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Objective: Chemotherapy is generally recommended as the first-line standard treatment in patients with liver metastasis from gastric cancer. However, the clinical impact of surgical treatment remains unclear in responders after chemotherapy. The present study aimed to investigate the tumor response and prognosis after chemotherapy and to assess the clinical indication of conversion surgery in responders., Methods: The study retrospectively reviewed the clinical data of 44 patients with liver metastasis from gastric cancer who were treated with chemotherapy between February 2002 and January 2019. These patients were classified into progressive disease (PD) and non-PD groups according to tumor response., Results: Among the 44 patients, 7 and 26 had peritoneal dissemination and ≥5 had metastatic liver nodules. Additionally, 15 and 29 patients had PD and non-PD, respectively. Surgical treatment was significantly correlated with tumor response (p < 0.0321). Prognostic differences between the PD and non-PD groups were significant (p < 0.0001). Moreover, gastrectomy and hepatectomy were significantly correlated with the number of liver metastases (≥5 vs. <5, respectively) in the non-PD group (p = 0.0025 and p = 0.0169, respectively). The 3-year survival rates among patients with non-PD undergoing both gastrectomy and hepatectomy (n = 6), gastrectomy alone (n = 7), and nonsurgical treatments (n = 16) were 100, 66.7, and 0%, respectively (p = 0.0026). Multivariate analysis identified peritoneal dissemination as an independent prognostic factor (p = 0.0225)., Conclusion: Our preliminary results suggest that conversion surgery for gastric cancer with liver metastasis might be clinically indicated in chemotherapy responders with <5 metastatic liver nodules and without peritoneal dissemination., (© 2020 S. Karger AG, Basel.)

Background: The necessity of surgical treatment of liver metastases of gastric cancer is still controversial., Patients and Methods: We conducted a multicenter retrospective cohort study of liver-limited metastasis of gastric cancer treated surgically between 2000 and 2010. In this study, 103 patients were registered, with nine patients excluded from the analysis as they did not meet the eligibility criteria., Results: Of the 94 patients, 69 underwent surgical resection, 11 underwent surgical resection combined with radiofrequency ablation or microwave coagulation therapy for small or deep tumors, and 14 underwent radiofrequency ablation or microwave coagulation therapy only. Synchronous and metachronous metastases were found in 37 and 57 patients, respectively. The 3- and 5-year overall survival rates of all the patients were 51.4 and 42.3 %, respectively. The 3- and 5-year relapse-free survival rates were 29.2 and 27.7 %, respectively. No significant difference in prognosis was observed between the patients who underwent surgical resection and those who underwent ablation therapy. The patients with hepatic solitary lesions and low-grade lymph node metastases of primary gastric cancer had significantly better overall survival and relapse-free survival., Conclusions: To our knowledge, this study is the largest series and first multicenter cohort study of liver-limited metastasis of gastric cancer. The study indicated that patients with a single liver metastasis with a grade lower than N2 lymph node metastasis of the primary lesion are the best candidates for liver resection.

Background: While recent research has shown that expression of ZEB-1 in a variety of tumors has a crucial impact on patient survival, there is little information regarding ZEB-1 expression in hepatocellular carcinoma (HCC). This study investigated the co-expression of ZEB-1 and E-cadherin in HCC by immunohistochemistry and evaluated its association with clinical factors, including patient prognosis., Methods: A total of 108 patients with primary HCC treated by curative hepatectomy were enrolled. ZEB-1 expression was immunohistochemically categorized as positive if at least 1% cancer cells exhibited nuclear staining. E-cadherin expression was divided into preserved and reduced expression groups and correlations between ZEB-1 and E-cadherin expression and clinical factors were then evaluated., Results: With respect to ZEB-1 expression, 23 patients were classified into the positive group and 85 into the negative group. Reduced E-cadherin expression was seen in 44 patients and preserved expression in the remaining 64 patients. ZEB-1 positivity was significantly associated with reduced expression of E-cadherin (p = 0.027). Moreover, significant associations were found between ZEB-1 expression and venous invasion and TNM stage. ZEB-1 positivity was associated with poorer prognosis (p = 0.025). Reduced E-cadherin expression was significantly associated with intrahepatic metastasis and poorer prognosis (p = 0.047). In particular, patients with both ZEB-1 positivity and reduced E-cadherin expression had a poorer prognosis (p = 0.005). Regardless of E-cadherin status, ZEB-1 was not a significant prognostic factor by multivariate analysis. There was no statistical difference in overall survival when E-cadherin expression was reduced in the ZEB-1 positive group (p = 0.24)., Conclusions: Positive ZEB-1 expression and loss of E-cadherin expression are correlated with poor prognosis in HCC patients and malignancy of ZEB-1 positive tumors involves EMT.

