Risk factors for intrahepatic recurrence after curative surgical treatment of colorectal liver metastases.

BACKGROUND/AIM: Hepatic resection has been regarded as the only curative treatment for colorectal liver metastases. After a first hepatectomy, 30% to 70% of patients develop intrahepatic recurrence. In this study, we retrospectively analyzed risk factors for intrahepatic recurrence. METHODS: From April 1990 to December 2006, 86 patients with colorectal liver metastases underwent curative hepatic resection at Kanagawa Cancer Center. Clinicopathological characteristics of 35 patients in the intrahepatic recurrence group were compared with those of 30 patients in the no recurrence group. RESULTS: The 5-year survival rate was 18.7% for patients in the intrahepatic recurrence group. Lymph node metastases of primary colorectal cancer and synchronous liver metastases were found to be independently associated with intrahepatic recurrence. CONCLUSION: We suggest that neoadjuvant chemotherapy before hepatectomy should be considered as feasible treatment for reducing intrahepatic recurrence in two cases; One case is resectable synchronous liver metastases from colorectal cancer, and the other is resectable metachronous liver metastases with primary regional lymph node metastases from colorectal cancer.

A phase I study of combination therapy with S-1 and irinotecan (CPT-11) in patients with advanced colorectal cancer.

PURPOSE: The aim of this study was to determine the maximum tolerated dose, recommended dose and dose-limiting toxicities of irinotecan (CPT-11) plus S-1 in advanced colorectal cancer. METHODS: S-1 was administered orally at 80 mg/m(2) per day for 14 consecutive days followed by a 2-week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 80 mg/m(2) per day, stepping up to 100, 120 or 150 mg/m(2) per day. Courses were repeated every 4 weeks, unless disease progression or severe toxicities were observed. RESULTS: A total of 21 patients were entered in this study. The maximum tolerated dose of CPT-11 was considered to be 150 mg/m(2), because 2 of 3 patients developed dose-limiting toxicities such as leukopenia, neutropenia, diarrhea and anorexia. The recommend dose of CPT-11 was set at 120 mg/m(2). Tumor response rate was 42.8% and median progression-free survival time was 10 months (95% confidential interval, 6.0-14.0 months). CONCLUSION: A combination of S-1 and CPT-11 showed a good safety profile and can be recommended for further phase II studies in patients with colorectal cancer.

Long-term survival after multimodal therapy in a patient demonstrating intrahepatic cholangiocarcinoma with hilar invasion and intrahepatic metastases.

Cholangiocarcinoma is a therapeutically challenging malignancy. This report describes a case where the patient received multimodal therapy, including surgery, adjuvant chemoradiation therapy, and combination chemotherapy and successfully achieved long-term survival. Specifically, the patient achieved an extended complete response after combination chemotherapy with TS-1 (an orally administered drug that is a combination of tegafur, 5-chloro-2, 4-dihydroxypyridine [CDHP], and oteracil potassium [Oxo]) and cisplatin for recurrence. This result suggests that chemoradiation or combination chemotherapy regimens using oral 5-fluorouracil (5-FU) analogues might therefore be helpful in patients with this malignancy. However, further clinical trials are required.

[A resected case of metastatic pancreatic cancer from cecal carcinoma].

A 64-year-old woman underwent an ileocecectomy in July 2002 for ruptured cecal carcinoma, which was a well-differentiated adenocarcinoma, stage II, ss, ly0, v0, n (-). In August 2005, abdominal CT revealed a tumor 20mm in diameter in the pancreatic tail, therefore, a distal pancreatectomy and splenectomy were performed. The pancreatic tumor resembled the moderately differentiated cecal adenocarcinoma, both having p53 and k-ras point mutations in common, and it was diagnosed as a metastasis of the cecal carcinoma.

[Case of GIST of the rectum successfully treated with imatinib mesylate neoadjuvant therapy].

