Current assessment of choledochoduodenostomy: 130 consecutive series.

Introduction Cholelithiasis usually can be managed successfully by endoscopic sphincterotomy. Choledochoduodenostomy (CDD) is one of the surgical treatment options but its acceptance remains debated because of the risk of reflux cholangitis and sump syndrome. The aim of this study was to assess the current features and outcomes of patient undergoing CDD. Patients and methods We retrospectively analysed the surgical results of consecutive 130 patients treated by CDD between 1991 and 2013 and excluded five cases with a malignant disorder. Indications for surgery included endoscopic management where stones were difficult or failed to pass and primary common bile duct stones with choledochal dilatation. Incidences of reflux cholangitis, stone recurrence, pancreatitis or sump syndrome were investigated and the data between end-to-side and side-to-side CDD were compared. Results Reflux cholangitis and stone recurrence was 1.6% (2/125) and 0% (0/125) of cases by CDD. There is no therapeutic-related pancreatitis in CDD. Sump syndrome was not also observed in side-to-side CDD. Conclusions This study is a first comparative study between end-to-side and side-to-side CDD. The surgical outcomes for CDD treatment of choledocholithiasis were acceptable. The incidence of reflux cholangitis, stone recurrence, pancreatitis and sump syndrome was very low.

Noninvasive estimation of fibrosis progression overtime using the FIB-4 index in chronic hepatitis C.

The FIB-4 index is a simple formula to predict liver fibrosis based on the standard biochemical values (AST, ALT and platelet count) and age. We here investigated the utility of the index for noninvasive prediction of progression in liver fibrosis. The time-course alteration in the liver fibrosis stage between paired liver biopsies and the FIB-4 index was examined in 314 patients with chronic hepatitis C. The average interval between liver biopsies was 4.9 years. The cases that showed a time-course improvement in the fibrosis stage exhibited a decrease in the FIB-4 index, and those that showed deterioration in the fibrosis stage exhibited an increase in the FIB-4 index with a significant correlation (P < 0.001). Increase in the ΔFIB-4 index per year was an independent predictive factor for the progression in liver fibrosis with an odds ratio of 3.90 (P = 0.03). The area under the receiver operating characteristic curve of the ΔFIB-4 index/year for the prediction of advancement to cirrhosis was 0.910. Using a cut-off value of the ΔFIB-4 index/year <0.4 or ≥ 0.4, the cumulative incidence of fibrosis progression to cirrhosis at 5 and 10 years was 34% and 59%, respectively in patients with the ΔFIB-4 index/year ≥0.4, whereas it was 0% and 3% in those with the ΔFIB-4 index/year <0.4 (P < 0.001). In conclusion, measurement of the time-course changes in the FIB-4 index is useful for the noninvasive and real-time estimation of the progression in liver fibrosis.

Viral load change and sequential evolution of entire hepatitis C virus genome in Irish recipients of single source-contaminated anti-D immunoglobulin*.

In hepatitis C virus (HCV) infection, serum viral load is important in the prediction of therapeutic efficacy. However, factors that affect the viral load remain poorly understood. To identify viral genomic elements responsible for the viral load, we investigated samples from a population of Irish women who were iatrogenically infected from a single HCV source by administration of HCV 1b-contaminated anti-D immune globulin between 1977 and 1978 (Kenny-Walsh, N Engl J Med 1999; 340: 1228). About 15 patients were divided into two groups, viral load increasing group (11 patients) and decreasing group (4 patients). Pairs of sera were collected from each patient at interval between 1.1 and 5.8 years. Full-length sequences of HCV genome were determined, and analyzed for changes in each patient. Sliding window analysis showed that the decreasing group had significantly higher mutation rates in a short segment of NS5B region that may affect the activity of RNA-dependent RNA polymerase. By comparing each coding regions, significantly higher mutation numbers were accumulated in NS5A region in the increasing group than the decreasing group (0.92 vs 0.16 nucleotides/site/year, P = 0.021). The mutation in certain positions of the HCV genome may be determinant factors of the viral load in a relatively homogeneous patient population.

A potent antiviral effect on hepatitis C viral dynamics in serum and peripheral blood mononuclear cells during combination therapy with high-dose daily interferon alfa plus ribavirin and intravenous twice-daily treatment with interferon beta.

