• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3967-3971
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• 2012

Aims: To explore the relationship between various molecular makers and liver metastasis of colorectal cancer (CRC). Method: Using immunohistochemistry, protein expression of CEA, nm23, c-met, MMP2, COX-2, VEGF, EGFR, and CD44 was assessed in 80 CRC cases. The Chi-square test and logistic regression were performed to analyze the relationship between these indicators and CRC liver metastasis. Results: There were significant differences in expression of CEA, MMP2, CD44, VEGF and EGFR between the liver metastasis and non metastasis groups (P < 0.05); no significant differences were noted for nm23, c-met, and COX-2 expression. Logistic regression analysis showed that only CEA, VEGF, and EGFR entered into the regression equation, and had significant correlations with CRC liver metastasis (${\alpha}$ inclusion= 0.10, ${\alpha}$ elimination = 0.15, R2 = 0.718). Conclusions: Combination detection of CEA, VEGF, and EGFR may be an effective means to predict CRC liver metastasis. Nm23, c-met, MMP2, COX-2, and CD44, in contrast, are not suitable as prognostic markers.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.1003-1007
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• 2013

Objective: This work aimed to investigate the correlations of tumor-associated macrophages (TAMs) and their subtypes M1 and M2 with liver metastasis of colorectal cancer, and provide useful references for seeking predictors of liver metastasis and studying mechanisms. Methods: 120 patients with colorectal cancer from 2000 to 2009 were divided into low, middle and high liver metastasis groups (group A, B and C, respectively). S-P immunohistochemical staining and microscopic observation were conducted to compare expression in CD68-positive cells (TAMs), CD80-positive cells (M1) and CD163-positive cells (M2) in three groups. Correlations of TAMs, M1, M2, and M2/M1 ratio with clinical and pathological parameters were analyzed. Results: With increase of liver metastatic ability, the number of TAMs decreased gradually, with no significant difference between any two of the three groups (P > 0.05), while the numbers of M1 and M2 were significantly decreased and increased, respectively, with significant difference between any two of three groups (P < 0.05 or P < 0.01). In addition, the M2/M1 ratio increased with increase of liver metastatic ability (P < 0.01). There was no statistical significance of correlation of TAMs with each clinical and pathological parameter. M1 was negatively related with lymphatic metastasis and liver metastatic ability. M2 was positively correlated with preoperative CEA level, lymphatic metastasis, tumor differentiation degree and liver metastatic ability. The same was the case for the M2/M1 ratio. Conclusions: Effects of TAMs on liver metastasis of colorectal cancer do not depend on the total number of TAMs, but on the number and proportion of functional subtypes M1 and M2. M2 number and M2/M1 ratio are more accurate predictors for liver metastasis of colorectal cancer.

• Biomolecules & Therapeutics
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• v.30 no.2
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• pp.162-169
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• 2022

We utilized Fas21, a resveratrol analog, to modulate the function of hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the angiogenic phase of murine liver metastasis by B16 melanoma and 51b colorectal carcinoma. Preangiogenic micrometastases were treated with Fas21 (1 mg/kg/day) or vehicle during the development of intra-angiogenic tracts. Mice treated with Fas21 showed reduced liver tumor foci in both liver metastasis models. Micrometastases were classified immunohistochemically, as well as according to their position coordinates and connection to local microvasculature. The volume of liver occupied by sinusoidal-type foci, containing infiltrating angiogenic capillaries, decreased by ~50% in Fas21-treated mice compared to vehicle-treated ones in both tumor metastasis models. The volume of portal foci, containing peripheral neoangiogenesis within a discontinuous layer of myofibroblasts, was similar in all experimental groups in both tumor metastasis models, but displayed enhanced necrotic central areas devoid of angiogenesis following Fas21 treatment. As a result, sinusoidal tumors from mice treated with Fas21 showed a 50% reduction in desmin(+)/asma(+) HSCs and CD31(+) vessel density, and a 45% reduction in intrametastatic VEGF mRNA compared with sinusoidal tumors from vehicle-treated mice. Necrotic portal metastases increased 2-4-fold in treated mice. In vitro, Fas21 reduced VEGF secretion by HSCs and 51b cells dose-dependently. Additionally, HSCs migration in response to tumor soluble factors was dose-dependently diminished by Fas21, as was LSEC migration in response to HSCs and tumor soluble factors. Resveratrol analog Fas21 inhibits the proangiogenic response of HSCs and LSECs during the development of murine liver metastasis.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.4959-4962
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• 2012