Background: In terms of timing of resection for synchronous liver metastases from colon cancer, some reports recommend leaving an interval (e.g., 3 months) after primary colorectal resection, because of reports of occasional and rapid remnant recurrence of residual liver metastases after simultaneous colorectal and liver resection (LR). For patients with metachronous liver metastasis (MLM), we prospectively examined the appropriateness of a 3-month interval to LR (i.e., delayed resection) following initial detection of hepatic lesions from the viewpoints of (1) detection of new metastases during this interval and (2) postoperative outcome., Methods: Seventy-nine consecutive patients with modified Japanese criteria H1 class MLM (i.e., ≤4 nodules, 6 cm or less in diameter) and without obvious extrahepatic lesions, presenting between 1990 and 2008, were included in this study. Between 1990 and 2001, 52 patients were treated by LR without an interval (i.e., nondelayed group); from 2002, 27 patients were prospectively scheduled for LR at an interval of 3 months after initial detection of metastases (i.e., delayed group). During the 3-month interval, no adjuvant chemotherapy was given. Just prior to LR, patients were re-evaluated using computed tomography (CT) and deoxy-2-[(18)F]fluoro-D: -glucose positron emission tomography (FDG-PET) to exclude cases unsuitable for surgery., Results: Out of 27 patients in the delayed group, 2 (7.4%) did not undergo LR after the 3-month interval and were excluded from the analysis: one because of multiple nodules in the bilateral lobe of the liver with pulmonary metastases and another because of para-aortic lymph node metastasis. Of the 25 patients for whom LR was indicated, 24 underwent LR as initially planned. In the remaining patient, after the 3-month interval, invasion of the tumor had occurred into the inferior vena cava (IVC) and other surgery in addition to the planned operation was required. When comparing the postoperative outcome data of the delayed group (n = 25) with the nondelayed group (n = 52), overall early recurrence within 1 year after LR was noticed in 30.9% (16/52) of the nondelayed group and 28.0% (7/25) of the delayed group; the incidence of only early extrahepatic recurrence decreased 5.1% in the delayed group (21.1% versus 16.0%, respectively). When comparing disease-free survival after liver resection, however, there was no significant difference between the groups., Conclusions: Delayed LR for MLM patients after initial detection of hepatic lesions is of no clinical benefit. Only in cases when extrahepatic lesions with MLM are suspected could an interval make such lesions clearer and assist in deciding on a suitable management plan.