Hepatitis C virus (HCV) is known to infect and replicate within peripheral blood mononuclear cells (PBMC), thereby enabling the direct evaluation of antiviral mechanisms by analyzing HCV dynamics in PBMC. To address potential molecular differences associated with distinct antiviral regimens, we studied HCV dynamics in both serum and PBMC in 44 patients with HCV genotype 1b and high viral load who were randomly assigned to the following 4 different treatment groups: 1) combination therapy with 6 MU daily of interferon alfa 2b (IFN-alpha2b) plus 800 mg of ribavirin; 2) monotherapy with 6 MU daily of IFN-alpha2b; 3) monotherapy with twice-daily intravenous administration with 3MU of IFN-beta; and 4) monotherapy with daily intravenous administration with 6 MU of IFN-beta. HCV-RNA levels were measured serially using highly sensitive real-time detection polymerase chain reaction (PCR). HCV dynamics in both the serum and PBMC showed a "biphasic" pattern. The exponential decay slopes of the second phase were significantly higher in the combination or twice-daily dosing regimen groups compared with groups 2 or 4 (0.10 +/- 0.08 vs. 0.02 +/- 0.09 or 0.16 +/- 0.09 vs. 0.02 +/- 0.04 day(-1); P <.05 or P <.0005, respectively). Moreover, the viral half-lives in the second phase were significantly shorter in these groups (73.2 +/- 42.5 vs. 240.1 +/- 120.7 or 56.0 +/- 44.6 vs. 361.6 +/- 293.5 hours; P <.05 or P <.05, respectively). Additionally, the slope of HCV decline in PBMC tended to be higher in the combination regimens, as compared with monotherapy. Taken together, our data on HCV dynamics provide molecular insight into utilization of combination or twice-daily dosing regimens to increase rates of sustained viral eradication of HCV.

Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells.

Glypicans are a family of glycosylphosphatidylinositol-anchored cell surface heparan sulfate proteoglycans implicated in the control of cellular growth and differentiation. Here we show that glypican-1 is strongly expressed in human breast cancers, whereas expression of glypican-1 is low in normal breast tissues. In contrast, the expression of glypican-3 and -4 is only slightly increased in breast cancers by comparison with normal breast tissues, and glypican-2 and -5 are below the level of detection by Northern blotting in both normal and cancer samples. Treatment of MDA-MB-231 and MDA-MB-468 breast cancer cells with phosphoinositide-specific phospholipase-C abrogated the mitogenic response to two heparin-binding growth factors, heparin-binding epidermal growth factor-like growth factor and fibroblast growth factor 2. Stable transfection of these cells with a glypican-1 antisense construct markedly decreased glypican-1 protein levels and the mitogenic response to the same heparin-binding growth factors, as well as that to heregulin alpha, heregulin beta, and hepatocyte growth factor. Syndecan-1 was also expressed at high levels in both breast cancer tissues and breast cancer cells when compared with normal breast tissues. There was a good correlation between glypican-1 and syndecan-1 expression in the tumors. However, clones expressing the glypican-1 antisense construct did not exhibit decreased syndecan-1 levels, indicating that loss of responsiveness to heparin-binding growth factors in these clones was not due to altered syndecan-1 expression. Furthermore, 8 of 10 tumors with stage 2 or 3 disease exhibited high levels of glypican-1 by Northern blot analysis. In contrast, low levels of glypican-1 mRNA were evident in 1 of 10 tumors with stage 2 or 3 disease and in 9 of 10 tumors with stage 1 disease. Taken together, these data suggest that glypican-1 may play a pivotal role in the ability of breast cancer cells to exhibit a mitogenic response to multiple heparin-binding growth factors and may contribute to disease progression in this malignancy.

Sequences in the NS5A protein of hepatitis C virus and the serum alanine aminotransferase response to interferon therapy in Japanese patients.

