High Incidence Of Liver Metastasis Research Articles

Overexpression of Transcription Termination Factor 1 is Associated with a Poor Prognosis in Patients with Colorectal Cancer

RNA polymerase 1 transcription termination factor (TTF1) mediates the transcription of ribosomal RNA (rRNA). In the current study, we investigated the clinical and biological significance of the TTF1 gene in colorectal cancer (CRC). The expression of TTF1 messenger RNA (mRNA) in tumor and normal tissues from 136 patients with CRC was examined by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). We also performed in vitro cell proliferation and migration assays in TTF1-expressing CRC cells. The biological role of TTF1 in CRC was further elucidated using gene set enrichment analysis (GSEA) with CRC samples. TTF1 expression was significantly higher in tumor tissues than in corresponding normal tissues (p = 0.016). In clinicopathological analysis, the high-TTF1 expression group showed a higher incidence of liver metastasis and lymphatic invasion than the low-TTF1 expression group (p < 0.05), and tended to have more frequent venous invasion than the low-TTF1 expression group. Furthermore, the high-TTF1 expression group had a significantly poorer prognosis than the low-TTF1 expression group (p = 0.011). Moreover, overexpression of TTF1 enhanced the proliferation and migration capacity of CRC cells in vitro. GSEA revealed that TTF1 was significantly associated with the RAS and MYC pathways, and this observation was confirmed in samples from 136 patients with CRC. TTF1 was involved in cancer progression via the RAS and MYC pathways in CRC, suggesting that TTF1 may be a prognostic indicator and therapeutic target in CRC.

Clinical manifestations in patients with alpha-fetoprotein-producing gastric cancer.

Patients with alpha-fetoprotein (afp)-producing gastric cancer have a high incidence of liver metastasis and poor prognosis. There is some controversy about clinical manifestations in these patients. Our study enrolled patients who, before surgery, had gastric cancer with serum afp exceeding 20 ng/mL [afp>20 (n = 58)] and with serum afp 20 ng/mL or less [afp≤20 (n = 1236)]. Clinical manifestations were compared between the groups. Early gastric cancer was more frequent (30.1% vs. 4%) and advanced gastric cancer was less frequent (69.9% vs. 96%) in the afp≤20 group than the afp>20 group (p < 0.001). Liver and lymph node metastasis occurred less frequently in the afp≤20 group (4.4% vs. 27.6%, p < 0.001, and 60.7% vs. 91.4%, p < 0.001, respectively). The 1-, 3-, 5-, and 10-year survival rates of afp≤20 patients were 75.2%, 53.4%, 45.8%, and 34.6% respectively. The 1-, 3-, 5-, and 10-year survival rates of patients with afp greater than 20 ng/mL, but 300 ng/mL or less, were 46.7%, 28.9%, 17.8%, and 13.3% respectively. The 1-, 3-, and 5-year survival rates of patients with serum afp greater than 300 ng/mL were 15.4%, 7.7%, and 0% respectively. The independent predictors for survival time were afp concentration, age, peritoneal seeding, liver metastasis, lymph node metastasis, vascular invasion, TNM stage, curative surgery, serosal invasion, and Lauren classification. Patients with high serum afp had a high frequency of liver and lymph node metastasis and very poor prognosis. More aggressive management with multimodal therapy (for example, chemotherapy, radiotherapy) might be needed when treating such patients.

Phase II study evaluating ipilimumab as a single agent in the first-line treatment of adult patients (Pts) with metastatic uveal melanoma (MUM): The GEM-1 trial.

9033 Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall survival (OS) at 5 years is 62% due to high incidence of liver metastasis that are fatal wi...

