonly metastasizes to the bone, and less commonly to nonosseous sites (eg, lymph nodes, liver, lung). With new therapies extending survival in mCRPC, it was hypothesized that the pattern of metastases is changing over time. The pattern of metastatic disease was evaluated in men with mCRPC, as reported in baseline characteristics of prospective clinical trials over 2 decades. This study identified all phase 2 and 3 therapeutic studies in men with mCRPC in PubMed and American Society of Clinical Oncology abstracts from 1990 to 2012. Studies were excluded if they did not report demographic data and sites of metastasis, or excluded patients with a specific site of metastatic disease (except brain). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. A total of 290 eligible studies (270 phase 2 studies and 20 phase 3 studies) involving 19,110 patients were identified. Between 1990 and 2012, the rate of nonosseous metastasis increased significantly at 1.6% per year (P < .0001), whereas the rate of osseous metastasis decreased at 0.5% per year (P < .0001). The rate of lymph node metastasis increased at 1.4% per year (P < .0001), but the rate of liver and lung metastasis remained relatively stable. A notable change was found in the pattern of metastasis in patients with mCRPC. Because these evolving patterns may have important implications in treatment selection and prognosis, it is crucial that future clinical trials of patients with mCRPC define patients with a uniform reporting of nonosseous metastasis.

The status of HBV infection influences metastatic pattern and survival in Chinese patients with pancreatic cancer

BackgroundIt has been proved that hepatitis B virus (HBV) infection alters the metastatic pattern and affects survival in colorectal cancer (CRC) and hepatocellular carcinoma (HCC), while the influence of HBV infection on metastatic pattern and survival in patients with pancreatic cancer (PC) has not been investigated yet.MethodsWe conducted an investigation to evaluate the impact of HBV infection on metastatic pattern and overall survival in PC. We collected the data of 460 PC patients treated in our hospital from 1999 to 2010. Serum HBV markers were tested with enzyme-linked immunosorbent assay. The impact of HBV infection on metastatic pattern and overall survival was analyzed.ResultsWe found that the incidence of synchronous liver metastasis was significantly higher in patients with HBsAg positive than those with HBsAg negative (46.0% vs 32.0%, P < 0.05), and higher in chronic HBV infection (CHB) group than both non HBV infection and resolved HBV infection group (61.1% vs 33.9%, P < 0.05, and 61.1% vs 28.7%, P < 0.05, respectively). What’s more, Kaplan-Meier analysis showed that CHB, resolved HBV infection and non HBV infection group had significant longer overall survival (OS) compared with inactive HBsAg carriers (IC) group (P=0.037, P=0.009, and P=0.019 respectively). But, in the multivariate analysis, only the CHB and non HBV infection group had significant better overall survival compared with IC group (P=0.010 and P=0.018 respectively).ConclusionsOur study found that HBV infection increased synchronous liver metastasis rate, and HBV infection status was an independent prognostic factor in PC patients.

Clinical characteristics and prognostic factors of prostate cancer with liver metastases

Liver metastasis from prostate cancer is uncommon and remains poorly understood. We computer searched the clinical records of all our patients registered into a database to identify patients that presented or developed liver metastases. A total of 27 prostate cancer patients with ultrasound or CT/MR imaging evidence of liver metastases were included in our analysis. The liver metastasis rate from metastatic prostate cancer was 4.29%. Eight (29.63%) patients had previously untreated, hormone-naive prostate cancer (synchronous liver metastases at diagnosis of prostate cancer), whereas 19 (70.37%) patients had already been diagnosed as having hormone-refractory prostate cancer. In the hormone-naive group, the median overall survival after liver metastases diagnosis was 38 months and half of the patients were still alive at the latest follow-up, whereas only 6 months in the hormone-refractory group (p = 0.003). High concentration of serum neuron-specific enolase and previous chemotherapy were associated with a significantly poor overall survival after liver metastases in the hormone-refractory group using Kaplan–Meier curves and logrank tests for univariate analysis.

CTLs/regulatory T-cells ratio as a prediction marker of chemotherapy in metastatic colorectal cancer.

e14684 Background: Many multiple anti cancer drugs regimens have been established for metastaticcolorectal cancer recently. We investigated cellular immunoreaction of these patients to their cancer. Methods: 32 metastatic colorectal cancer patients have been started chemotherapies. Their PBMCs were harvested and investigated their character by Fac scan with fluorescent labeled antibodies (CD3,CD8, CD4, CD25, Foxp3) at before and after chemotherapy. Results: After chemotherapy, both CTLs(CD3, CD8 positive) and regulatory T cells (CD4, CD25, Foxp3 positive) were decreased in number among all patients. On the other hand, CTL/T reg ratio were significantly increased among tumor marker decreased patients and significantly decreased among tumor marker increased or stable patients. CEA levels among 85.7% of increased CTL/T reg ratio patients became to decrease less thanhalf. CEA levels among 66.7% of decreased CTL/T reg ratio patients became to increase or to be stable, if their regimens have not been changed. The Reactive Rate of chemotherapy of CTL/T reg ratio increased patients was significantly higher than that of ratio decreased or stable patients. (P=0.021) The Disease Control Rate of chemotherapy of CTL/T reg ratio increased patients was higher than that of ratio decreased patients. Both resectability rate of liver metastatic lesion and early tumor shrinkage rate were higher at the CTL/T reg ratio increased patients group than at the other patients group. Conclusions: We found that the CTL/T reg ratios of PBMC in metastatic colorectal cancer patients were useful for prediction of the effect of chemotherapy.