The objective of this retrospective study was to investigate prognostic factors associated with survival of patients with extensive stage small cell lung cancer (ES-SCLC). Included were 200 patients admitted to the Liberation Army General Hospital with a diagnosis of ES-SCLC. The demographics of patients, disease characteristics, pre-treatment biochemical parameters and therapeutic plan were assessed or evaluated. Univariate analysis found that second-line chemotherapy, radiotherapy, and no liver metastasis were associated with improved survival. Tumor response to first-line chemotherapy and normal initial hemoglobin levels were also associated with a survival benefit (all P-values ${\leq}$ 0.0369). Multivariate Cox regression analysis indicated that liver metastasis and the total number of all chemotherapy cycles were independent prognostic factors of survival. The morbidity risk in patients with liver metastasis was 2.52-fold higher than that in patients without liver metastasis (hazard ratio (HR)=2.52 (1.69-3.76); P<0.0001). However, one unit increase in the total number of chemotherapy cycles decreased the risk of death by 0.86-fold (HR=0.86 (0.80-0.92); P<0.0001). Absence of liver metastasis and ability of a patient to receive and tolerate multiple lines of chemotherapy were associated with longer survival.

• Journal of Gastric Cancer
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• v.11 no.1
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• pp.23-30
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• 2011

Purpose: ${\alpha}$-fetoprotein (AFP)-producing gastric cancer is a rare tumor with high rates of liver metastasis and a poor prognosis. Many studies have been performed but there have been no comprehensive investigations of the clinicopathological and prognosis. Materials and Methods: Six hundred ninety four patients with gastric cancer who underwent a curative gastric resection in Hanyang University Hospital from February 2001 to December 2008 were evaluated retrospectively after excluding active or chronic hepatits, liver cirrhosis and preoperative distant metastasis. Among them, thirty five patients had an elevated serum level of AFP (>7 ng/ml) preoperatively. The clinicopathological features of AFP-producing gastric cancer were analyzed. Results: There was poorer differentiation, a higher incidence of lymph node metastasis, more marked lymphatic and vascular invasion in the AFP-positive group than in the AFP-negative group. The 5-year survival rate of the AFP-positive group was significantly poorer than that in the AFP-negative group (66% vs. 80%, P=0.002). A significantly higher incidence of liver metastasis was observed in the AFP-positive group than in the AFP-negative group (14.3% vs. 3.6%, P=0.002) with a shorter median time period from the operation to the metachronous liver metastasis (3.7 months vs. 14.1 months, P=0.043). Multivariate survival analysis revealed the depth of invasion, degree of lymph node metastasis and AFP-positivity to be the independent prognostic factors. Conclusions: AFP-producing gastric cancers have an aggressive behavior with a high metastatic potential to the liver. In addition, their clinicopathological features are quite different from the more common AFP-negative gastric cancer.

• Molecules and Cells
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• v.45 no.5
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• pp.329-342
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• 2022

The liver is the predominant metastatic site for pancreatic cancer. However, the factors that determine the liver metastasis and the specific molecular mechanisms are still unclear. In this study, we used human pancreatic cancer cell line Hs766T to establish Hs766T-L3, a subline of Hs766T with stable liver metastatic ability. We performed RNA sequencing of Hs766T-L3 and its parental cell line Hs766T, and revealed huge differences in gene expression patterns and pathway activation between these two cell lines. We correlated the difference in pathway activation with the expression of the four core transcriptional factors including STAT1, NR2F2, GATA2, and SMAD4. Using the TCGA database, we examined the relative expression of these transcription factors (TFs) in pan-cancer and their relationship with the prognosis of the pancreatic cancer. Among these TFs, we considered GATA2 is closely involved in tumor metastasis and may serve as a potential metastatic driver. Further in vitro and in vivo experiments confirmed that GATA2-mediated transcriptional activation of Notch3 promotes the liver metastasis of Hs766T-L3, and knockdown of either GATA2 or Notch3 reduces the metastatic ability of Hs766T-L3. Therefore, we claim that GATA2 may serve as a metastatic driver of pancreatic cancer and a potential therapeutic target to treat liver metastasis of pancreatic cancer.

