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In contrast to the relatively stable climate of the past 10,000 years, during glacial times the North Atlantic region experienced large-amplitude transitions between cold (stadial) and warm (interstadial) states. In this modeling study, we demonstrate that hydrological interactions between the Atlantic thermohaline circulation (THC) and adjacent continental ice sheets can trigger abrupt warming events and also limit the lifetime of the interstadial circulation mode. These interactions have the potential to destabilize the THC, which is already more sensitive for glacial conditions than for the present-day climate, thus providing an explanation for the increased variability of glacial climate.

Background/aims: Some hepatocellular carcinoma nodules do not show tumor stain by hepatic angiography or enhanced computed tomography. The aim of this study was to clarify the prognosis of hepatocellular carcinoma with no tumor stain treated by percutaneous ethanol injection., Methodology: Twenty patients who had hepatocellular carcinoma with no tumor stain were treated by percutaneous ethanol injection between January 1990 and June 1998. No patients had received any anticancer treatments before percutaneous ethanol injection. Recurrence-free survival, predictive factors for recurrence and recurrent patterns were examined. Overall survival was also examined., Results: Ten of the 20 patients showed intrahepatic recurrences in other parts of the treated lesions, although no local recurrence was observed. Median recurrence-free survival time, 1-, 3- and 5-year recurrence-free survival rates were 2.8 years, 66%, 43% and 22%, respectively. A serum alpha-fetoprotein level of 20 ng/mL or less was the only factor that was significantly associated with prolonged recurrence-free survival. Of the 12 recurrent nodules in 10 patients, 9 occurred in different segments of the treated lesion and 8 were histopathologically confirmed to be well-differentiated hepatocellular carcinoma. Overall survival rates 1, 3, and 5 years after percutaneous ethanol injection were 100%, 82%, and 75%, respectively., Conclusions: Percutaneous ethanol injection may be useful for the treatment of hepatocellular carcinoma with no tumor stain.

The chemokine receptors CXCR4 and CCR5 are considered to be potential targets for the inhibition of HIV-1 replication. We have reported that T134 and T140 inhibited X4 HIV-1 infection specifically because they acted as CXCR4 antagonists. In the present study, we have generated a T134-resistant virus (trHIV-1(NL4-3)) in a cell culture with gradually increasing concentrations of the compound. The EC(50) of T134 against trHIV-1(NL4-3) recovered after 145 passages was 15 times greater than that against wild-type HIV-1(NL4-3). This adapted virus was resistant to other CXCR4 antagonists, T140, AMD3100, and ALX40-4C, and SDF-1; from 10 to 145 times greater than that against wild-type HIV-1(NL4-3). On the other hand, T134, T140, and ALX40-4C were still active against AMD3100-resistant viruses (arHIV-1(018A)). The trHIV-1(NL4-3) contained the following mutations in the V3 loop of gp120: N269K, Q278T, R279K, A284V, F285L, V286Y, I288T, K290E, N293D, M294I, and Q296K; an insertion of T at 290; and Delta274-275 (SI). In addition, many other mutations were recognized in the V1, V2, and V4 domains. Thus, resistance to T134 may be the consequence of amino acid substitutions in the envelope glycoprotein of X4 HIV-1. The trHIV-1(NL4-3) could not utilize CCR5 as an HIV infection coreceptor, although many amino acid substitutions were recognized. The trHIV-1(NL4-3) acquired resistance to vMIP II, which could inhibit both X4 and R5 HIV-1 infection. However, neither the ligands of CCR5, RANTES, and MIP-1alpha, nor a CCR5 low molecular antagonist, TAK-779, were able to influence the infection of trHIV-1(NL4-3). Those results indicated that alternation of coreceptor usage of trHIV-1(NL4-3) was not induced.

Betulinic acid, a triterpenoid isolated from the methyl alcohol extract of the leaves of Syzigium claviflorum, was found to have a potent inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Betulinic acid derivatives were synthesized to enhance the anti-HIV activity. Among the derivatives, 3-O-(3',3'-dimethylsuccinyl) betulinic acid, designated YK-FH312, showed the highest activity against HIV-induced cytopathic effects in HIV-1-infected MT-4 cells. To determine the step(s) of HIV replication affected by YK-FH312, a syncytium formation inhibition assay in MOLT-4/HIV-1(IIIB) and MOLT-4 coculture, a multinuclear-activation-of-galactosidase-indicator (MAGI) assay in MAGI-CCR5 cells, electron microscopic observation, and a time-of-addition assay were performed. In the syncytium formation inhibition assay or in the MAGI assay for de novo infection, the compound did not show inhibitory effects against HIV replication. Conversely, no virions were detected in HIV-1-infected cell cultures treated with YK-FH312 either by electron microscopic observation or by viral yield in the supernatant. In accordance with a p24 enzyme-linked immunosorbent assay of culture supernatant in the time-of-addition assay, YK-FH312 inhibited virus expression in the supernatant when it was added 18 h postinfection. However, Western blot analysis of the cells in the time-of-addition assay revealed that the production of viral proteins in the cells was not inhibited completely by YK-FH312. These results suggest that YK-FH312 might affect the step(s) of virion assembly and/or budding of virions, and this is a novel mechanism of action of an anti-HIV compound.

The chemokine receptors CXCR4 and CCR5 are considered to be potential targets for the inhibition of HIV-1 replication. We found that the synthetic peptides T134 and T140 (see text for full names) inhibited X4 HIV-1 infection with selectivity and low toxicity because they acted as CXCR4 antagonists. However, high concentrations of T134, T140, and ALX40-4C (see text for full name) increased the expression of CCR5 and R5 HIV-1 infection, as did stromal cell-derived factor 1 (SDF-1). In contrast to CXCR4 antagonists and SDF-1, viral monocyte inflammatory protein (vMIP) II inhibited not only anti-CXCR4 monoclonal antibody (MAb) but also inhibited anti-CCR5 MAb binding to human peripheral blood mononuclear cells, and inhibited both X4 and R5 HIV-1 strains. T134, T140, ALX40-4C, and SDF-1 increased viral transcription in the treated cells. In addition, ALX40-4C and SDF-1 also increased nuclear transcription factor (NF)-kappaB. However, the mechanisms of action of T134 and T140 are different from those of clinically used anti-HIV drugs. Thus, synergistic activities were observed in the concomitant treatment with T134 and reverse transcriptase inhibitors or protease inhibitors. Our findings, presented here, are noteworthy in regard to the potential clinical use of these agents as drugs for the treatment of AIDS.