Abstract A36: Expression profiling reveals characteristics of host-tumor interactions that promote liver metastasis of colorectal cancer

Abstract Colorectal cancer (CRC) is the third most frequent cancer and the third leading cause of cancer deaths in the United States. Metastasis is the major cause of death. When diagnosed at the localized stage, the five-year survival rate is approximately 90%, however, after metastasis has occurred, the survival rate drops to less than 12%. The most frequent target organ is the liver. Successful metastasis depends on productive collaborations between tumor cells and host-derived cells in the tumor microenvironment as well as long distance communication mediated by molecular signals from the primary tumor that stimulate immune cell mobilization between the primary tumor and target organ environments and the hematopoietic compartment. Prior to the arrival of metastatic cells in the secondary organ, signals from the primary tumor direct organ specific mobilization of bone marrow derived cells to prepare a niche that promotes the attachment of cancer cells and their subsequent development into a metastatic lesion. These complex processes occur asymptomatically, thus despite its devastating impact on the patient, metastasis is often diagnosed at the final stage when very little can be done to alleviate its effects. To understand the mechanisms underlying these processes and identify the molecular regulators, particularly at the early stages, we established an orthotopic mouse model of liver metastasis of CRC that can recapitulate all stages of tumor growth and metastasis. We used in vivo selection to isolate a highly metastatic mouse carcinoma cell line, CT26-FL3, from CT26 colon adenocarcinoma cells. Tumors derived from CT26-FL3 were more proficient in inducing a metastasis-friendly host environment as compared to the parental cell line. We hypothesized that the transition from CT26 to CT26-FL3 was driven by genetic alterations resulting from interactions between tumor cells and host environment, thereby contributing to a higher incidence of liver metastasis from tumors derived from CT26-FL3. We further hypothesized that molecules secreted by the primary tumor can direct genetic changes in the liver microenvironment that promote the creation of a fertile niche for invading cancer cells. By identifying these alterations in both the tumor cells and the host microenvironment, we can begin to understand the mechanisms by which host-tumor interactions promote liver metastasis of CRC. We therefore carried out microarray analyses to: 1) determine the genetic signatures of the parental CT26 and highly metastatic CT26-FL3 cells, and 2) determine the genetic changes in the liver microenvironment in mice bearing CT26-FL3 tumors prior to metastasis. The results identified a number of genes in signaling, cancer, metabolic, and various signaling pathways that were differentially expressed between CT26 and CT26-FL3, and between liver from tumor-bearing mice and non-tumor bearing mice. More importantly, the results showed that several genes in the chemokine and the cytokine-cytokine receptor pathways were expressed by up to 50-fold or higher in CT26-FL3 cells or in the liver microenvironment of tumor-bearing mice. The products of these genes are likely mediators of the complex cross-talk between the primary tumor and the liver microenvironment. Using our orthotopic mouse model, we examine the kinetics of the changes in gene expression during metastatic progression to assess the potential of these gene products alone or in combination as viable markers in blood serum for early diagnosis of metastasis, or as targets to alleviate metastatic disease. Citation Format: Yu Zhang, Celestia Davis, Maria Marjorette O. Peña. Expression profiling reveals characteristics of host-tumor interactions that promote liver metastasis of colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A36.

Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer

We examined the effects of hyperglycemic conditions on liver metastasis of colorectal cancer (CRC). Angiotensin (A)-II increased growth, invasion, and anti-apoptotic survival in HT29 and CT26 cells. In contrast, angiotensinogen (ATG) increased these features in HT29 cells but not in CT26 cells. HT29 cells expressed A-II type 1 receptor, chymase, and rennin, whereas CT26 cells did not express renin. Renin expression and ATG-induced cell growth, invasion, and survival induced and increased as glucose concentration increased in HT29 cells and also CT26 cells. An inhibitor of renin or chymase abrogated A-II production in HT29 cells. Reduction of hepatic ATG production by cholesterol-conjugated antisense S-oligodeoxynucleotide suppressed liver metastasis of HT29 cells. An examination of 121 CRC patients showed that diabetes in CRC cases was associated with higher blood HbA1c, higher renin and A-II concentrations in the primary tumors, and higher incidence of liver metastasis than in nondiabetic cases. These results suggest that diabetes-associated angiotensin activation enhances liver metastasis of CRC and may therefore provide a possible target for antimetastatic therapy in CRC.