Background: Recent studies have shown that intraoperative blood loss and blood transfusions promote postoperative recurrence of hepatocellular carcinoma (HCC). Hyperbaric oxygen therapy (HBOT) is a specific method of oxygen administration, which is independent of fluid therapy or blood transfusion. The aim of the present study was to assess the usefulness of acute HBOT after liver resection for patients with HCC in order to minimize the requirement for perioperative blood transfusions., Patients and Methods: Forty-one consecutive patients who showed Hb level < 9.0 mg/dl at the end of hepatic resection were randomly assigned to a control group (n = 21) or an HBOT group (n = 20). HBOT at 2.0 atm. with inhalation of 100% oxygen for a duration of 60 min was performed at 3, 24, and/or 48 h after the end of the hepatectomy. Regarding postoperative hepatic hemodynamics, liver function tests, and outcome data, prospective comparisons were completed in both groups. The two groups of patients were similar with respect to results from preoperative assessments., Results: In six patients from the HBOT group, who experienced intraoperative major bleeding or showed fatal hepatic hypoxia (ShvO(2) < 50%), the levels of ShvO(2) and serum lactate were significantly improved after HBOT. When compared to the control group, the HBOT group showed better changes of ShvO(2), serum lactate, and bilirubin levels for the first 3 postoperative days following surgery. Additionally, the HBOT group did not experience any fatal complications and had a lower incidence of postoperative hyperbilirubinemia than the control group. We also observed that postoperative NK cell activity and cancer-free survival in the HBOT group tended to be better than in the control group, although the differences did not reach significance., Conclusion: These results suggest that acute HBOT after hepatectomy, aimed at reducing perioperative erythrocyte transfusions, may be employed for overcoming deficiencies in systemic and hepatic oxygen supply and thus diminishing postoperative complications. As an added benefit, such therapy may affect postoperative immunological responses and long-term survival after liver resection in HCC patients. Further analyses of the use of HBOT is warranted to confirm surgical outcome data and to assess the economic impact on healthcare costs.

Background and Objectives: B7-H4 is a novel molecular B7 ligand that plays an important role as a negative regulator of the T cell-mediated immune response. However, the clinical significance of B7-H4 expression in gastric cancer remains uncertain. Here, we assessed B7-H4 expression in blood of patients with gastric cancer to determine whether or not it can predict tumor progression and prognosis., Methods: We measured B7-H4 mRNA expression by quantitative RT-PCR in five gastric cell lines as well as in blood specimens from 94 patients with gastric cancer and from 22 healthy volunteers., Results: Significantly more B7-H4 mRNA copies were found in gastric cell lines and in blood from patients with gastric cancer than in blood from healthy volunteers (P < 0.0001 and P < 0.0001, respectively). B7-H4 expressed in 71 (75.5%) of 94 patients with gastric cancer significantly correlated with depth of tumor invasion, lymph node metastasis, and overall stage (P = 0.006, P = 0.001, and P < 0.001, respectively). The 5-year survival rate was significantly lower in patients with than without B7-H4 expression (P = 0.04)., Conclusions: The evaluation of B7-H4 expression in blood is a useful tool for predicting the progression of gastric cancer and prognosis., (2010 Wiley-Liss, Inc.)

Background/aims: It is important to minimize surgical invasiveness in the therapy of patients with hepatocellular carcinoma (HCC) complicated with cirrhosis. Laparoscopic hepatectomy is feasible for such patients. However, most procedures undertaken at the present time are non-anatomic partial resection or limited resection, except for left hepatectomy and bisegmentectomy 2 and 3. Because anatomic hepatic resection for small HCC yielded more favorable results than non-anatomic resection, we conducted laparoscopic anatomic hepatic resection as image-navigated surgery by referring to portal 3D images., Methodology: Detailed descriptions of laparoscopic anatomic resection, such as segmentectomy and subsegmentectomy are presented. Preoperative 3D images clarified the anatomical relationships between HCC and its portal territory and enabled determination of the transection line. Laparoscopic anatomic resection was completed with mini-laparotomy or -thoracotomy with equal success to the conventional procedure under an open approach., Results: Five patients with primary HCC with cirrhosis underwent the above procedure between January 2008 and February 2009. There were 2 male and 3 female patients, with a median age of 74.4 (70-80) years. All procedures were successful, with no conversions to open surgery required. The median operation time was 251 min (range: 222-280 min), and the median estimated blood loss was 183 ml (range 50-320 ml). There was no surgical mortality and major morbidity., Conclusions: These procedures contributed reduced invasiveness, even for elderly patients with cirrhosis: low blood loss and no postoperative complication. Laparoscopic anatomic hepatic resection based on navigation of the portal 3D images might be useful not only to facilitate minimally invasive surgery but also to improve the therapeutic efficacy.