Transcatheter arterial embolization (TAE) has been widely performed for patients with hepatocellular carcinoma (HCC). However, the method of evaluating the therapeutic effect of TAE has not been established. We examined the rate of necrotic area to whole tumor (TN) by CT, the tumor regression rate (TR) and the reduction rate in serum alpha-fetoprotein (AFP) levels in patients with HCC who received hepatic resection within 3 months after TAE. In the evaluation of TN, the lipiodol accumulation in tumor was regarded as being necrotic. Rates of necrotic area, which were also examined pathologically (PN) in resected tumors, were compared with TN, TR and AFP reduction rates, respectively. Eighty-eight patients were enrolled in this study, and there was a significant positive correlation between TN and PN (r = 0.80, p < 0.001). Although TR significantly correlated to PN (p = 0.001), the correlation coefficient between them was low (r = 0.34). The correlation coefficients between AFP reduction rate and PN was 0.76 (p < 0.001) in 26 patients (30%) with an AFP level >/=200 ng/ml before TAE. The evaluation method using lipiodol accumulation in CT is the most useful for assessing the therapeutic effect of TAE, particularly when a sufficiently long interval exists between TAE and the evaluation, because of the highest correlation coefficient between TN and PN, and the availability of TN for all patients. The reduction rate in serum AFP levels was also useful in patients with AFP levels >200 ng/ml before treatment., (Copyright 2000 S. Karger AG, Basel)

Background/aims: Sequential administration with methotrexate and 5-fluorouracil (sequential MTX/5-FU) has synergistic cytotoxic activity for several malignant diseases, but its activity in pancreatic cancer has not been fully evaluated. The aim of this study was to evaluate the antitumor activity and toxicity of sequential MTX/5-FU in metastatic pancreatic cancer., Methodology: All patients were required to have a pathologic diagnosis of pancreatic adenocarcinoma with measurable metastatic lesions, and no prior chemotherapy. Sequential MTX/5-FU was administered weekly as followed; MTX 100 mg/m2 intravenous bolus infusion was given, followed 3 h later by 5-fluorouracil 600 mg/m2 intravenous infusion over 30 min., Results: Thirty-one patients were enrolled and assessable for response and toxicity. There were no complete responses, 4 partial responses, 10 no change and 17 progressive disease. The response rate was 12.9% (95% confidence interval: 1.1-24.7%) and the duration of response was 7.1 months (range: 5.5-9.1 months). The median survival was 4.0 months. Chemotherapy was well tolerated, although grade 3-4 toxicities such as neutropenia and diarrhea were seen infrequently., Conclusions: The sequential MTX/5-FU had marginal antitumor activity with mild toxicity against metastatic pancreatic cancer.

Background/aims: The prognosis of patients with advanced pancreatic cancer is extremely poor. To improve their prognosis, providing effective chemotherapy is necessary. The aim of this study was to evaluate the anti-tumor activity and toxicity of combined chemotherapy (FP therapy) using 5-fluorouracil and cisplatin in Japanese chemo-naive patients with advanced pancreatic cancer., Methodology: Thirty-seven previously untreated patients with histologically proven pancreatic adenocarcinoma were treated with FP therapy. 5-fluorouracil was administered at 500 mg/m2/day by continuous intravenous infusion for 5 days and cisplatin was administered at 80 mg/m2 intravenously on the 1st day. Therapy was repeated every 4 weeks until there was evidence of disease progression or unacceptable toxicity., Results: Three patients achieved partial responses, whereas none exhibited a complete response. The overall response rate was 8% (95% confidence interval, 2-22%) and the response durations were 6, 9 and 12 months, respectively. The median survival time of patients was 5 months. Toxicities were generally mild and acceptable, although nausea/vomiting was the most commonly observed toxicity., Conclusions: FP therapy on this schedule had limited anti-tumor activity for pancreatic cancer, indicating that, practically, it should not be performed in Japanese patients with advanced pancreatic cancer.

The combination of bisulfite treatment and PCR-single-strand DNA conformation polymorphism (SSCP) analysis is proposed for quantitative methylation assay. We applied this procedure to the methylation analysis of the hMLH1 promoter region in colorectal cancer. An analysis of mixtures of known amounts of methylated and unmethylated DNA revealed a linear relation. Using a calibration curve, proportions of methylated DNA were calculated. The hMLH1 promoter region was highly methylated in about 80% of microsatellite instability (MSI) (+) colorectal cancers, but in none of the MSI(-) colorectal cancers. A significant correlation existed between hypermethylation of the hMLH1 promoter and MSI, as in previous reports. In conclusion, bisulfite-PCR-SSCP (BiPS) analysis could be applied to the rapid identification of methylation status in multiple samples, quantification of methylation differences, and detection of methylation heterogeneity in amplified DNA fragments., (Copyright 1999 Academic Press.)

Background/aims: There is more potential for misclassification of adenocarcinoma of the pancreas than for many other cancers because of the difficulty of accurate diagnosis., Methodology: We analyzed the clinicopathological features of 105 patients who were suspected of having unresectable adenocarcinoma of the pancreas on their 1st visit to our outpatient clinic., Results: Ten of 105 patients (10%) had been misdiagnosed as having pancreatic carcinoma. The final diagnoses were made mainly using dynamic computed tomography (CT) and/or histologic examination. The incidence of weight loss (> or = 7% of total-body weight, within 6 months before diagnosis) in the misdiagnosed patients was significantly lower than that in pancreatic carcinoma patients (30% vs. 67%, p=0.02). Serum CA19-9 abnormality (> 100 U/ml) was observed less frequently in the misdiagnosed patients than in the patients with pancreatic carcinoma (40% vs. 77%, p=0.01). The detection of a dilated main pancreatic duct and/or pancreatic mass by imaging modalities was less frequent in the misdiagnosed patients (p<0.01)., Conclusions: Dynamic CT and/or histologic examination may be essential when making a definite diagnosis of advanced pancreatic carcinoma. In addition, weight loss, serum CA19-9 abnormality, detection of a dilated main pancreatic duct and/or pancreatic mass may also be useful in making a differential diagnosis of this disease.