Abstract 457: Significance of angiotensin targeting on treatment of liver metastasis in colorectal cancer patients with diabetes

Abstract We examined the effects of hyperglycemic conditions on liver metastasis of colorectal cancer (CRC). Angiotensin (AT)-II increased growth, invasion, and anti-apoptotic survival in HT29 and CT26 cells. In contrast, angiotensinogen (ATG) increased these features in HT29 cells but not in CT26 cells. HT29 cells expressed AT-II type 1 receptor, chymase, and rennin, whereas CT26 cells did not express renin. Renin expression and ATG-induced cell growth, invasion, and survival induced and increased as glucose concentration increased in HT29 cells and also CT26 cells. An inhibitor of renin or chymase abrogated A-II production in both cells. Reduction of hepatic ATG production by knockdown suppressed liver metastasis of HT29 cells. An examination of 121 CRC patients showed that diabetes in CRC cases was associated with higher blood HbA1c, higher renin and AT-II concentrations in the primary tumors, and higher incidence of liver metastasis than in nondiabetic cases. These results suggest that diabetes-associated AT activation enhances liver metastasis of CRC. We then examined an antimetastatic therapy by anti-AT treatments in CRC. In a streptozotocin-induced BALB/c mouse diabetes model that was fed a high-calorie diet, the blood sugar level increased and was associated with enhanced CT26 liver metastases. In this diabetic mouse model, liver metastasis of CT26 cells was suppressed by anti-AT treatment with a chymase inhibitor, a renin inhibitor, and an AT-II receptor blocker. Moreover, concurrent hypoglycemic and anti-AT treatments showed a synergistic inhibitory effect on CT26 cell liver metastasis. These results suggest that AT activation ability associated with diabetic conditions enhances liver metastasis of colon cancer. Therefore, treatment with anti-AT and hypoglycemic agents might be relevant for suppressing liver metastasis. This scheme should be examined in a clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 457. doi:1538-7445.AM2012-457

Abstract 2325: Increase in neuroblastoma metastasis after dual inhibition of VEGF and Notch

Abstract Purpose: Vascular endothelial growth factor (VEGF) inhibition is a validated cancer treatment. However, even in responsive tumors, acquired resistance is common. Notch proteins also function as key angiogenic effectors, and cross-regulate VEGF expression, raising the question of whether combined treatment would enhance tumor suppression. We hypothesized that dual VEGF/Notch blockade would inhibit tumor growth in experimental SY5Y neuroblastoma. Methods: SY5Y neuroblastoma cells were lentivirally transfected to express Notch1-decoy (N1D) or GFP (control). Proliferation was assessed in vitro under both hypoxia and normoxia using BrdU assays. To examine the effect of N1D on tumor growth, 10[6] cells were xenografted intrarenally in nude mice and treated with placebo or bevacizumab (BV) twice a week. Tumor progression was monitored by bioluminescence. Metastatic burden in target organs was quantified by bioluminescence and histology. Vascular disruption due to N1D and BV treatment was evaluated by immunostaining. IACUC approval was obtained for all experiments. Results: Expression of soluble N1D was confirmed by immunoblotting conditioned media. SY5Y+N1D cells proliferated more rapidly in hypoxia than control SY5Y+GFP cells (p&amp;lt;0.01). In vivo, BV treatment alone significantly reduced tumor growth as compared to placebo (p=0.026). However, combined treatment (N1D + BV) did not further reduce SY5Y tumor growth as compared to BV treatment alone (p=0.684). Interestingly, dual-treated mice developed higher metastatic burdens in liver than mice treated with either agent alone or controls by bioluminescence (p=0.006). By histology, dual-treated mice displayed a higher incidence of liver metastasis (7/9 mice) vs. mice treated with BV only (3/10 mice). Immunostaining demonstrated disruption of tumor vessel architecture in BV- and N1D + BV-treated mice. Conclusion: Dual VEGF/Notch targeting of SY5Y tumors resulted in increased metastatic burden, without affecting primary tumor growth, as compared to either treatment alone. Recent data indicates that tumoral hypoperfusion can promote progression, potentially by selecting for biologically aggressive behaviors. Our results suggest that dual Notch/VEGF blockade causes an enhanced propensity to metastasize. These data warrant further preclinical investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2325. doi:1538-7445.AM2012-2325

Clinicopathological Characteristics of Alpha-Fetoprotein-Producing Gastric Cancer

Purposeα-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 MethodsSix 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.ResultsThere 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.ConclusionsAFP-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.