A 56-year-old man with abnormal chest X-P and stool occult bleeding was admitted. Colonoscopy detected rectal cancer and sigmoid al polyps. The biopsy results suggested that the rectal lesion was well- to moderately-differentiated adenocarcinoma and the sigmoidal polyp contained well -differentiated adenocarcinoma. CT scan revealed multiple lung, liver and lymph node metastasis. We judged the case to be inoperable and decided to start systemic chemotherapy (FOLFOX4). After treatment with chemotherapy, the tumor shrank and metastatic lesions disappeared. Low anterior resection was done, and final pathological examination revealed a complete response of the main tumor by treating with FOLFOX4.

A 64 -year-old female received oral S-1 chemotherapy followed by mFOLFOX6 chemotherapy for postoperative liver and lung metastasis of sigmoid colon cancer. The tumor progression was observed after twelve courses of mFOLFOX6 chemotherapy, and then FOLFIRI+bevacizumab chemotherapy was performed. After two courses of FOLFIRI+bevacizumab chemotherapy, leucopenia was observed. The chemotherapy was then discontinued and G-CSF was administered. Two days later she complained of high fever and dry cough, and was admitted to the hospital. A diffuse ground-glass appearance of bilateral lung was observed on chest X-ray and CT. Drug-induced interstitial pneumonitis was suspected, and Pneumocystis carini pneumonia was considered in the differential diagnosis. Oral administration of prednisolone and sulfamethoxazole/trimethoprim did not improve the symptoms, so steroid pulse therapy was performed. Steroid pulse therapy improved respiratory symptoms, but CT findings did not change remarkably. After nine weeks in the hospital, she was discharged with home oxygen therapy. Interstitial pneumonitis induced by FOLFIRI+bevacizumab chemotherapy is rare, but the number of cases may increase with increased use of this regimen. The possibility of interstitial pneumonitis should always be considered when the patient presents with a respiratory disorder while receiving systemic chemotherapy.

Background: As a pleiotropic cytokine, transforming growth factor-beta (TGF-beta) controls the functions of proliferation, adhesion, and differentiation, and contributes to cancer promotion and suppression. Moreover, it is related to the epithelial-mesenchymal transition process and T cell differentiation associated with inflammation. The Smad4 protein is the downstream mediator of TGF-beta. In this study, we examined the relationship between Smad4 expression and clinicopathological features in patients with hepatocellular carcinoma (HCC)., Methods: Expression of Smad4 was assessed in five HCC cell lines and in paired cancerous and noncancerous tissues in three patients with HCC, using Western blotting analysis. Moreover, Smad4 expression in 121 HCC patients was evaluated by using immunohistochemistry., Results: Only the Li7 and HT17 cell lines expressed the Smad4 protein. All human samples expressed the protein. Immunohistochemistry showed that Smad4 expression tended to be strong in small HCC nodules less than 45 mm in diameter (P=0.06) and in the infiltrated part of the tumor capsule. Postoperative survival analysis indicated that HCC patients with strong Smad4 expression had shorter disease-specific survival than those with weak expression (P=0.04). Multivariate analysis also showed that Smad4 expression could be one predictor of prognosis, but the correlation was not significant (P=0.07)., Conclusions: Although TGF-beta/Smad4 signaling may have various biological effects on human malignancies, strong Smad4 expression in HCC is likely to suggest poor prognosis. The information has implications for predicting HCC prognosis and developing targeted therapeutics.

A 75-year-old woman underwent resection of gastrointestinal stromal tumor (GIST) of small intestine in 1999. In January 2006, she suffered liver dysfunction and abdominal CT revealed she had a large liver metastasis. At first the tumor in the right lobe progressed to the medial segment and seemed unresectable. She twice underwent transarterial embolization and treatment with 400mg/day of imatinib mesylate. Then percutaneous transhepatic portal embolization was performed. As a result, liver metastasis markedly decreased in size, and extended right lobectomy of the liver was performed in June 2006. A large portion of the liver metastasis showed necrosis, but histopathological examination revealed focal remnants of viable tumor cells. In March 2007, radiofrequency ablation was performed for recurrence of remnant liver. The patient has been treated by imatinib mesylate and is alive with no evidence of tumor recurrence.