• Korean Journal of Clinical Oncology
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• v.14 no.2
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• pp.142-145
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• 2018

Metastases to the liver can be found in various malignancies, most commonly originating from the colon, rectum, pancreas, stomach, esophagus, breast, lung, and melanoma. Surgical resection of liver metastasis is generally considered to be the definitive therapy fore cure. However, many patients are unable to undergo surgical resection due to medical comorbidities or multifocal extent of malignant disease affecting the liver. Among patients not eligible for surgery, other therapies exist for treatment in order to down stage the disease for surgical resection or for palliation. Radioembolization of hepatic metastases has shown to improve outcomes among patients with variety of malignancies including more common malignancies such as colorectal cancer. Yttrium-90 (Y-90) radioembolization has been successfully used in the management of hepatic metastases. A small series of metastatic sarcoma to the liver treated with radioembolization showed a promising response. We report a case of metastatic gastric leiomyosarcoma to the liver treated with Y-90 glass microspheres therapy using the radiation segmentectomy approach, previously described for hepatocellular carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4699-4701
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• 2012

Objective: To explore the effect of portal vein chemotherapy on liver metastasis after surgical resection of colorectal cancer. Methods: 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. Results: 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). Conclusion: Portal vein chemotherapy could be an effective treatment in preventing liver metastasis after surgical resection of colorectal cancer.

• Journal of Chest Surgery
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• v.55 no.5
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• pp.397-404
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• 2022

Background: Distant recurrence of esophageal cancer (EC), even after radical resection, is common, and the most frequent site of EC metastasis is the liver. However, a multidisciplinary treatment strategy for postoperative liver metastasis (LM) from EC has yet to be established; in particular, the role of liver-directed therapy (LDT) remains uncertain. We investigated the clinicopathological features and outcomes of patients undergoing post-esophagectomy LM with versus without LDT to explore its therapeutic implications. Methods: Among 624 consecutive patients undergoing R0/R1 esophagectomy for EC, 30 were identified in whom LM had developed as the initial recurrence. Their characteristics were retrospectively reviewed. Results: Six of the 30 subjects underwent LDT for metachronous LM. Five of those 6 also received systemic chemotherapy. A comparison between the 6 LDT and 24 non-LDT cases revealed no significant differences in major clinicopathological and operative factors, except for concurrent metastasis to extrahepatic organs (1/6 vs. 15/24, p=0.044). Twenty-nine of the 30 patients died during the study period, whereas 1 who had received multimodal treatment with LDT remained alive more than 200 months after multiple LM had been detected. Kaplan-Meier analysis for survival after LM demonstrated significantly prolonged survival in LDT cases compared to non-LDT cases treated with systemic chemotherapy alone (p=0.014). Even when the analysis was limited to patients without extrahepatic metastasis, this significant prognostic advantage of LDT was maintained (p=0.047). Conclusion: Multimodal treatment combined with LDT might be beneficial for patients with metachronous LM from EC and should therefore be considered a potential treatment option.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.4001-4005
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• 2012

Backgrouds: The hedgehog (Hh) signaling pathway is composed of patched (PTCH) and smoothened (SMO), two transmembrane proteins, and downstream glioma-associated oncogene homolog (Gli) transcription factors. Hh signaling plays a pathological role in the occurrence and development of various cancers. Methods: To investigate the expression of SMO protein in colon cancer and its association with clinicopathological parameters and postoperative liver metastasis, immunohistochemistry was performed with paraffin-embedded specimens of 96 cases. Relationships between SMO protein expression and clinicopathological parameters, postoperative liver metastasis were analyzed. Results: IHC examination showed that SMO protein expression was significantly increased in colon cancer tissues compared to normal colon tissues (P = 0.042), positively related to lymph node metastases (P = 0.018) and higher T stages (P = 0.026). Postoperative live metastasis-free survival was significantly longer in the low SMO expression group than in those with high SMO expression ($48.7{\pm}8.02$ months vs $28.0{\pm}6.86$ months, P=0.036). Multivariate analysis showed SMO expression level to be an independent prognostic factor for postoperative live metastasis-free survival (95% confidence interval [CI] =1.46-2.82, P = 0.008). Conclusions: Our results suggest that in patients with colon cancer, the SMO expression level is an independent biomarker for postoperative liver metastasis, and SMO might play an important role in colon cancer progression.