Long-term results of gastrectomy for α-fetoprotein-producing gastric cancer

alpha-Fetoprotein (AFP)-producing gastric cancer is a rare tumour. It is said to have a high incidence of liver metastasis and poor prognosis. This study sought to evaluate long-term outcomes in such patients. Records of consecutive patients with gastric carcinoma who underwent preoperative measurement of serum AFP levels and gastrectomy were reviewed to identify those who satisfied the following criteria: preoperative AFP level exceeding 40 ng/ml with a decrease after gastrectomy, or raised preoperative AFP level (10-39 ng/ml) and resected tumour showing histologically characteristic features or immunohistochemically positive AFP production. Of 3374 patients with gastric cancer, 53 (1.6 per cent) met the selection criteria. Tumours were characterized by a high incidence of nodal (79 per cent) or liver (53 per cent) metastasis. Preoperative serum AFP levels showed no correlation with tumour size, depth of invasion, disease stage or survival. The 5-year survival rate was 34 per cent. Five patients survived after recurrence following multimodal treatment. A rising AFP level during follow-up always led to tumour recurrence, but the level remained normal in 11 of 31 patients with recurrence. AFP-producing tumours represent a small subgroup of gastric cancer with high metastatic potential. Postoperative serum AFP level can help predict recurrence but a normal level does not mean absence of recurrence. Prognosis is not as poor as previously thought, and multimodal treatment may be worthwhile even in patients with recurrent tumour.

Inhibition of osteopontin reduces liver metastasis of human pancreatic cancer xenografts injected into the spleen in a mouse model

Pancreatic cancer is associated with the poorest prognosis of any digestive cancer due to the high incidence of liver metastasis. This study evaluated the possibility that osteopontin (OPN) RNA interference (RNAi) and anti-OPN antibody (Ab) could have antimetastatic effects. The differential gene expression was measured in a parental cell line, HPC-3, and an established highly liver metastatic cell line, HPC-3H4. This study investigated the effect of OPN RNAi and anti-OPN Ab on the metastatic ability of HPC-3H4 to the liver. An OPN RNAi-expressing vector was introduced into HPC-3H4 cells (HPC-3H4/miOPN), in which OPN production was reduced to the level of the parental HPC-3 cells. Finally, the ability of anti-OPN Ab to suppress liver metastasis was investigated. Osteopontin was upregulated 11.1-fold in HPC-3H4 in comparison to HPC-3. The metastatic rate of HPC-3H4/miOPN was significantly reduced to 25% in comparison to the 100% metastatic rate of HPC-3H4 and control HPC-3H4/miNeg cells (P < 0.01). The metastatic rate of the group given anti-OPN Ab was 50%. OPN RNAi and anti-OPN Ab had remarkable inhibitory effects against liver metastasis by the pancreatic cancer cell line.

Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer

The calcium-binding protein, S100A4, with an inverse association of E-cadherin, is known to correlate with prognosis in various cancers. In this study, we investigated the expression of the S100A4 and E-cadherin status in relation to the clinicopathological parameters of pancreatic cancer. The expression status of these two proteins was examined in 72 specimens of primary pancreatic carcinoma with immunohistochemistry. Fifty-six of 72 (78%) surgical specimens of primary pancreatic cancer were positive for S100A4 according to immunohistochemistry. Thirty-one (43%) specimens of pancreatic cancer showed positive expression of E-cadherin. The inverse association of S100A4 and E-cadherin expression was significant in the cancers (p < 0.0001). The S100A4 expression correlated significantly with the pathological T stage and poorer prognosis (p = 0.024). The 41 E-cadherin-negative cases showed poorer prognoses and a higher incidence of liver metastasis (p = 0.0344, p = 0.027). The 10 cases with S100A4-negative/E-cadherin-positive cancers showed a significantly better prognosis than the others (p < 0.05). The histological grade (p = 0.004), nodal status (p < 0.0001) and S100A4-positive status (p = 0.048) were highly significant independent prognostic predictors (p < 0.05). These results suggest that S100A4 overexpression combined with reduced E-cadherin expression play important roles in tumor progression and metastasis in pancreatic cancer. The combined examination of these two molecules is useful in evaluating the outcome of pancreatic cancer patient.