We present a case of pancreatic cancer demonstrating symptomatic improvement with systemic chemotherapy using 5-fluorouracil and cisplatin (FP therapy). A 43 year-old man had pancreatic cancer with para-aortic lymph node metastases. He received FP therapy and achieved a partial response. After the initiation of chemotherapy, his symptoms such as severe pain and fatigue improved remarkably. Serum interleukin-6 levels correlated with these symptoms; the level was high before chemotherapy, but the levels were decreased during the courses of FP therapy. It is important to achieve symptomatic improvement in patients with pancreatic cancer, and serum interleukin-6 levels may be useful to evaluate a symptomatic response to chemotherapy.

Zinostatin stimalamer (SMANCS) is a lipophilic intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). Thirty HCC patients underwent transcatheter arterial injection of 4 mg SMANCS-lipiodol emulsion. Their responses were evaluated by computed tomography 1 month after treatment. Complete response (CR) was defined as disappearance or 100% necrosis of all tumors. Partial response (PR) was defined as > or = 50% reduction and/or > or = 50% necrosis. We regarded the lipiodol accumulation in tumors as being necrotic. CR and PR were observed in 8 patients (27%) and 4 patients (13%), respectively, and the overall response rate (CR + PR/all patients) was 40% (12/30). Of 12 patients whose serum alpha-fetoprotein levels had been more than 200 ng/ml before treatment, 5 patients (42%) showed more than 50% reduction in this level within 1 month after treatment. Toxicity was quite acceptable, although grade 4 toxicity (WHO) was observed as liver dysfunction in 1 patient. Transarterial chemotherapy with SMANCS, which is well tolerated, appears to have moderate antitumor effect in patients with HCC.

The aim of the study was to determine whether past exposure to hepatitis B virus (HBV) influences the risk of the development of hepatocellular carcinoma (HCC) in Japanese patients with chronic liver disease (CLD). We conducted a hospital-based case-control study of 141 HCC patients with CLD and 151 controls with CLD but without HCC. Past exposure to HBV was assessed by antibody to hepatitis B core antigen (anti-HBc) positivity. Ninety-two patients (65%) with HCC were anti-HBc positive compared with 65 patients (43%) with CLD alone (P < 0.01). A multivariate analysis using logistic regression modelling revealed that anti-HBc positivity significantly increased the risk of the development of HCC [odds ratio (OR) 2.0, P = 0.01]. In the anti-HBc-positive patients, a significantly increased risk of HCC was seen among the patients positive for anti-HBc alone (OR, 2.6; P < 0.01). However, a significant OR was not obtained among the patients with a transient HBV infection implied by positivity for both antibody to hepatitis B surface antigen and anti-HBc (OR, 1.5; P = 0.48). These results indicate that past exposure to HBV is a risk factor for HCC in Japanese CLD patients, especially when they have no serological evidence of immunity to HBV.

Undifferentiated carcinoma of the liver is very rare. A 54-year-old man was admitted to our hospital for a detailed examination of multiple liver tumors. These tumors were high or low echoic on ultrasonography, but not enhanced by contrast medium in dynamic computed tomography. A fine-needle aspiration biopsy specimen of the tumor showed undifferentiated carcinoma. The serum level of neuron-specific enolase was high (357 ng/ml) and the immunohistochemical stain of the biopsy specimen was positive for synaptophysin. We diagnosed the patient as having undifferentiated carcinoma of the liver with neuroendocrine features. The patient was treated with combined systemic chemotherapy: etoposide 100 mg/m2/day for three days plus cisplatin 80 mg/m2/day on day one. He achieved a partial response, the duration of which was 7+ months. The serum neuron-specific enolase levels were decreased to the normal range after chemotherapy. Primary liver carcinoma with neuroendocrine features is extremely rare, but in a suspicious case it is important to measure the serum levels of neuroendocrine markers and make a histological confirmation, because chemotherapy may be effective for this disease.

Background: Percutaneous ethanol injection (PEI) therapy currently is widely used for small hepatocellular carcinoma (HCC). However, only limited information is available regarding needle tract implantation after PEI treatment., Methods: Records of HCC patients who underwent PEI between March 1990 and April 1997 at the National Cancer Center Hospital (n = 177) were reviewed to clarify the incidence, risk factors, and outcome of needle tract implantation of HCC., Results: PEI was performed for 348 HCC patients with a median tumor size of 20 mm. Needle tract implantation was found in 4 patients (10, 13, 15, and 46 months, respectively, after PEI). The size of the PEI-treated HCC tumors in these patients was 20, 27, 28, and 30 mm, respectively, in greatest dimension. All tumors were enhanced in the early phase on dynamic computed tomography (CT), and were found to have moderate tumor cell differentiation on biopsied specimens. Of the four implanted tumors, three were resected and the remaining tumor was treated with extrabeam radiotherapy. At last follow-up, 2 of the 4 patients had died (1 of variceal bleeding 60 months after PEI and the other from cancer 61 months after PEI) and 2 were still alive (14 and 20 months, respectively, after PEI) with no evidence of active tumor., Conclusions: Needle tract implantation after PEI is not unusual, especially when HCC tumors are > or =2 cm in greatest dimension, enhanced in the early phase on dynamic CT, and/or moderately differentiated on biopsied specimens.

Although pancreatic cancer (PC) continues to be a formidable disease, numerous treatment strategies are evolving that we hope will result in improved patient survival. To prolong the survival of patients with PC, it is essential to detect PC at the earliest stage possible and to develop effective nonsurgical treatments for this disease. The current strategies for the early diagnosis of PC include the development of diagnostic modalities and screening programs for the early detection of PC and the determination of high-risk groups for PC. K-ras mutations in pancreatic juice obtained endoscopically have been studied recently in association with the early diagnosis of PC, although the interpretation of the presence of a mutated K-ras gene requires caution. The role of the current nonsurgical treatments for PC has been limited. Identification of an effective new chemotherapeutic agent is a high priority, and the enrollment of patients with PC with metastatic disease into well-designed clinical trials is essential. New targets for therapy based on the understanding of the molecular biology of PC may provide avenues for future trials. We must continue to search actively for more accurate methods of diagnosis and more effective methods of treatment for PC.