A 60-year-old man, with a high risk GIST of the rectum, suspected of the infiltration to the prostate and measuring 10 cm in diameter, underwent resection after neoadjuvant therapy of imatinib mesylate. Perineal approach was added because intraperitoneal dissection was not enough, however, the infiltration to the prostate was denied completely due to a reduction in the tumor size, thus total peritoneal resection was avoided. It seems that neoadjuvant therapy with imatinib mesylate is useful for resectability and for the preservation of the functions of ambient organs.

Impact of plasma tissue inhibitor of matrix metalloproteinase-1 on long-term survival in patients with colorectal cancer.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) not only inhibits matrix metalloproteinases but also stimulates tumor growth. In this study, long-term follow-up results were analyzed to clarify the prognostic value of plasma TIMP-1. Preoperative plasma TIMP-1 was measured from peripheral blood samples of 87 Japanese patients with colorectal carcinoma. All the patients underwent surgical resection and were followed for 5 years prospectively. The median follow-up period was 70 months (60-79 months). The cutoff value of plasma TIMP-1 was set at 170 ng/ml based on the ROC curve. Sensitivity and specificity to predict 5-year survival was 66.7 and 55.0% with this cutoff value. In univariate analyses for overall survival, lymph node metastasis, serosal invasion, peritoneal metastasis, liver metastasis, metastasis to other distant organs and TIMP-1 were significant. In multivariate analyses, lymph node and liver metastases, metastasis to other distant organs and plasma TIMP-1 were independent prognosticators, but p values of TIMP-1 did not reach statistical significance. Our results suggested that the preoperative plasma TIMP-1 concentration could be a useful prognosticator of long-term survival in patients with colorectal carcinoma.

Overexpressed cyclo-oxygenase-2 in the background liver is associated with the clinical course of hepatitis C virus-related cirrhosis patients after curative surgery for hepatocellular carcinoma.

BACKGROUND: The probable role of cyclo-oxygenase-2 (COX-2) in the development of hepatocellular carcinoma (HCC) in patients with chronic liver diseases has been accepted to be relevant. The purpose of the present study was to determine whether overexpressed COX-2 in the background liver affects the clinical course of hepatitis C virus (HCV)-related cirrhosis patients after curative surgery for HCC. METHODS: Twenty-nine clinical stage I HCC patients with HCV-related cirrhosis, who underwent curative surgery, were enrolled in the present study (22 men and seven women, age range 53-73 years; follow-up period; range 22-159 months, median 61 months). The COX-2 expression in the cirrhotic liver was examined by immunohistochemistry using the avidin-biotin-peroxidase complex technique on paraffin-embedded formalin-fixed tissue. The COX-2 expression was scored, then correlated with monitored alanine aminotransferase (ALT) levels during the follow-up period after surgery, response to alternative therapy aiming to improve elevated ALT levels, and recurrence/survival after surgery. RESULTS: The COX-2 expression scores were significantly higher in the high-ALT group than in the low-ALT group (Mann-Whitney, P = 0.010), and were significantly higher in non-responders to the alternative therapy than in responders (Mann-Whitney, P = 0.028). The higher COX-2 expression in the cirrhotic liver was the significant independent risk factor for residual liver recurrence (Cox multivariate analysis, P = 0.014), but not for survival. CONCLUSIONS: Overexpressed COX-2 in the background liver may play an important role in prolonged acceleration of necroinflammation, resistance to the alternative therapy, and recurrence/new development of HCC in HCV-related cirrhosis patients.

Lateral lymph node dissection for lower rectal cancer.