Author reply

We thank Dr. Rivoire and colleagues for their interest in our study.1 Because patients in our study had been referred to the John Wayne Cancer Institute (Santa Monica, CA) for management of metastatic melanoma, their demographic characteristics depended on referral patterns. However, the 70% rate of liver involvement in our study was comparable to the 75% rate reported in the small study conducted by Aoyama et al.2 Our study cannot be compared with the report of Gragoudas et al.,3 who enrolled patients before the diagnosis of metastatic disease. However, we should point out that patients in that study were treated between 1975 and 1986, a period that covers some of the earlier years of our review. Therefore, their higher incidence of liver metastases cannot be explained by the use of more current imaging techniques. Because our study cohort consisted of patients with established metastases, no conclusions can be drawn based on the characteristics of the primary tumor. There was no control group of patients with nonmetastatic ocular melanoma for comparison. As stated previously, our study was a retrospective analysis of prospectively collected clinical data. The criteria used to determine surgical versus nonsurgical treatment were not available. However, statistical analysis allowed us to identify 3 criteria that might be considered when selecting candidates for surgical resection: a disease-free interval > 45 months, fewer than 5 metastatic lesions, and no other evidence of disease. We agree with Dr. Rivoire and colleagues that the literature contains few reports on surgical resection of metastases from an intraocular primary melanoma and very little information on the management of hepatic metastases from this type of primary malignancy. The 75% rate of hepatic metastases reported by Aoyama et al.2 represented only 9 patients (from a cohort of 12). In the absence of large prospective studies, which remain impractical for this patient population, our findings serve two purposes. First, they underscore the importance of considering surgical intervention for metastatic disease. Second, they emphasize the urgent need for more effective systemic therapies.

Gastrointestinal Carcinoid Tumors: Factors that Predict Outcome

Gastrointestinal (GI) carcinoids are neuroendocrine tumors originating in multiple locations throughout the GI tract. The prognosis for patients with GI carcinoid tumors is diverse. To determine the factors that significantly affect prognosis, we reviewed our experience. Between 1992 and 2000 a total of 70 patients with GI carcinoid tumors underwent surgical resection at our institution. The patients were grouped into three categories based on the origin of the carcinoid tumor: foregut, midgut, hindgut. The mean age of the patients was 56 +/- 2 years. All patients with foregut carcinoids had symptoms upon presentation, whereas 61% of those with midgut carcinoids and only 37% of those with hindgut carcinoids had symptoms ( p < 0.001). The factors that most strongly affected survival on univariate analysis were a symptomatic presentation and the site of origin. Patients with foregut or midgut lesions had lower 5-year disease-free survivals than those with hindgut tumors. Moreover, the size of the primary tumor and the presence of liver metastases were not independent predictors of survival. Despite the larger tumor size and the higher incidence of liver metastases, patients with foregut carcinoids appear to have the same prognosis as those with midgut carcinoids. These data therefore suggest that the outcomes of patients with carcinoid tumors are highly dependent on the presence of symptoms and the site of origin.

High Frequency of c-Met Expression in Gastric Cancers Producing Alpha- Fetoprotein

Gastric cancers producing α-fetoprotein (AFP) have a poor prognosis and a high incidence of liver metastasis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are known to induce mitosis and cell movement and to promote tumor progression. In the present study, c-Met and HGF expression in AFP-producing gastric cancer was compared with those gastric cancers that do not produce AFP. Twenty-six patients with AFP-producing gastric cancers [AFP(+)] and 26 patients stage-matched gastric cancers without AFP production [AFP(–)] were evaluated for c-Met and HGF expression and proliferating cell nuclear antigen-labelling index using immunohistochemical analysis. A higher frequency of c-Met expression was observed in the AFP(+) group than in the AFP(–) group (p < 0.01). A higher expression of c-Met might be one explanation for the poorer prognosis of AFP-producing gastric cancers.

The immunohistochemical expression of BCL-2 oncoprotein in colorectal adenocarcinoma.