The vast majority of pancreatic cancer patients have advanced disease at the time of diagnosis and they eventually become so emaciated that death primarily occurs from cancer cachexia. Cancer cachexia may be mediated by certain cytokines such as interleukin-6. In this study, we measured serum interleukin-6 levels in 55 patients with histologically proven pancreatic cancer and investigated their relationships to the clinical status of pancreatic cancer. A control population of 20 normal healthy adults and 25 chronic pancreatitis patients with comparable gender and age distribution characteristics was also studied. Serum interleukin-6 levels were measured using a quantitative sandwich enzyme-linked immunosorbent assay. Thirty pancreatic cancer patients (54.5%) had detectable levels, although interleukin-6 levels were detectable in only one healthy control and in two chronic pancreatitis patients. The specificity of serum interleukin-6 in this population was 93.3%, resulting in high diagnostic accuracy (72.0%). Among the pancreatic cancer patients, the detection rates of serum interleukin-6 levels increased significantly with the disease extent (p < 0.01). Moreover, a significant difference was also found in the detection rates between the 30 pancreatic cancer patients with body weight loss (76.7%) and the remaining 25 patients without weight loss (28.0%, p < 0.01). These results may provide new insight into both diagnosis and treatment of pancreatic cancer, because the diagnostic accuracy of serum interleukin-6 was high and because anti-interleukin-6 therapeutics could improve symptoms in pancreatic cancer patients with high interleukin-6 levels.

Progressive weight loss and nutritional deterioration are commonly found in patients with advanced pancreatic cancer. There have been few studies of whether nutritional support improves survival for these patients. We retrospectively investigated the relationship between calorie intake and survival in 50 patients who died from cancer. The survival period was calculated from the day when their serum albumin level measured < 3.0 mg/dl. Total calorie intake was calculated on the basis of diet and parenteral nutrition for the week before the day when serum albumin levels fell to < 3.0 mg/dl. Patients were divided into a low- and a high-calorie intake group using the median of calorie intake per predictive basal metabolism. The survival period was significantly longer for the high- than for the low-calorie intake group (median 50 vs. 32 days, p = 0.02). We also investigated the relationships between calories of parenteral nutrition and survival. High-calorie parenteral nutrition subgroups tended to survive longer than low-calorie parenteral nutrition subgroups irrespective of enteral nutrition. Sufficient calorie intake may have the potential to prolong survival for patients with advanced pancreatic cancer.

Chemotherapy is of limited value in the treatment of hepatocellular carcinoma (HCC), since there are no established chemotherapeutic regimens proven to be effective. The aim of the present study was to determine predictive factors for tumor response to systemic chemotherapy in HCC patients. The relationship between patients' characteristics and tumor response was examined in 147 previously untreated HCC patients receiving systemic chemotherapy. Ten patients showed partial response (PR) and none showed complete response (CR). The response rate for all single anticancer agents was less than 10% and the overall response rate was 6.8%. The response rate in patients with unilateral HCC was significantly higher than in those with bilateral HCC. However, there were no responders among patients with a performance status of 2-3, ascites, a tumor occupying more than 50% of the entire liver, tumor thrombus in the main portal trunk or a serum bilirubin level of more than 2.0 mg/dl. There was a close relationship between patients' characteristics and tumor response. It is concluded that patients with fairly advanced HCC and/or poor hepatic reserve should not be given systemic chemotherapy.

Gastrointestinal hemorrhage from hepatocellular carcinoma invading the duodenum is very rare. A 60-year-old man with multiple hepatocellular carcinoma was admitted to our hospital because of massive melena and hematemesis. We succeeded in hemostasis of an esophageal variceal rupture by endoscopic varicial ligation. The duodenum could not be observed endoscopically due to extramural compression to the stomach from the liver tumor. Massive gastrointestinal hemorrhage occurred again and the patient died of hepatic failure. The postmortem examination revealed that the liver tumor had invaded the second portion of the duodenum and perforated into the lumen.

Background: Radiotherapy plus bolus 5-fluorouracil (5-FU) is generally accepted as the standard treatment for locally advanced pancreatic carcinoma. To intensify the antitumor effect of chemotherapy, the authors administered protracted 5-FU infusion with concurrent radiotherapy. The aim of this study was to determine the feasibility and effectiveness of this combined therapy., Methods: Twenty patients, all of whom had histologically confirmed exocrine pancreatic carcinoma that was nonresectable but confined to the pancreatic region, were enrolled in a Phase II trial of protracted 5-fluorouracil infusion (200 mg/m2/day) with concurrent radiotherapy (50.4 gray in 28 fractions over 5.5 weeks). Chemotherapy began on the first day of radiation and continued through the entire radiation course. Thereafter, weekly infusions (500 mg/m2) were administered until disease progression., Results: Of the 20 patients, 17 (85%) completed the scheduled course of chemoradiotherapy. Grade 3 or worse toxicity, graded according to World Health Organization criteria, was observed in 4 patients (20%). Two patients (10%) achieved partial response, and disease remained stable in 16 patients (80%). After the completion of combined therapy, serum CA 19-9 levels were reduced by more than 50% in 10 of 12 patients (83%) who had pretreatment CA 19-9 levels of 100 U/mL or greater. The median progression free survival and 1-year progression free survival rate were 4.9 months and 29.5%, respectively. The median overall survival and 1-year overall survival rate were 10.3 months and 41.8%, respectively., Conclusions: This treatment showed moderate activity against locally advanced pancreatic carcinoma and was accompanied by an acceptable toxicity level.

The measurement of somatic cell mutation may assist in the assessment of human cancer risk. The glycophorin A (GPA) assay, which measures the frequency of variant erythrocytes in persons with blood type MN, was used to directly assess in vivo mutability in 30 patients with hepatocellular carcinoma (HCC). HCC patients showed significantly increased frequencies of both hemizygous (MO) and homozygous (MM) variants, due to somatic loss of expression of the N allele, when compared with 27 patients with chronic liver disease and 21 healthy controls. The mean elevations of the MO and MM variant frequencies (VF) in HCC patients were 2-3-fold greater than the comparable VF in the control groups. The mean MO and MM VF in the patients with chronic liver disease was slightly elevated compared to that in healthy controls, but the difference was not significant. In the 19 anti-hepatitis C virus (HCV)-positive patients with a history of blood transfusion, significant linear relations between VF and the duration of HCV infection were observed for MO and MM. These data indicate a high background frequency of somatic mutations in HCC patients. The GPA assay may prove to be a useful estimation of the individual's risk of development of HCC.