BACKGROUND AND AIMS: Chronic hepatitis C is a slowly progressive disease and eventually causes hepatocellular carcinoma in many patients. Although interferon (IFN) therapy has been used for viral eradication, its success rate is only about 30%. In patients in whom it has failed (non-responders), there are several patterns of serum alanine aminotransferase (ALT) values, and detection of serum HCV-RNA during and after IFN therapy and improved long term prognosis were reported in patients whose serum ALT values were normalised by IFN therapy even if HCV viraemia persisted. The present study sought to clarify the virological characteristics contributing to these differences. METHODS: Complete or partial length dominant sequences of hepatitis C virus genotype 1b (HCV-1b) were determined by direct sequencing. Firstly, the complete sequences of HCV-1b genomes were determined in six non-responders; three showed normalisation of serum ALT values during IFN-alpha therapy and the other three did not. Subsequently, the amino acid residues that were different in the two groups were further analysed retrospectively in another 82 patients. RESULTS: Comparison of the sequences suggested an association between amino acids 2154-2172 of HCV-1b and serum ALT normalisation. A retrospective analysis of 82 patients revealed that the number of amino acid substitutions in this region was the only statistically significant variable associated with ALT normalisation (odds ratio 31.0; 95% confidence interval 5.0-286) in multivariate analyses. CONCLUSIONS: A HCV genomic region that correlates with the ALT response to IFN therapy appears to be present in virologically IFN ineffective patients.

Overexpression of lymphangiogenic growth factor VEGF-C in human pancreatic cancer.

Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic polypeptide that has been implicated in cancer growth. In this study, we characterized VEGF-C expression in cultured human pancreatic cancer cell lines and determined whether the presence of VEGF-C in human pancreatic cancers is associated with clinicopathologic characteristics. VEGF-C mRNA transcripts were present in all five tested cell lines (Capan-1, MIA-PaCa-2, PANC-1, COLO-357, and T3M4). Immunoblotting with a highly specific anti-VEGF-C antibody revealed the presence of VEGF-C protein in all the cell lines. Northern blot analysis of total RNA revealed an approximately 2.2-fold increase in VEGF-C mRNA transcript in the cancer samples compared with the normal pancreas. Immunohistochemical analysis confirmed the expression of VEGF-C and its receptor flt-4 in the cancer cells within the tumor mass. Immunohistochemical analysis of 51 pancreatic cancer tissues revealed the presence of strong VEGF-C immunoreactivity in the cancer cells in 80.4% of the cancer tissues. The presence of VEGF-C in these cells was associated with increased lymphatic vessels invasion and lymph node metastasis, but not with decreased patient survival. These findings indicate that VEGF-C and its receptor are commonly overexpressed in human pancreatic cancers and that this factor may contribute to the lymphangiogenic process and metastasis in this disorder.

Pancreaticobiliary maljunction: etiologic concepts based on radiologic aspects.

BACKGROUND: The purpose of this study was to develop a new concept of the embryonic etiology of pancreaticobiliary maljunction (PBM) based on cholangiopancreatograms. METHODS: The subjects were 202 patients with PBM (60 men and 142 women) in whom the junction of the pancreatic and bile ducts was radiologically diagnosed as being located outside of the duodenal wall; 133 of the 202 patients also had congenital cystic dilatation of the bile duct (CCBD). RESULTS: The length of the duct from the junction to the orifice of the major papilla (the common channel) ranged from 0.5 to 5 cm on the cholangiopancreatograms. Small radicles of the pancreatic duct arose from the common channel in 36 of the 202 patients. This finding suggests that the common channel is itself the main pancreatic duct in patients with PBM. Moreover, cholangiopancreatography revealed that in 99 of the 202 patients, there was a narrowed duct segment distal to the biliary cyst in patients with CCBD or distal to the normal bile duct in those without CCBD; the length of the narrowed segment varied. Histologic examination revealed smaller branches that had arisen from this narrowed segment in 2 anatomic specimens. This also suggests that the narrowed ductal segment belongs to the pancreatic duct system. CONCLUSION: PBM is an anomaly that is probably caused by a disturbance in the embryologic connections (misarrangement) of the pancreatic and biliary duct system that occurs extremely early during gestation when the bile duct joins with the ventral pancreatic duct system. PBM is not due to an arrest of the normal migration of the common channel into the duodenal lumen during embryonic development.

Risk factors for distant recurrence of hepatocellular carcinoma in the liver after complete coagulation by microwave or radiofrequency ablation.