The immunoreactivity for bcl-2 oncoprotein was determined in tumor tissue samples from 40 patients with colorectal adenocarcinoma. Positive immunoreactivity for bcl-2 oncoprotein was seen in 14 of the 40 tumor tissue samples (35%) and was found to be associated with a significantly higher incidence of synchronous liver metastasis (P = 0.043); however, there was no correlation between the immunoreactivity for bcl-2 oncoprotein and tumor size, depth of tumor invasion, lymph node metastasis, or clinical stage of the disease. Among 33 patients who had undergone curative resection, disease-free survival did not differ significantly between 10 with bcl-2-positive tumors and 23 with bcl-2-negative tumors (P = 0.498). The present study showed that the positive immunohistochemical expression of bcl-2 oncoprotein was associated with a significantly higher incidence of liver metastasis from colorectal cancer, but it had no effect on the disease-free survival of patients who had undergone curative resection.

Neoadjuvant Chemoradiation for Adenocarcinoma of the Pancreas

Pancreaticoduodenectomy is performed on carefully selected patients as part of a protocol-based clinical research program emphasizing the importance of multimodality management for patients with potentially resectable adenocarcinoma of the pancreatic head. Treatment schemas emphasize the importance of minimizing toxicity and treatment duration, while attempting to improve therapeutic efficacy. Cytotoxicity is enhanced by combining radiation therapy with more potent radiation-sensitizing agents. Because of the high incidence of liver metastases, systemic therapy is continued after chemoradiation and surgery with systemic agents of low toxicity directed at specific molecular events involved in pancreatic tumorigenesis such as inhibition of angiogenesis, induction of apoptosis, or arrest of the cell cycle.

Lymph node metastasis in carcinoma of the body and tail of the pancreas.

There have been no precise reports concerning lymph node metastatic involvement in carcinoma of the body and tail of the pancreas. Histopathological examination of lymph node involvement in 30 specimens obtained from patients who underwent pancreatic resection and wide dissection of lymph nodes, including para-aortic lymph nodes, for carcinoma of the body and tail of the pancreas was performed. Fourteen of 30 patients had lymph node involvement. The highest incidence of lymph node involvement was around the splenic artery (five of 30 patients), aorta (four of 30) and coeliac trunk (four of 30). No significant difference in survival rate between the lymph node-negative group and the lymph node-positive group was observed, but all patients in the positive group died within 2 years after surgery, and four patients with para-aortic lymph node involvement died from recurrence within 10 months after surgery. Survival rates were significantly worse in patients with histopathological extrapancreatic nerve plexus invasion, retropancreatic tissue invasion, tumour diameter more than 4 cm, histological portal system vein wall invasion and carcinoma invasion of the surgical margins. Although aggressive extended surgery including para-aortic node dissection has been performed, the postoperative survival rate is still low in patients with carcinoma of the body and tail of the pancreas. The high incidence of liver metastasis after surgery is a prime cause of the poor outcome, and effective therapy for postoperative liver recurrence requires evaluation.

Prognostic relevance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in gastric cancer.

Expression of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) was evaluated in 125 surgically resected gastric cancers by immunohistochemical analysis. Tissue was stained immunohistochemically with a monoclonal antibody against human uPA and monoclonal antibodies against human PAI-1 and PAI-2. In addition, DNA ploidy patterns were determined by cytofluorometer after staining with propidium iodide. We found that 82 (66%) of the 125 gastric cancers expressed uPA as diffuse cytoplasmic staining, as intensely outlined luminal borders. PAI-1 expression was observed in 62 (50%) of 125 gastric cancer as a fine, diffuse and granular pattern in the cytoplasm. PAI-2 expression was observed in 65 (52%) of the 125 gastric cancers as a diffuse cytoplasmic staining. uPA-positive tumours showed a higher incidence of infiltration, lymph node metastasis and peritoneal dissemination that uPA-negative ones. Patients with uPA-positive tumours proved to have a significantly poorer prognosis than those with negative ones. PAI-1-negative tumours showed a higher incidence of liver metastasis and carried a poorer prognosis than PAI-1-positive ones. There was no significant correlation between uPA or PAI-1 expression and DNA ploidy patterns. Conversely, there was no significant relationship between PAI-2 expression and clinicopathological parameters and prognosis. According to the expression of uPA and PAI-1 status, groups of 19 uPA(-)/PAI-1(-), 44 uPA(+)/PAI-1(-), 23 uPA(-)/PAI-1(+) and 39 uPA(+)/PAI-1(+) were subdivided. Tumours with uPA(+)/PAI-1(-) had a significantly higher incidence of liver metastasis, lymph node metastasis and serosal invasion than the other groups of tumours. Patients with uPA(+)/PAI-1(-) tumours had a significantly poorer prognosis than those with uPA(-)/PAI-1(+) tumours. These results indicate that uPA expression is a useful biological prognostic indicator, and that uPA expression is a useful biological prognostic indicator, and that uPA and PAI-1 may play an important part in the tumour progression and metastasis in gastric cancer.