Background/aims: There is no effective treatment for hepatocellular carcinoma (HCC) with extrahepatic metastases. This study investigated the survival and causes of death in HCC patients with extrahepatic metastases., Materials and Methods: We retrospectively analyzed 34 HCC patients with extrahepatic metastases who received systemic chemotherapy without other anticancer treatment except prior hepatectomy. We classified causes of death as cancer death and death from other causes, and subclassified cancer deaths into hepatic cause, extrahepatic cause and cachectic cause. Each cause of death was analyzed in the two subgroups comprised of 10 patients with bone metastases alone and 22 patients with metastatic lesions in sites other than bone., Results: Thirty-two of the 34 patients had died at the time of analysis. The median survival time and the 1-year survival rate were 4.6 mo and 20.3%, respectively. Incidence of hepatic cause, extrahepatic cause, cachectic cause and death from other causes were 21 (66%), 7 (22%), 2 (6%) and 2 (6%), respectively. In the subgroup of 10 patients with bone metastases alone, nine (90%) died from hepatic causes, but none died from extrahepatic causes. In the group of 22 patients with metastatic lesions in sites other than bone, 7 (32%) patients died from extrahepatic causes., Conclusion: The causes of death in HCC patients with extrahepatic metastases depended on metastatic site at the time of diagnosis. The results of this study may be useful in the design and analysis of future clinical trials of the HCC therapy.

We studied the effect of heavy alcohol intake (ethanol intake > or = 80 g/day for > or = 5 yr) on long-term results in 53 patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) who had undergone curative hepatic resection. Cell proliferative activity in the tumor and non-tumorous liver was also assessed by counting argyrophilic nucleolar organizer region-associated proteins (Ag-NOR) in the resected specimens. Twenty patients (20 males, 0 females) were positive for heavy alcohol intake [AI(+)] and 33 (28 males, 5 females) were not [AI(-)]. All patients were positive for HCV antibody and negative for hepatitis B surface antigen. Carcinoma recurred within 3 to 51 postoperative months in 42 (79.2%) of the 53 patients. The median disease-free survival time was 12.6 mo in the AI(+) group and 25.4 mo in the AI(-) group (P < 0.01). The AI(+) group also had significantly poorer survival than the AI(-) group (P < 0.05, 3-year survival rate: 66.7% vs. 93.5%). HCC tumor in the AI(+) group showed significantly increased proliferative activity compared with that in the AI(-) group (P < 0.05, Ag-NOR number: 2.3 +/- 0.8 vs. 1.9 +/- 0.4). However, there was no significant difference between the numbers of Ag-NORs in non-tumorous liver from these two groups (1.5 +/- 0.2 vs. 1.5 +/- 0.2). Patients with heavy alcohol intake should be followed particularly closely, even if they have received curative surgery, since heavy alcohol intake is closely related to a poor postoperative prognosis.

Background/aims: Intrahepatic recurrence frequently occurs in patients with hepatocellular carcinoma (HCC) even after successful percutaneous ethanol injection (PEI). This study investigated factors predicting recurrence after PEI for solitary HCC., Materials and Methods: The subjects were 31 patients with solitary HCC (10-29 mm) who received successful PEI. We investigated the relationship of pretreatment clinicopathological variables to recurrence-free survival including: age, gender, alcohol abuse, tumor size, tumor staining, tumor differentiation, serum alpha-fetoprotein (AFP) level, associated liver disease, and Child-Pugh classification. Differences in recurrence-free survival among subgroups classified by each factor were evaluated using log-rank tests., Results: Median recurrence-free survival time, 1 and 2 years recurrence-free survival rates of all 31 patients were 1.57 years, 72.2% and 45.4%, respectively. Among the 9 variables evaluated, serum AFP level of 20 ng/ml or less (p < 0.005) and absence of cirrhosis (p = 0.025) were factors favoring longer recurrence-free survival significantly., Conclusion: These results indicate that HCC patients with higher serum AFP level or coexistent cirrhosis should be followed more closely even after successful PEI.

Background/aims: The characteristics of patients with multicentric hepatocellular carcinoma (HCC) differ from those of patients with intrahepatic metastatic HCC. However, there are few reports regarding the long-term results in patients with HCC of multicentric occurrence. The purpose of this study was to clarify the prognosis of a group of patients with multicentric HCCs., Materials and Methods: We evaluated the outcome in 28 patients with multiple hepatocellular carcinoma (HCC) suggestive of multicentric occurrence, all of whom underwent hepatic resection. The disease-free survival, recurrence pattern and survival were analyzed in the two subgroups of 12 patients with single advanced HCC (AdHCC) nodule and an early HCC (eHCC) or early advanced HCC (eAdHCC) nodule [Group A] and 16 patients with two AdHCC lesions [Group B]. These data were also compared with those of 58 patients with solitary AdHCC [Group C]., Results: Both the disease-free survival and survival periods for Groups A and C were significantly longer than those for Group B, while no significant difference was seen between Group A and C. No significant differences among the three groups were recognized in the incidence of various types of recurrence pattern., Conclusions: The long-term results in patients with multicentric HCC apparently vary depending on the pathological condition at the time of operation. Among patients with multicentric HCC, those with AdHCC combined with an eHCC or eAdHCC are likely to show improved prognosis as a result of hepatic resection.

Background/aims: This study was conducted to clarify the effect of percutaneous ethanol injection (PEI) in combination with transcatheter arterial embolization (TAE) on prolonging the survival time of patients with postoperative recurrence of hepatocellular carcinoma (HCC)., Materials and Methods: The subjects were 97 consecutive patients (pts) treated for postoperative recurrent HCC between February 1987 and March 1993. Of these, 25 pts received both TAE and PEI and 72 pts received TAE alone. In the TAE & PEI group, treatment was selected according to the indications: 15 pts received TAE for multiple recurrences following PEI, and the other 10 pts received PEI for a new or residual lesion following TAE. Fourteen demographic, pathological, and clinical variables were evaluated to estimate the relative risk of pts treated with TAE & PEI or with TAE alone., Results: The 1-, 3- and 5- year survival rates in the TAE & PEI group were 100%, 73.2% and 27.2%, respectively, and those in the TAE alone group were 88.9%, 30.2% and 5.5%, respectively. Based on multi-variate Cox regression analysis, the relative risk of cancer death in the TAE & PEI group was 0.32 (95% confidence interval, 0.15 to 0.67)., Conclusion: The combination of TAE and PEI had a positive palliative effect and increased survival time of patients with postoperative recurrent HCC, compared to results obtained by TAE alone.