Abstract 4675: Effect and safety of FOLFOXIRI+B-mab as preoperative chemotherapy for multiple liver metastases of colorectal cancer.

Abstract Background; R0 resection for liver metastases of colorectal cancer is one of the promising treatment to improve prognosis of advanced colorectal cancer. Powerful regimen FOLFOXIRI including 3 cytotoxic drugs; 5FU, irinotecan and oxaliplatin was reported as promising treatment for advanced colorectal cancer (J Clin Oncol 2007; 25: 1670-76). In our department Phase I/II study of FOLFOXIRI+B-mab including fluoroiuracil/oxaliplatin/irinotecan/bevacizumab for advanced liver metastases of colorectal cancer as pre-operative chemotherapy has been conducted now, and Phase I was concluded. In this study, we report effect and safety of FOLFOXIRI+B-mab in Phase I study. Methods: The study was designed as a single-arm, open-label phase I/II trial. Phase I was conducted as sequential dose escalation to define the maximum- tolerated dose (MTD) of irinotecan. Patients who are colorectal cancer with 4 or more liver metastases and no other distant metastases are included. The regimen includes bevacizumab; 5 mg/kg, oxaliplatin; 85 mg/m2, l-LV; 200 mg/m2, 5FU; 400 mg/m2 administered on day 1, followed by 5FU; 2400 mg/m2 continuously administered for 46 hours. Dose escalation of Irinotecan was planned from level 1; 150 mg/m2, level 2; 180 mg/m2 and level 0; 125 mg/m2. In Phase II, R0 resection rate of liver metastases as primary endpoint will be evaluated using MTD of irinotecan estimated in Phase I. Results: Currently, 9 patients were enrolled. In level 1, 1 patient showed Grade 3 diarrhea as dose-limiting toxicity and for the other 5 patients 150 mg/m2 of irinotecan was tolerable. In level 2, 2 patients showed DLT; one was Grade 3 diarrhea in the 1st cycle and the other one was febrile neutropenia in the 2nd cycle. Then 180 mg/m2 of irinotecan was over the MTD. Then Phase I study was concluded and recommend dose of irinotecan was decided as 150 mg/m2. In all adverse event, Grade 3/4 neutropenia was detected in 66%. Excluding hematological toxicity, Grade 3 or worse adverse event was 2 cases of Grade 3 diarrhea. In the 6 patients, one patient have dropped out, 4 patients were performed R0 resection and one patient could not be performed R0 resection after 6 cycles of regimen. All 5 patients showed PR and average of reduction rate was 62.7%. There was no pathological CR in the 4 patients who was performed R0 resection. There was no severe postoperative complication in them. Conclusion: This regimen is safe and shows high PR rate. So, the regimen is effective and improve R0 resection rate for multiple liver metastases of colorectal cancer. Further investigation of this study is still ongoing now. Citation Format: Yasushi Ichikawa, Ayumu Goto, Noriotoshi Kobayashi, Motohiko Tokuhisa, Takashi Ishikawa, Kenichi Kondo, Atsushi Ishibe, Kazuteru Watanabe, Mitsuyoshi Ota, Shoichi Fujii, Hirotoshi Akiyama, Kuniya Tanaka, Itaru Endo. Effect and safety of FOLFOXIRI+B-mab as preoperative chemotherapy for multiple liver metastases of colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4675. doi:10.1158/1538-7445.AM2013-4675