Gestational trophoblastic disease metastatic to the central nervous system.

To evaluate characteristics of patients with central nervous system (CNS) lesions of gestational trophoblastic disease (GTD) and determine prognostic and therapeutic implications applicable to management. We retrospectively reviewed the records of 454 patients treated at the Southeastern Regional Trophoblastic Disease Center between 1966 and 1992 with at least 2 years of follow-up, and identified 42 (9.3%) with CNS metastases. Sixteen patients presented for primary therapy and 27 patients had received significant therapy prior to presentation. Three heavily treated moribund patients died before their first cycle of chemotherapy and were excluded from analysis. Brain metastases were documented by physical exam and radionuclide imaging (before 1976), computed tomography scan (after 1976), or magnetic resonance imaging (after 1986). Patients received multiagent chemotherapy with methotrexate, actinomycin D, and chlorambucil (MAC)- or etoposide-based regimens. All patients received radiation therapy. No intrathecal chemotherapy was given. Craniotomy was employed in seven cases. Remission was defined as three weekly hCG levels below assay sensitivity (< 5 mIU/ml). Overall survival was 44%. Twelve of 16 patients (75%) who presented with CNS metastases with no prior therapy (Group A), 5 of 13 (38%) patients who had prior treatment (Group B), and none of 10 patients who developed CNS metastases during therapy (Group C) survived (P < 0.05). Two of four patients who failed in the CNS after treatment for CNS lesions were salvaged. Demographic characteristics of Groups A and B were similar. No significant differences with respect to WHO score, interval from pregnancy to onset of disease, or age among these groups were found. Group B patients had a four-fold higher incidence of liver metastases. Survival of Group A patients was not related to conventional clinical prognostic factors. Inverse (nonsignificant) correlations were found for Group B patients between survival and WHO score, hCG level, size and number of metastatic lesions, but not type of prior therapy. Survival was higher in those with prior molar pregnancies (56%) as contrasted with aborted (50%) or term (27%) gestations. Selective use of craniotomy helped alleviate intracranial pressure and resect refractory foci. Chemotherapy combined with radiation therapy in GTD patients with CNS metastases yields survival rates comparable to those reported for intrathecal methotrexate regimens. Tumor burden as indicated by hCG level and size/number of metastases in previously treated patients may correlate with survival. Patients who develop CNS metastases during active therapy have a very poor outcome.

Experiments on the toxicity of locoregional liver chemotherapy with 5-fluoro-2'-deoxyuridine and 5-fluorouracil in an animal model.

A major problem in the treatment of cancer are primary tumors and metastases of the liver. While hepatomas are rare in Western Europe, there is a high incidence of liver metastases, deriving mainly from colorectal cancer [25]. At the time of detection these metastases are mostly disseminated and therefore inoperable, in contrast to their primaries. Improvements in surgical technique and knowledge makes successful wedge resection and hemihepatectomy possible. However, this treatment mode is applicable to a limited number of patients only with certain surgical preconditions (isolated metastasis, general operability, and remaining liver tissue more than 20% [18]). Overcoming the immunological problems of organ transplantation enables successful liver transplantation to be performed today. However, this method in particular cannot be regarded as a routine treatment because of the lack of donors and remaining immunological problems [19]. Patients with disseminated liver metastases have therefore been candidates for systemic chemotherapy. Many cytotoxic single- and combination chemotherapy schedules have been tested over the years, but none of the combinations tested was superior to 5-fluorouracil (5-FU) monotherapy, resulting in up to 20% tumor response for 3–5 months [22]. Because of these disappointing results other approaches are currently under investigation.