Background: Percutaneous ethanol injection (PEI) therapy is now widely used for small hepatocellular carcinomas (HCC). However, only limited information is available regarding local tumor recurrence after PEI treatment., Methods: We investigated the relationship of pretreatment clinicopathologic variables (tumor size, tumor cell differentiation and tumor staining) to local recurrence in 170 PEI-treated HCC nodules (measuring 5-39 mm in greatest dimension) in 84 patients., Results: Local recurrence was observed in 17 of 170 PEI-treated nodules. Among these, 13 local recurrences were observed as the first event of progression after PEI. Local recurrence rates at 1, 2, and 4 years were 6.6%, 14.2%, and 14.2%, respectively, and all recurrences were observed within 2 years after PEI. Of the 3 variables investigated, large tumor size (31 mm or larger in greatest dimension) was significantly associated with a higher local recurrence rate., Conclusions: This study demonstrated that tumor size influences the local efficacy of PEI for small HCC. Therefore, we recommend that a reasonable indication for PEI therapy is HCC lesions measuring less than 30 mm in greatest dimension.

The clinical features of 65 patients with advanced pancreatic cancer treated between 1984 and 1993 were analyzed retrospectively to identify the significant prognostic factors. All the patients had presented unresectable or metastatic disease on imaging diagnostic evaluation and had received systemic chemotherapy. The overall median survival time and 1-year survival rate were 3.9 months and 9.8%, respectively. The independent favorable prognostic factors identified by multivariate analysis using the Cox proportional hazards model were a performance status of 0-1, a serum carcinoembryonic antigen level of < 10 ng/ml, and an absence of distant metastasis. A prognostic index calculated from the regression coefficients for these three factors was used to classify the patients into three groups, with good, intermediate, and poor prognoses. The median survival time for these three groups was 7.4, 3.5, and 2.0 months, respectively (p < 0.001). The results of this study may be useful in the design and analysis of future clinical trials of systemic chemotherapy for advanced pancreatic cancer.

Background/aim: We studied the influence of alcohol abuse (ethanol intake > 80 gm/day for > 5 yr.) on recurrence in 81 patients with hepatocellular carcinoma who had undergone curative hepatic resection. Twenty-nine patients were positive for alcohol abuse [AA(+)] and 52 were not [AA(-)]., Results: Recurrence of carcinoma within 2 and 27 postoperative months was observed in 45 (55.6%) of the 81 patients. The median disease-recurrence time was 12.0 mo in the AA(+) group and 24.1 mo in the AA(-) group (p<0.01). The patterns of recurrence were classified into the following 4 types: single-nodular type (intrahepatic single nodule); multi-nodular type (intrahepatic multiple nodules); whole liver type (diffuse recurrence over the whole remnant liver); and extrahepatic type (extrahepatic recurrence alone). Five (29.4%) of the 17 patients with recurrence in the AA(+) group demonstrated the whole liver type, compared with only 2(7.1%) of the 28 patients in the AA(-) group (p<0.05)., Conclusion: Patients with alcohol abuse should be followed up particularly closely, even if they have received curative surgery, since alcohol abuse is strongly related to postoperative recurrence.

Background: Intratumoral DNA heterogeneity provides important information regarding biologic and clinical behavior. The purpose of this study was to evaluate the incidence of DNA heterogeneity in small hepatocellular carcinoma (HCC) nodules., Methods: The DNA content of 28 surgically resected small HCC nodules (< or = 3.0 cm) was measured using flow cytometry of fresh or frozen samples taken from different parts of each nodule with reference to the macroscopic features., Results: Of the 28 small HCC nodules, 14 (50.0%) had only DNA diploid stemline characteristics. Five nodules (17.9%) manifested DNA diploid and DNA aneuploidy within the same tumor. Of the remaining nine nodules (32.1%) that showed only DNA aneuploidy, two contained tumor tissues with apparently different DNA content. Thus, DNA heterogeneity was found in 7 (25.0%) of 28 nodules. DNA heterogeneity correlated well with macroscopic histologic features. All four early HCC were composed of only DNA diploid cells, whereas three of six nodule-in-nodule lesions were composed of DNA heterogeneous cells, in which the inner obviously cancerous nodule showed DNA aneuploidy and the outer well differentiated HCC portion demonstrated DNA diploid. Four of 18 overt HCC nodules showed DNA heterogeneity; 2 of these 4 nodules showed both diploid and aneuploid peaks, and the other 2 two showed different aneuploid peaks within the same nodule., Conclusions: DNA heterogeneity correlating with macroscopic features is found frequently even in small HCC nodules. Therefore, multiple sampling based on macroscopic features is required for the accurate assessment of DNA ploidy, particularly when the information about DNA ploidy is used as a prognostic indicator.

A phase II study of cisplatin was performed in 13 previously untreated patients with unresectable biliary tract carcinoma. The drug was given intravenously at a dose of 80 mg/m2/day once every 4 weeks. Of 13 patients evaluated, 1 showed partial response lasting 3 months, while no patients showed complete response. Of 9 patients, whose serum level of carcinoembryonic antigen (CEA) was high (> or = 10 ng/ml) before treatment, 4 showed > or = 50% reduction in serum CEA level after treatment. The current study indicates that cisplatin does not have significant antitumor activity against biliary tract carcinoma.

The clinical value of radiotherapy for hepatocellular carcinoma (total tumor dose: 50-70 Gy) was evaluated in seven autopsied patients with nine tumors. A partial response as defined by the WHO criteria for chemotherapy was observed in three tumors (33%). Progressive and marked shrinkage of the noncancerous liver tissue within the irradiated field was also observed in all cases. Histological examination revealed viable cancer cells in all cases. These results indicate that local radiotherapy applying 50-70 Gy achieved some clinical benefit, but was not capable of curing hepatocellular carcinoma.