A 46-year-old female was admitted to Kagoshima University Hospital with a complaint of epigastralgia and dysphasia. Gastrointestinal scopy revealed advanced gastric cancer in the upper third of the stomach. Pathological diagnosis of the biopsy specimen was moderately-differentiated adenocarcinoma. Abdominal CT suggested multiple liver metastases, so a combination of biweekly paclitaxel(PTX)and S-1 was started. After five courses of this regimen, the liver metastases and primary tumor were remarkably regressed. PTX was discontinued because of a grade 3 adverse effect of numbness. Nevertheless S-1 monotherapy for liver metastases resulted in a complete response. She has been well without tumor re-growth for 4 years. The combination of PTX and S-1 may be an effective regimen for gastric cancer with liver metastases.

We report the case of 67-year-old man who was given a diagnosis of advanced gastric adenocarcinoma. Complete response of multiple liver and paraaortic lymph node metastases occurred in this patient after combination chemotherapy with systemic injection of paclitaxel and oral administration of novel dihydropyrimidine- dehydrogenase- inhibitory fluoropyrimidine (S-1). Following 7 courses of the biweekly paclitaxel and S-1 combination chemotherapy, the patient underwent total gastrectomy with D3 extended lymph node dissection. According to the operative findings, the tumor was curatively removed along with the liver metastases and paraaortic lymph node metastases. Biopsy of the liver was performed and the pathological diagnosis indicated no gastric adenocarcinoma cells. The pathological report showed that the lymph node metastases had completely disappeared with single exception and minute cancerous lesions were identified in the gastric mucosa and submucosa. Therefore, the histological efficacy was evaluated as Grade 2. For postoperative chemotherapy, oral S-1 administration only was chosen. However, 6 months later, biweekly paclitaxel and S-1 combination chemotherapy was administered in sequence as a second adjuvant chemotherapy because the serum level of the tumor marker was elevated. The patient is fine and has not shown any recurrence at other sites 37 months after surgery. Salvage surgery following paclitaxel and S-1 chemotherapy may be feasible for patients with advanced gastric cancer and complete regression of distant metastases. Biweekly paclitaxel and S-1 combination chemotherapy has been used safely and its administration may be continued for a long time in an outpatient clinic setting for the treatment of advanced gastric cancer.

We evaluated efficacy of biweekly paclitaxel and S-1 for advanced gastric cancer patients with liver metastases. A total of 14 patients had multiple liver metastases. None of whom received chemotherapy before the current regimen. The patients were given 80 mg-130 mg/m(2) of paclitaxel every two weeks and 80 mg of S-1 during the first two weeks. Chemotherapeutic efficacy for liver metastases was 50%. The 3-year-survival rate of the 14 patients was 50%, which was significantly higher than that of historical control patients (p<0.01). Two patients received gastrectomy with curative intent. Histological exploration revealed disappearance of liver metastases. In conclusion, biweekly paclitaxel+S-1 regimen was one of the promising therapies for advanced gastric cancer patients with liver metastases.

Background/aims: Alpha-fetoprotein (AFP)-positive gastric cancer (APGC) which occupied well-defined gastric cancer entity, reportedly has an aggressive behavior with hematogenous metastasis. However, little information regarding the clinicopathological and biological behaviors of APGC is available due to the small size of reported series., Methodology: We retrospectively analyzed the clinical features of APGC in 556 patients with gastric cancer who underwent preoperative measurement of serum AFP levels and gastrectomy in Kagoshima University Hospital. APGC was regarded as any cancer with preoperative serum AFP levels above the cutoff level of 5 ng/mL. Clinicopathological features of APGC were assessed using the General Rules of Gastric Cancer. Of the 556 patients, 97 patients underwent immunohistochemical evaluation of AFP expression in the primary tumor. Both p53 and MIB-1 expression were examined at the same time and compared with AFP expression. Biological aggressiveness of APGC was estimated., Results: Serum AFP positivity was detected in 4.3% of cases (range, 0-2202 ng/mL). Patients were divided into 25 APGC patients and 531 non-APGC patients. APGC displayed deeper tumor invasion, increased nodal involvement, increased venous invasion, and increased CEA concentrations compared to gastric cancer in non-APGC. Surgical outcomes for APGC were significantly worse than those for non-APGC (p < 0.05). All recurrences in patients with APGC involved hepatic metastasis. Abnormalities of p53 were more frequent for APGC than for non-APGC (p < 0.05)., Conclusions: APGC was strongly associated with hematogenous factors such as venous invasion, hepatic metastasis and aggressive biological factors (p53 abnormalities). Considering the aggressive biological behavior of APGC, we must closely follow up for patients with such tumor, including postoperative adjuvant therapy.