BACKGROUND/AIMS: This study was conducted to evaluate the effects of lateral lymph node dissection (LLD) on overall survival, disease-free survival, and local recurrence for the patients with lower rectal cancer. METHODOLOGY: From 1990 through 2000, 169 consecutive patients with T2 (TNM classification) or more advanced, extended lower rectal cancer (located below the peritoneal reflection) underwent curative resection at Kanagawa Cancer Center were reviewed. One hundred and forty-three patients who underwent LLD and the 26 patients who did not were entered in this study. RESULTS: Cox's multivariate regression analysis showed T stage (TMN classification), N stage (TNM classification), and LLD were found to be significantly related to the rates of both cumulative survival and disease-free survival. That mean LLD was identified as a significant prognostic factor. But disease-free survival did not differ significantly between the patients who underwent LLD and those who did not undergo LLD in stage I, II, or III disease (p = 0.3681, p = 0.1815, and p = 0.0896, respectively). The local recurrence rate was similar in patients who received LLD (17.5 percent) and in those who did not receive LLD (23.1 percent; p = 0.498). But 7 patients with lateral lymph node metastasis (33.3 percent) remained disease free. And these patients had local lateral lymph node metastasis and benefited from LLD. CONCLUSIONS: LLD can substantially improve outcomes in selected patients at high risk for lateral lymph node metastasis. A randomized controlled clinical study is necessary to clarify the role of LLD in the treatment of rectal cancer.

Antitumor activity of a combination of trastuzumab (Herceptin) and oral fluoropyrimidine S-1 on human epidermal growth factor receptor 2-overexpressing pancreatic cancer.

The cytotoxic effect of trastuzumab in combination with oral fluoropyrimidine S-1 on human epidermal growth factor receptor 2 (HER2)-overexpressing human pancreatic cancer cell line TRG in vitro and in vivo was investigated. HER2 expression in TRG was analyzed by RT-PCR and flow cytometry. For in vitro experiments, 5-fluorouracil (5-FU) was used instead of S-1. In vivo studies were conducted with TRG xenografts in athymic mice. Trastuzumab (10 mg/kg) was administered intraperitoneally once a week for 4 weeks. S-1 (10 mg/kg) was administered orally 5 days a week for 4 weeks. The results showed that TRG cells were positive for HER2 mRNA and overexpressed HER2 protein. Either trastuzumab or 5-FU concentration-dependently inhibited the growth of TRG cells. The combination of trastuzumab and 5-FU resulted in a significant inhibition of growth of TRG cells compared to either agent alone (P<0.001). Incubation of TRG cells with peripheral blood mononuclear cells after treatment with trastuzumab enhanced the antiproliferative effect of trastuzumab, which could be the result of antibody-dependent cellular cytotoxicity. The combination of trastuzumab and S-1 resulted in a significant reduction in xenograft volume compared to each agent alone (P<0.0001). In conclusion, this study showed that combination therapy with trastuzumab and S-1 may be effective for HER2-overexpressing pancreatic cancer patients.

Clinicopathological features of skip metastasis in colorectal cancer.

BACKGROUND/AIMS: Japanese general rules for the staging of colorectal cancer conventionally classify lymph node metastasis into three groups according to location with respect to the primary tumor. Skip metastasis, in which distant nodes are positive but regional nodes are negative, is often encountered but poorly understood. We studied the clinicopathological features of skip metastasis in colorectal cancer. METHODOLOGY: The location of positive nodes was classified in 323 patients with Dukes' stage C colorectal cancer. Skip n2 lymph node metastasis was defined as positive N2 metastasis without negative N1 or N3 metastasis. Clinicopathological findings and survival were compared between the patients with skip n2 metastasis (skip n2 group) and those with n1 (n1 group) or n2 metastasis (n2 group). RESULTS: There were 211 patients in the n1 group, 91 in the n2 group, and 21 in the skip n2 group. Pathological examination showed that the skip n2 group had fewer positive nodes than the n1 and n2 groups, but was positioned between these groups with respect to the degree of lymphatic invasion. Cumulative survival was significantly poorer in the n2 group than in the skip n2 group (p = 0.039 by log-rank test). Survival was similar in the skip n2 group and n1 group. There was also no difference in survival between patients in the skip n2 group and patients with one, two, or three N1 metastases. CONCLUSIONS: Lymph nodes with skip n2 metastasis are most likely sentinel nodes of the primary tumor in patients with colorectal cancer. The prognosis of patients with skip n2 metastasis is therefore better than that of patients with n2 metastasis and similar to that of patients with n1 metastasis.