Prognostic Impact of N Staging in 715 Medullary Thyroid Cancer Patients

This institutional study aimed at quantifying a medullary thyroid cancer (MTC) patient's risk of lung, liver, or bone metastasis. Without quantitative information regarding risk factors for lung, liver, and bone metastasis, risk stratification is liable to be haphazard, resulting in poor cost-effectiveness of screening programs. Included in this study were 715 patients with MTC for whom histopathologic information was available for each lymph node removed. Seventy-two patients (10.1%) were diagnosed with lung metastasis, 58 patients (8.1%) with liver metastasis, and 34 patients (4.8%) with bone metastasis. Multivariate analyses were limited to patients revealing no more than 1 type of distant metastasis to avoid confounding by other distant metastasis. Extrathyroidal extension and 1 to 10 involved nodes indicated a small risk of lung metastasis [3%-4%; odds ratio (OR) 3-4], tumors greater than 40 mm and 11 to 20 involved nodes implied an intermediate risk (13%; OR 6), and more than 20 involved nodes entailed a high risk (26%-30%; OR 14-16). In the multivariate logistic regressions on liver and bone metastasis, in which the number of involved nodes was omitted on statistic grounds, extrathyroidal extension signified a strong risk of liver metastasis (19%, OR 23), whereas no clinical-pathologic variables were significantly associated with bone metastasis. Cumulative rates of lung, liver, and bone metastasis, plotted against the number of lymph node metastases, were similar. N categories encompassing 1 to 10 (N1), 11 to 20 (N2), and more than 20 (N3) lymph node metastases are important prognostic classifiers that should be incorporated into MTC staging systems for better risk stratification.

Liver-directed chemotherapy of cetuximab and bevacizumab in combination with oxaliplatin is more effective to inhibit tumor growth of CC531 colorectal rat liver metastases than systemic chemotherapy

Colorectal carcinoma is, through to its high rate of liver metastasis (mCRC), the second most cause of cancer death worldwide. Tumor resection represents the only potential cure. In cases of unresectable disease systemic chemotherapy (sCHT) remains the therapy of choice. Modern sCHT regimens including biological agents can induce tumor response that leads to curative surgery of initially unresectable mCRC. However, liver-directed therapy via hepatic arterial infusion (HAI) may produce higher response rates than sCHT. Herein we studied whether a HAI of cetuximab (CE) plus bevacizumab (BE) with or without oxaliplatin (OX) can inhibit tumor growth in a rat model. WAG/Rij rats underwent subcapsular hepatic tumor implantation. After 10 days animals received either HAI or sCHT of CE plus BE, OX or all three drugs. Saline-treated animals served as controls. Tumor growth was estimated at day 10 and 13. On day 13 liver and tumor tissue was studied histologically and immunohistochemically. In controls the tumors grew about 50 %. OX alone was not capable of inhibiting tumor growth. In contrast, CE plus BE given as HAI significantly reduced tumor growth compared to sCHT (p < 0.05). HAI of CE plus BE combined with OX yielded an even more pronounced inhibition of tumor growth. Immunohistochemistry revealed a decreased tumor cell proliferation and tumor vascularization. The present study demonstrates that HAI of CE plus BE is effective to inhibit tumor growth. This effect is even more pronounced in combination with OX. Systemic application of these agents cannot achieve comparable effects.

Effect of Portal Vein Chemotherapy on Liver Metastasis after Surgical Resection of Colorectal Cancer

To explore the effect of portal vein chemotherapy on liver metastasis after surgical resection of colorectal cancer. Patients fulfilling the eligibility criteria were assigned to receive either surgery plus 1-week continuous infusion of 5-FU (study group) or surgery alone (observational group). Patients in the study group received portal vein chemotherapy, whereby 5-FU (1000 mg/d) and heparin (5000 IU/d) infusion was initiated from the day of surgery and lasted for 7 consecutive days. Liver metastasis was monitored during five years follow-up postoperatively. Sixty four patients were recruited and assigned to the study group (12 with colon and 20 with rectal cancer) or the control group (10 with colon and 22 with rectal cancer). Liver metastasis rate was 12.5% in study and 25.0% in observational group, the difference being significant (P<0.01). Portal vein chemotherapy could be an effective treatment in preventing liver metastasis after surgical resection of colorectal cancer.

Stem cell gene Girdin: a potential early liver metastasis predictor of colorectal cancer

The objective of this study is to investigate the liver's metastasis-related genes and the relationship between Girdin protein expression and clinical and pathological characteristics and prognosis in colorectal cancer. The differential expression of genes between tumor cells from cases with liver metastasis and those from cases without liver metastasis were detected using an RT(2) Profiler™ PCR Array. The expression of the stem cell gene Girdin was analyzed using immunohistochemistry staining. Subsequently, the relationship between Girdin and clinicopathological parameters of colorectal cancer was determined. The Girdin protein was verified as a gene related to liver metastasis and was expressed positively in 161 (37.01 %) of the 435 cases examined. The expression of Girdin protein was related to histological grade and distant metastasis (P = 0.007 and 0.007, respectively). After analyzing survival rates, cases with highly expressed Girdin protein were shown to attain a significantly higher rate of liver metastasis and poorer postoperative, disease-specific survival than those with no or low expressed Girdin protein (P = 0.001). In the Cox regression test, the depth of tumor invasion, histological grade, duke's stage, distant metastasis, and the Girdin protein were detected as an independent prognostic factor (0.020, 0.032, 0.001, 0.001, and 0.010, respectively). The Girdin protein may be a potential new early liver metastasis biomarker of colorectal cancer.