Adenosquamous carcinoma of the esophagus is an uncommon type of esophageal tumor. In the present case, a 54-year-old man without symptoms was diagnosed with esophageal squamous cell carcinoma, based on endoscopic examination of a biopsy specimen. Endoscopy and barium roentgenography revealed a superficial plateau-type lesion, 2 cm in length, in the lower esophagus. Esophagectomy with lymphadenectomy was performed via a right thoraco-abdominal approach. The histological diagnosis was adenosquamous carcinoma with no lymph node metastasis. Three years after the surgery, multiple liver metastases were detected by computed tomography. The patient was treated with a combination of low-dose 5-fluorouracil(350 mg/body/day) and low-dose cisplatin (7 mg/body/day). Because the first course of chemotherapy was very effective and the number of liver metastases was reduced,a further 6 courses were administered. After 6 courses of chemotherapy, no liver metastases were detected. Based on the present findings, we recommend low-dose 5-fluorouracil/cisplatin therapy for liver metastasis from esophageal adenosquamous carcinoma.

We treated a 57-year-old male with liver metastasis derived from an alpha-fetoprotein-producing early gastric cancer. Eleven months after distal gastrectomy with D2 lymph node dissection, the patient underwent hepatectomy of segment 4 to resect a liver tumor 3 cm in diameter found by abdominal computed tomography. Immunohistochemical examination of the stomach and liver specimens, using anti-alpha-fetoprotein antibody, showed partial alpha-fetoprotein expression in both the primary gastric and metastatic hepatic tumors. The patient's serum alpha-fetoprotein level had been elevated at 302 ng/mL before hepatectomy, but the level remained below 5 ng/mL postoperatively. The patient remains alive without tumor recurrence 3 years after hepatectomy. There have been few previous reports of good outcome after curative resection of a metachronous liver metastasis derived from alpha-fetoprotein-producing gastric cancer. The assessment of serum alpha-fetoprotein level may be useful for detecting and monitoring liver metastasis in gastric cancer, especially for alpha-fetoprotein-producing tumors.

Background: It has been suggested that tissue factor (TF) plays an important role in tumor metastasis. Its expression in sarcoma cells was reported to up-regulate the vascular endothelial growth factor (VEGF) gene and thereby enhance tumor angiogenesis, which is essential to tumor metastasis. Although many malignant tumors have been reported to express this protein constitutively, recent clinical studies have focused mainly on the correlations among TF expression, tumor progression, and histologic grade. Therefore, to address the role of TF and the underlying mechanism of hematogenous metastasis of colorectal carcinoma, the authors analyzed the correlations among TF expression, hepatic metastasis, and VEGF gene expression in surgical specimens. Furthermore, they analyzed the prognostic significance of TF expression with respect to overall patient survival., Methods: Expression of TF and VEGF genes in 67 advanced colorectal carcinoma specimens was studied by immunohistochemistry and Northern blot analysis, respectively. The correlations among TF expression, hepatic metastasis, and other factors were analyzed with univariate and multivariate statistics. Survival rates were calculated using the Kaplan-Meier method., Results: Univariate and multivariate analyses showed TF expression to be a significant (P = 0.0001) and independent risk factor for hepatic metastasis, whereas a weak but insignificant correlation was observed between TF and VEGF gene expression. The outcomes in the TF positive group were significantly worse in all cases (P = 0.0001) and in the cases without synchronous hepatic metastasis (P = 0.0156)., Conclusions: Although the precise mechanisms are unknown, TF expression is a suitable indicator of both hepatic metastasis and prognosis for colorectal carcinoma patients., (Copyright 2000 American Cancer Society.)