Water-generated negative air ions activate NK cell and inhibit carcinogenesis in mice.

Negative ions are considered to have potential health benefits, but few studies have examined their effects in vivo. We studied water-generated negative ions (WNI) with respect to physical properties as well as immunologic activation and anti-tumor activity (inhibition of carcinogenesis and tumor growth) in mice. Electrically, generated negative ions (ENI) served as control. Water-generated negative ions had a long life, significantly enhanced the cytotoxic activity of natural killer cells, and significantly decreased the incidence of cancer and inhibited tumor growth. Anti-tumor effects were attributed to enhancement of natural killer cell activity. The mechanisms and applications of negative ions warrant further investigation.

[A case of flat elevated type carcinoma in adenoma of the duodenum with gastric cancer].

Duodenal adenoma is rare, and there have been very few case reports of flat elevated type adenoma. We report a case of flat elevated type carcinoma in adenoma of the duodenum with gastric cancer. A 58-year-old man was referred to our hospital for gastric cancer. Endoscopic examination revealed the gastric cancer and a flat elevated tumor in the descending part of the duodenum, measuring 6 cm in diameter. The biopsy specimen of the duodenal lesion was diagnosed as adenoma. Distal gastrectomy and segmental partial resection of the duodenum were performed with no complication. Histologically, the gastric cancer was poorly differentiated adenocarcinoma with submcosal invasion and without lymph node metastasis, and the duodenal tumor was a well differentiated carcinoma in villous adenoma. The duodenal adenocarcinoma was limited to the mucosal layer and the resected margins were free of tumor. It is difficult to distinguish a carcinoma from a benign elevated lesion in the duodenum. Therefore, a resection of the whole tumor is necessary. Though endoscopic resection is the first choice of therapy, a surgical partial resection is necessary when it is difficult. Then, a segmental resection may be one of the useful procedures of surgery.

Growth index, assessed with Ki-67 and ssDNA labeling; a significant prognosticator for patients undergoing curative resection for hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: The aggressiveness and greater malignant potential of cancers are characterized by several biological phenomena such as accelerated growth invasiveness, and the ability to form distant metastasis. Thus, knowledge of such biological difference may be a more accurate prognosticator for cancer patients. Tumor growth depends on the degree of imbalance between cell production and loss. This study aimed to clarify a possible role for the modified prognosticator, growth index (GI); defined as the difference between Ki-67 (%) and single-stranded DNA (ssDNA) (%) labeling indices, in patients undergoing curative resection for hepatocellular carcinoma (HCC). METHODS: Tissue specimens were obtained from 40 HCC patients who underwent curative surgery. Immunohistochemical staining was performed using the avidin-biotin-peroxidase-complex method. RESULTS: The GI in HCC ranged from -1.90% to 28.65%, median 3.73. GI was related to histologic grade, intrahepatic metastasis, and pathologic T stage. Cumulative survival was poorer in patients with higher GI (> or = median value). Multivariate analysis demonstrated that GI is an independent prognosticator along with vascular invasion and intrahepatic metastasis. CONCLUSIONS: The higher GI values were significantly associated with histologic aggressive features of HCCs, and GI was a significant independent prognosticator in HCC patients after curative resection.

Wernicke encephalopathy presented in the form of postoperative delirium in a patient with hepatocellular carcinoma and liver cirrhosis: a case report and review of the literature.

OBJECTIVE: Although Wernicke encephalopathy has been reported in the oncological literature, it has not previously been reported in postoperative cancer patients. METHODS: In this communication, we report a patient of hepatocellular carcinoma with liver cirrhosis who developed Wernicke encephalopathy in the form of postoperative delirium. Preoperatively, the patient had a very good appetite and had eaten all the food of an 1800 cal/day diet until 1 day before operation. The operation was done without any complications. The patient developed delirium 2 days after the lobectomy of the liver. The level of delirium remained unchanged until administration of thiamine starting on day 7 postoperatively, which resulted in palliation of delirium without brain damage. Laboratory data demonstrated that the serum thiamine level at day 6 postoperatively was below the lower limit of normal. As the mechanism of Wernicke encephalopathy, we thought that decreased ability to store thiamine due to liver cirrhosis led to depletion of thiamine faster than had been expected. RESULTS AND SIGNIFICANCE OF THE RESEARCH: In cancer patients, clinicians must always remain aware of the possibility of Wernicke encephalopathy, especially in patients with liver dysfunction, which decreases the ability to store thiamine in the liver. Early detection and intervention may alleviate the symptoms of delirium and prevent irreversible brain damage.