We compared tumor sizes determined by computed tomography (CT) with those of the resected specimens in 26 patients with pancreatic cancer in order to clarify whether or not the size of a pancreatic tumor can be accurately determined by CT. From the precontrast, postcontrast and arterial dominant phases of dynamic CT, the arterial dominant phase was found to yield the highest correlation between CT measured tumor size and that of the resected specimens (P < 0.01). The correlation coefficient was, however, not high (r = 0.67). CT alone may therefore be insufficient to determine tumor size in pancreatic cancer accurately.

We present a case of pancreatic leiomyosarcoma with liver metastasis diagnosed by liver tumor biopsy. A 66-year-old man had a pancreatic tumor and hepatic tumors, which were hypoechoic and mixed echoic on ultrasonography, respectively. They were stained in enhanced computed tomography and angiography. A fine needle aspiration biopsy of the liver tumor was performed, and the pathological examination of the biopsied specimen suggested the tumor cells to have originated from smooth muscle. Under a diagnosis of pancreatic leiomyosarcoma with liver metastasis, the patient was treated with several anticancer agents. The tumor, however, spread to multiple organs and he dies of the disease two years nine months after the start of treatment. The diagnosis of pancreatic leiomyosarcoma was confirmed by autopsy.

We present a case of liver abscess after percutaneous ethanol injection (PEI) therapy for the treatment of recurrent hepatocellular carcinoma (HCC). The 56-year-old woman had a past history of cholecystoduodenostomy for cogenital dilatation of the bile duct, and pneumobilia was observed in the intrahepatic bile ducts prior to PEI. The abscess was successfully treated by percutaneous abscess drainage and antibiotic therapy. Klebsiella pneumonia, one of the most common causative organisms of biliary tract infection, was isolated from the abscess. Thus, biliary tract infection related to the previous biliary-enteric anastomosis operation may have been one of the causative factors in the liver abscess in this patient. The rare experience reported here suggests that a careful search for coexistent abscess at the time of PEI is important in HCC patients with biliary-enteric anastomosis, especially in those with pneumobilia.

A phase 2 study of cisplatin was performed in 28 previously untreated patients with unresectable hepatocellular carcinoma. The drug was given intravenously at a dose of 80 mg/m2/day every 4 weeks. Of 26 patients evaluated, 4 (15.4%) showed partial responses lasting for > 3 months, while no patient achieved a complete response. Of 22 patients whose serum level of alpha-fetoprotein (AFP) was high (> 400 ng/ml) before treatment, 6 (27.3%) showed a > 50% reduction in serum AFP levels after treatment. The current study indicates that cisplatin is an anticancer agent worthy of further testing in patients with this disease.

A total of 71 consecutive patients with unresectable hepatocellular carcinoma were analyzed retrospectively to determine the significant prognostic factors. All the patients received systemic chemotherapy in a phase 2 study from 1980 to 1990, with no other anticancer treatment. Median survival time and 1-yr and 2-yr survival rates were 5.6 mo, 23% and 5%, respectively. By the univariate analysis, a performance status of 0-1 and tumor size less than 50% of the liver cross-sectional area were shown to be the factors most significantly favoring a better prognosis. By the multivariate analysis using the Cox proportional hazards model, a performance status of 0-1 (p less than 0.001), absence of tumor thrombus in the main portal trunk (p = 0.003) and age less than 60 yr (p = 0.036) were independent favorable prognostic factors. A prognostic index was calculated from these three factors according to the following equation: 1.8109 x (0 = performance status of 0-1 and 1 = performance status of 2-3) + 0.9322 x (0 = tumor thrombus absent in the main portal trunk and 1 = present) + 0.6996 x (0 = age less than 60 yr and 1 = age greater than or equal to 60 yr). This index was used to classify the patients into three groups with a good, intermediate and poor prognosis. The median survival times for these three groups were 9.8, 3.8 and 1.9 mo, respectively (p less than 0.01). The results of this study may be useful in the design and analysis of future clinical trials of systemic therapy for hepatocellular carcinoma.

Focal acinar cell dysplasia (FACD) was studied in 138 autopsied pancreases by multiple transsection examination and was found in 13 of the pancreases (9.4%). The average number of FACD per pancreas identified in our study was 5.7, ranging from 1 to 20, and the total number was 60. The location of FACD was 22 in head, 18 in body, and 20 in tail of the pancreas. FACD were rare lesions and found in only 41 of 2,819 slides (1.5%). The incidence of FACD seemed to be higher among males than among females, among patients with cancer in other sites than among those with no cancer, among diabetics than among nondiabetics, among heavy smokers than among nonsmokers, and among alcohol abusers than among abstainers. The males and heavy smokers had significantly more nodules of FACD per pancreas than females and nonsmokers. Simple and atypical hyperplasia of pancreatic ducts were found in 119 (86.2%) and 18 (13.0%), respectively. All pancreases with FACD had simple ductal hyperplasia. FACD and atypical ductal hyperplasia coexisted in one patient who had a history of heavy smoking, and this patient had the most nodules of FACD per pancreas among patients with FACD. No FACD was observed in pancreases without ductal hyperplasia. These findings suggested heavy cigarette smoking was one of the possible causes of FACD and ductal hyperplasia of pancreas.

A nine year retrospective survey was carried out at the National Cancer Center Hospital in order to define the diagnostic clues and most suitable diagnostic assessment in resectable pancreatic cancer patients. Forty six cases were detected (27 pancreatic head cancers, 19 pancreatic body and tail cancers). There were 8, 26, 3 and 9 cases of t1, t2, t3 and t4 tumour size cancers, respectively. Abdominal pain and/or discomfort and back pain were the most common initial symptoms and chief complaints. Jaundice was present only in pancreatic head cancer cases. Abnormal GTT and CA 19-9 were the biochemical tests most commonly found abnormal, irrespective of tumour size. ERCP followed by US and CT were the most accurate technical tests. The best care toward the awareness of the initial symptoms needs to be followed, as a first choice, by a proper biochemical (CA 19-9, GTT) and technical (US, ERCP, CT) assessment in the hope of identifying those patients whose prognosis might be improved by an early operation.