This article describes the significance of mRNA expression of VEGF, MMP-2, MMP-9, and MT1-MMP in human colorectal cancer metastases, particularly hepatic metastases. The levels of gene expression were quantified by Northern blot hybridization in tumor and nontumor tissues obtained from 66 primary cases. Significantly higher levels of expression of VEGF mRNA were observed in patients with synchronous hepatic metastases (n = 15) and/or lymph node metastases than in those without. Patients with synchronous hepatic metastases had significantly higher levels of mRNA expression of all MMP genes than in those without, and no apparent correlation was seen between MMP mRNA expression and other clinicopathologic variables. Also in a study including 4 cases of metachronous hepatic metastases after surgery. VEGF, MMP-9, and MT1-MMP mRNA expression were significantly higher in patients with hepatic metastases than in those without, indicating that these are predictable markers for hepatic metastases. Immunohistochemical examination revealed that VEGF and MT1-MMP were localized mainly in cancer cells, whereas MMP-2 and MMP-9 were distributed throughout stromal cells such as fibroblasts and leukocytes in tumor tissues.

Background/aims: The matrix metalloproteinase (MMP) family play important roles in the invasion of cancer cells by degrading the extracellular matrices. The current study was designed to determine the expression pattern of membrane-type matrix metalloproteinase-1 (MT1-MMP) in hepatocellular carcinomas and its participation in invasion potential., Methods: MT1-MMP mRNA expression was examined in 25 human hepatocellular carcinoma specimens using Northern blot, and the correlation to clinicopathological features was evaluated. In situ hybridization and immunohistochemistry were performed to study the localization and the cells responsible for the production., Results: Northern blot analysis revealed high levels of MT1-MMP mRNA expression in tumorous portions in all cases, whereas in non-tumorous portions moderate or faint expression was evident in 22/25 cases. In 21/25 cases, the expression levels in tumorous portion were higher than those in non-tumorous portion. In particular, hepatocellular carcinoma with capsule infiltration demonstrated significantly higher expression than those without (p<0.05). In situ hybridization and immunohistochemical study revealed MT1-MMP transcripts and proteins in cancer cells and stromal cells, respectively. MT1-MMP positive cells were preferentially observed in the invading border of tumor nests. The MMP-2 transcript showed a similar pattern to that of MT1-MMP by in situ hybridization., Conclusion: The present study showed that the MT1-MMP gene is strongly expressed in hepatocellular carcinoma cells and is involved in the invasion potential of hepatocellular carcinoma, and also that MT1-MMP may be one of the key molecules responsible for the invasion potential of hepatocellular carcinoma. Furthermore, the evidence suggests that MT1-MMP and MMP-2 cooperate in the process of cancer invasion.

The prognosis for hepatocellular carcinoma (HCC) depends mainly on the clinicopathological characteristic regarding invasion and metastasis. In addition, another distinguishing feature of HCC is the high incidence of concomitant liver cirrhosis, in which the extracellular matrix proliferates markedly. Therefore, the present study was designed to investigate the molecules responsible for the invasion potential of HCC by focusing on matrix metalloproteinase (MMP) in particular, MMP-2 and MMP-9 and the corresponding tissue inhibitor of metalloproteinase (TIMP-2 and TIMP-1), because these enzymes participate in the degradation of the extracellular matrix including the basement membrane. Tumorous and adjacent nontumorous liver samples were obtained from 23 HCC patients who underwent a partial hepatectomy. In 16 of the 23 HCC samples, transcripts for MMP-9 were detected in the tumorous tissues, and 15 of 16 of these samples showed stronger expression in the tumorous tissues than in the nontumorous tissues. On the other hand, MMP-2 messenger RNA (mRNA) was detected in 18 of the 23 cases. Eight of these 18 cases showed more intense expression in the tumorous tissues than in the nontumorous tissues, whereas the expression levels were lower in the tumorous tissues than in the nontumorous tissues in 7 of 18 samples. With respect to the correlation between the clinicopathological features and mRNAs expression, it was found that the expression of MMP-9 mRNA in HCC with capsular infiltration was significantly higher than in HCC without capsular infiltration. HCC with capsular infiltration also tended to have a higher ratio of MMP-9 mRNA expression to TIMP-1 mRNA expression. In addition, the expression of MMP-2 mRNA in nontumorous cirrhotic tissues was significantly higher than in nontumorous tissues from patients with chronic hepatitis. Immunohistochemical examinations revealed that MMP-9 immunoreactivity was the most intense in the HCC cells, particularly in those cells in the marginal areas of the tumorous tissues. In conclusion, the present study shows that MMP-9 is closely participated in capsular infiltration in HCC.

Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. However, the relationship between the vascularity of HCC and the expression of angiogenic factors has not been investigated. In addition, no detailed studies have examined the possible involvement of angiogenic factors in the grade of malignancy of HCC. The aim of this study was to determine which angiogenic factors regulate tumor angiogenesis and contribute to the invasive ability of liver tumors, especially of HCC. Northern blot analysis was used to examine the transcriptional expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), and acidic FGF in resected surgical specimens (20 HCC and 9 metastatic liver tumors). Correlations between messenger RNA (mRNA) expression and arteriographic findings, as well as histopathological findings, were evaluated. Immunohistochemistry was performed to identify the localization of cells expressing VEGF in HCC. Higher levels of VEGF mRNA were observed in 12 of 20 HCC and 2 of 9 metastatic liver tumors than in corresponding nontumorous tissues. The degree of VEGF mRNA expression was significantly correlated with the intensity of tumor staining in angiograms (P<.01). On immunohistochemical observation, VEGF protein was intensely detected in HCC cells. Furthermore, basic FGF mRNA was detected in 9 of 20 HCC and was related to the capsular infiltration of cancer cells (P<.05). In contrast, no significant difference was observed in the very low levels of acidic FGF mRNA found in the tumorous and nontumorous portions of the liver. In conclusion, these results suggest that VEGF contributes to angiogenesis of liver tumors, whereas basic FGF may be involved in the invasion of HCC into the surrounding tissues.

Images were obtained both with a biliary agent, 99mTc-Sn-N-pyridoxyl-5-methyltryptophan (99mTc-PMT), and with 67Ga-citrate in 40 cases of hepatocellular carcinoma and in 43 cases of other hepatic diseases and results were compared. Positive results were obtained by delayed 99mTc-PMT imaging in 25 (63%) of 40 cases of hepatoma: the hepatic tumor showed increased uptake in 18 cases (45%) and equilibrated uptake in 7 cases (18%). Positive 67Ga-citrate imaging was found in 28 (70%) of the 40 cases of hepatoma: increased uptake was seen in 24 cases (60%) and equilibrated uptake in 4 cases (10%). Of 15 cases of hepatoma giving negative results in the 99mTc-PMT study, 7 cases (47%) took up 67Ga-citrate, and 6 of these showed increased 67Ga-citrate uptake by the hepatic tumors. A certain relation existed between the degree of histological differentiation of hepatomas and the intensity of 99mTc-PMT uptake by those tumors, while such a histological correlation was denied for 67Ga-citrate uptake by the tumors. Delayed 99mTc-PMT imaging is preferable to 67Ga-citrate imaging for increasing the specificity of diagnosis of hepatoma. 67Ga-citrate should be used in those cases that do not give positive results with 99mTc-PMT.

Delayed imaging was performed after the intravenous administration of Tc-99m DEIDA and Tc-99m PMT in 18 patients with hepatocellular carcinoma. Using Tc-99m DEIDA imaging, sharp uptake by liver tumors was observed in four patients (22%), but the uptake was similar to that of the surrounding normal liver in eight patients (44%). Using Tc-99m PMT imaging, the uptake by the tumor was notable in ten patients (56%) and normal in two (11%). Tc-99m PMT and Tc-99m DEIDA were both concentrated in hepatocellular carcinomas, but the former showed intense uptakes more frequently, and thus is suggested to be useful in the diagnosis of hepatocellular carcinoma.