Expression of survivin mRNA associates with apoptosis, proliferation and histologically aggressive features in hepatocellular carcinoma.

The clinical impact of survivin on human cancer pathogenesis and prognosis has been investigated. To clarify the clinical effect of survivin on tumor behavior and prognosis of patients with hepatocellular carcinoma (HCC), the expression of survivin mRNA in 40 samples of HCC tissue and matched-adjacent liver tissue, as well as 7 healthy hepatic tissue samples were measured by a real-time reverse transcription polymerase chain reaction. The expressed level of survivin mRNA (log copies/microg total RNA) in healthy liver tissue was 1.95+/-0.44, in morbid liver tissue adjacent to the tumors was 4.79+/-0.96, and in HCC tissue was 5.87+/-0.73 (values are mean +/- SD and P<0.001). The amount of survivin mRNA in HCC tissues correlated negatively with the apoptotic indices (r=-0.573 and P<0.001) and correlated positively with the proliferation indices (r=0.433 and P=0.005). Expression of survivin was significantly related with histologic grade (P=0.011) and pathological tumor stage (P=0.017). Patients with HCC tumors that had a large amount of survivin mRNA (> or = mean) had lower survival rate (P=0.030), but multivariate analysis showed only Ki-67 labeling index, histologic grade, and pathologic T stage to be the independent prognosticators. These findings indicate that survivin is associated with reduced tumor cell apoptosis, increased tumor cell proliferation, and histologically aggressive tumor features, and may play an important role in tumor progression of HCC. However, further examination is needed to clarify its predictive significance for HCC patients.

Prognostic impact of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with colorectal cancer.

BACKGROUND: Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in plasma has been reported to be related to disease progression in patients with colorectal cancer. However, the prognostic significance of plasma TIMP-1 has not been clarified. PATIENTS AND METHODS: Concentrations of TIMP-1 protein were measured by enzyme-linked immunosorbent assay in plasma samples of 87 preoperative patients who subsequently underwent resection, and prognosis was compared. The cut-off value of plasma TIMP-1 was defined as 170 ng/ml. RESULTS: When clinicopathological factors between patients with positive and those with negative plasma TIMP-1 were analyzed, significant differences were observed in lymph node metastasis, serosal invasion, curability and Dukes' classification. Univariate analysis of these factors demonstrated that depth of invasion, metastases to lymph nodes, peritoneum, liver and distant organ, lymphatic and vessel invasions, curability. Dukes' classification and plasma TIMP-1 concentration were significant. By multivariate analysis excluding patients with distant or peritoneal metastases, histological type, lymphatic invasions, lymph node metastasis and plasma TIMP-1 were retained in the final model. CONCLUSION: These results suggested that plasma TIMP-1 may be a useful prognostic marker for survival in patients with colorectal carcinoma.

Serum alanine aminotransferase levels and survival after hepatectomy in patients with hepatocellular carcinoma and hepatitis C virus-associated liver cirrhosis.