Twenty-two patients with measurable metastatic gastric cancer, refractory to prior chemotherapy, were treated with a combination chemotherapy of 5-fluorouracil (5FU) and cisdiamminedichroloplatinum (II) (CDDP). 5FU was continuously infused for five consecutive days at a dose of 800 mg/m2/day, and CDDP was given intravenously for five days at a dose of 20 mg/m2/day over 30 min every four weeks. All patients had received only one regimen of prior chemotherapy, and 10 of the 22 had been pretreated with combination of etoposide, doxorubicin and CDDP (EAP). It was possible to evaluate 20 of the 22 patients treated for response and toxicity. Nine of the 20 patients achieved a partial response, the response rate being 45% (23-67% with 95% confidence limits). The nine patients who responded included three who had been pretreated with EAP, indicating that 5FU + CDDP can be used as a second line chemotherapy against gastric cancer, even when the initial intensive chemotherapy, such as EAP, has failed to obtain or maintain a response. High grade toxicities (WHO grade 3 or 4) of leukocytopenia, thrombocytopenia and stomatitis were seen in 20, 25 and 40%, respectively. No treatment-related death was, however, observed. The above results suggest that 5FU + CDDP could be promising in a phase II trial with a large number of cases.

Continuous venous infusion of 5-fluorouracil (5FU) was investigated in 18 patients with measureable advanced cancer of the pancreas. 5FU was given for 7 days in a dose of 500 mg/m2 by continuous venous infusion over a 24-hour period and then followed by a dose of 170 mg/m2 for more than 28 days. Ten patients had no change including 1 patient with minor response, and 4 patients had disease progression. Serum CA19-9 levels were measured serially after chemotherapy in 13 of 14 evaluable patients. In 3 of 10 patients who showed high levels before treatment, serum CA19-9 levels were significantly decreasing after treatment.

From January, 1983 to July, 1987, advanced cancer patients, who have since died, were analysed as to the influence of their mental state after being told of the terminal nature of their disease. After obtaining family consent, 27 out of total of 65 patients were told the true nature of their disease, in contrast to the remaining 38 terminal patients who were kept unaware that they had cancer on the insistence of their families. The depression observed just before death was the marker used to determine the patients' mental distress during the terminal period, and it was noted that the incidence of this terminal depression was higher in the uniformed patients, and highest in those with pain who had not been told. Thus it was concluded that informing a patient that he or she has terminal cancer does not always induce mental distress, even in patients in an advanced cancer stage. Further, the pain that cancer causes must be effectively fought, since this was the major cause of mental distress during the terminal stage of the disease.

The incidence of gastric cancer in Japan is among the highest in the world. Unremitting efforts have been devoted by many Japanese researchers to improving the situation. They defined and classified early gastric cancer. With the development of diagnostic methods and the prevalence of gastric mass surveys, the rate of diagnosis of early gastric cancer has increased markedly. The five-year survival rate for early gastric cancer at present lies between 90 and 100%. These excellent results have been obtained by the collaboration of radiologists, endoscopists, surgeons and pathologists.

UFT was given to two patients with carcinoid tumor of the stomach and the effect of the drug was evaluated. The first patient was a 67-year-old female. She was admitted because of upper abdominal tumor. Exploratory laparotomy revealed gastric tumor and additional huge tumor with liver metastasis and peritoneal dissemination. Histology of biopsy specimens from gastric tumor and metastatic lesions was a composite type, of carcinoid tumor. Postoperatively UFT (600 mg/day) was given to the patient. During three months of the treatment the size of the large tumor reduced from 10 X 10 cm to 4 X 4cm. The second patient was a 55-year-old male. He was admitted because of severe diarrhea. Biopsy from gastric lesion and metastatic skin lesions revealed carcinoid tumor. After administration of UFT and Mitomycin C, metastatic skin lesions became smaller and some of the lesions disappeared. Two cases suggest a possibility that UFT may be effective for carcinoid tumor of the stomach.

2,2'-dihydroxy-di-N-propylnitrosamine (DHPN) at a dose of 250 mg/kg was injected subcutaneously into 28 male Syrian golden hamsters once a week. They were sacrificed and dissected at intervals of one to two weeks beginning from the 8th week until the 20th week after the injection. Pancreatography was performed on every hamster and the chronological changes in their pancreatograms were compared with the histological findings. Marked atypical hyperplasia almost indistinguishable from carcinoma in situ was observed histologically beginning at the 13th week, and infiltrating adenocarcinoma was seen in all the hamsters in and after the 16th week. The pancreatography made it possible to depict even minute changes at an early stage that corresponded to the histological findings. One example was that a slight stenosis in the branch was detected at the 13th week and the picture of stenosis was observed in the main pancreatic duct at the 14th-15th week. This was followed by obstruction in and after the 16th week. These findings support the possibility that the neoplastic process in the hamster pancreas occurs in the branch region earlier than in the main pancreatic duct.

The effect of cis-diamminedichloro platinum (II) (CDDP) was evaluated in 14 patients with advanced pancreatic carcinoma. Prior chemotherapy was done in 7 cases and the remaining 7 were fresh cases. The drug was given at a dose of 80 mg/m2 I.V. every 3 weeks, with hydration and mannitol diuresis. Four cases out of 14 showed no change, while the remaining 10 cases showed progressive disease. The response rate was 0%. Most of the patients who showed myelosuppression had received prior chemotherapy. Non-hematologic toxicity occurred in 9 patients (64%) and consisted of nausea in 9, vomiting in 7 and anorexia in 9. Values of serum creatinine and BUN were transiently elevated.

The clinical features of patients with macroamylasemia are diverse. A certain correlation between macroamylasemia and the disease of the pancreas or hepato-biliary system may exist, because among 7 patients in this series 4 patients were diagnosed as acute pancreatitis or relapsing pancreatitis and another patient was performed choledochotomy and manipulation of papilla of Vater may had a effect on pancreas. Among other 2 patients, one was completely symptomless and had no abnormal findings and in another the action of anticancer drugs is suspected. The course of macroamylasemia is usually chronic but in this series one patient had acute transient macroamylasemia and another one had intermittent macroamylasemia during exacerbations of pancreatitis. The serum amylase levels are mostly 2-4 times above normal with one exception (192 Somogyi units) and urinary amylase values are low with one exception (1922 Somogyi units) during exacerbation of pancreatitis. Characteristic zymogram of macroamylase on electrophoresis is also reported.