We examined whether sustained alleviation of inflammation as monitored by serum alanine aminotransferase (ALT) levels was associated with longer survival in hepatectomized hepatocellular carcinoma (HCC) patients with hepatitis C virus-associated liver cirrhosis (HCV-LC). Thirty-four hepatectomized patients with HCV-LC and HCC as a single nodule, and for whom more than 5 years had elapsed after the hepatectomy, were studied. They had no histologic evidence of portal or hepatic vein invasion. They were subdivided into two groups according to their serum ALT levels in the 2 years after hepatectomy: the low ALT group comprised 13 patients whose serum ALT levels showed a sustained low level below 80 IU, and the high ALT group comprised 21 patients whose serum ALT levels showed several peaks or plateaus above 80 IU. The patients had been followed-up prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography for recurrence for > 5 years. The survival period, non-recurrence interval and number of recurrences were observed. Recurrences were treated with transcatheter chemoembolization in all cases. The cumulative survival rate in the low ALT group was significantly better than that in the high ALT group (P < 0.05). The 5-year survival in the low ALT group was as high as 92.3% (12 of 13) compared with 33.3% (7 of 21) in the high ALT group (P < 0.05). The cumulative non-recurrence rate in the low ALT group was also significantly better than that in the high ALT group (P < 0.01). The survival period correlated well with the interval until the first recurrence (r = 0.545, P = 0.006). There was a tendency for the number of recurrences in the low ALT group (1.5 +/- 0.4, mean +/- SE) to be fewer than that in the high ALT group (2.2 +/- 0.4), although this was not significant. Sustained alleviation of inflammation, as indicated by low ALT levels, provides a survival advantage mainly due to the longer non-recurrence interval, and possibly because of fewer recurrences, in hepatectomized HCC patients with HCV-LC.

Platelet-derived endothelial cell growth factor (PD-ECGF) is up-regulated in human hepatocellular carcinoma (HCC) and the corresponding hepatitis liver.

BACKGROUND/AIMS: Platelet-derived endothelial cell growth factor (PD-ECGF) is one of the angiogenic factors. The aim of this study was to examine the PD-ECGF concentrations in hepatocellular carcinoma, background liver, and normal liver tissues, and to elucidate their significance on clinicopathological outcomes. METHODOLOGY: The concentration of PD-ECGF in the tissue extract was determined by enzyme-linked immunosorbent assay. RESULTS: PD-ECGF concentrations were significantly higher in hepatocellular carcinoma and background liver tissues compared with normal control liver (p = 0.003, p = 0.001, respectively). PD-ECGF concentrations in hepatocellular carcinoma tissues were positively correlated with intratumoral arteriole densities (r = 0.667, p = 0.009), and were higher in less differentiated carcinomas (p = 0.039). However, tumor PD-ECGF concentration did not affect the patients' disease-free survival rates. Those in the background liver tissues were positively correlated with histological activity index scores (r = 0.650, p = 0.001) and serum alanine aminotransferase levels (r = 0.0452, p = 0.035). CONCLUSIONS: PD-ECGF is up-regulated in hepatocellular carcinoma and the corresponding hepatitis liver. The PD-ECGF concentrations in hepatocellular carcinoma correlated positively with microvessel density, lower differentiation, yet not with patients' prognosis. The concentrations of PD-ECGF in the corresponding hepatitis liver correlated positively with the degree of active hepatitis.

[Examination of percutaneous microwave coagulation and radiofrequency ablation therapy for metastatic liver cancer].

Percutaneous microwave coagulation therapy (PMCT) and radio frequency ablation therapy (RFA) as treatments for metastatic liver cancer were examined. PMCT or RFA was administered for 18 metastatic liver cancer lesions (primary lesion: 11 colon rectal cancer, one esophagus cancer, one thyroid cancer, one pancreatic cancer, one pheochromocytoma) in 16 patients from July 1999 to March 2002. RFA was performed 1 time for 12 minutes in principle, using a Cool-tip RF system from Radionics. Patients had a mean age of 58.8 years and the mean diameter of the neoplasms was about 22 mm. Critical complications were not seen. The rate of partial recurrence was 35.3% as of March, 2002, in an average observation period of 7.3 months. On the other hand, with the medical treatment for the hepatocellular carcinoma provided during this period, the rate of partial recurrence was 14.8%. The treatment of metastatic liver cancer by PMCT and RFA is associated with a high rate of a recurrence as compared with hepatocellular carcinoma, and needs to be examined to discover ways of adaptation and improvement of the technology.