BACKGROUND: In patients with hepatocellular carcinoma (HCC), recurrences in the distant liver often are observed after curative treatment. Microwave coagulation therapy (MCT) and radiofrequency ablation (RFA) have been developed as less invasive alternatives than surgical resection for small HCCs. In the current study, risk factors for distant recurrence of HCC were analyzed in patients in whom complete coagulation was achieved. METHODS: Ninety-two patients with HCCs < 3 cm in greatest dimension were treated by MCT or RFA percutaneously or laparoscopically. Eighty-four patients in whom complete coagulation was achieved without recurrence in the same subsegment as the primary nodule were included in this study. Distant recurrences were observed in 22 patients. Fifteen possible risk factors for a distant recurrence were analyzed. RESULTS: When comparing the patients with a recurrence of HCC nodules in the remnant liver to those without recurrence, the authors observed a statistically significant difference only in serum alpha-fetoprotein. The distant recurrence-free survival was analyzed by the Kaplan-Meier method. A statistically significant difference was observed in hepatitis C virus (HCV) infection as an etiopathic agent of underlying liver diseases (P < 0.005) and in the number of the primary HCC nodules (P < 0.05, log-rank test). A multivariate stepwise Cox hazard model revealed that HCV infection and the number of primary HCC nodules were statistically independent risk factors. CONCLUSIONS: Patients who had more than two HCC nodules accompanied by HCV infection had a high incidence of recurrence of HCC in the remnant liver, even when coagulation by microwave or ablation by radiofrequency was complete.

CD81 nucleotide mutation in hepatocellular carcinoma and lack of CD81 polymorphism in patients at stages of hepatitis C virus infection.

Mechanisms determining the chronicity or the pattern of clinical course of hepatitis C virus (HCV) infections have not been clarified. Recently, CD81 was reported to bind the E2 protein of HCV and was suggested to function as a cellular receptor for HCV. Accordingly, the hypothesis was examined that CD81 polymorphism, if it exists, might correlate with certain clinical courses of HCV infection. CD81 cDNA sequences were determined from peripheral blood mononuclear cells (PBMCs). Twenty-four Japanese subjects were enrolled initially as follows: patients with chronic hepatitis C without cirrhosis (n = 3), patients with cirrhosis (n = 3), patients with cirrhosis complicated by hepatocellular carcinoma (HCC) (n = 3), patients with persistent HCV viremia without ALT elevation (n = 3), those with positive anti-HCV antibodies without evidence of HCV viremia (n = 3), and healthy volunteers (n = 9). In all PBMCs samples analyzed, no polymorphism was found in the CD81 cDNA sequence. The sequence was different, however, from the one reported previously at three nucleotide positions: a transversion to thymine instead of cytosine at nt 1130, a deletion at nt 1206, and a guanine insertion at nt 71. Subsequently, CD81 cDNA sequences from PBMCs and HCC tissue were compared among the other 6 patients with chronic hepatitis C bearing HCC. A comparative study of the CD81 sequences from HCC and PBMCs revealed that various nucleotide mutations existed only in the HCC samples in 3 out of 6 patients. Several mutations in the 3' non-coding region of CD81 cDNA were observed exclusively in HCC tissue suggesting its possible role in hepatocarcinogenesis. Because of the absence of polymorphisms, however, CD81 is unlikely to affect the progression of chronic hepatitis C in terms of chronicity, hepatitis activity, or disease stage.

Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer.

Vascular endothelial growth factor (VEGF) is a potent angiogenic polypeptide that activates 2 distinct high-affinity tyrosine kinase receptors, flk-1/KDR and flt-1. In the present study, we characterized the expression of VEGF and its receptors flk-1/KDR and flt-1 in the normal human pancreas and in human pancreatic cancer tissues and cell lines. VEGF, flk-1/KDR and flt-1 mRNA levels were elevated in cancer tissues compared with normal pancreas. By immuno-histochemistry, VEGF, flk-1/KDR and flt-1 immunoreactivity co-localized in many of the cancer cells within the tumor mass. Three (AsPC-1, Capan-1 and MIAPaCa-2) of 6 pancreatic cancer cell lines expressed flk-1/KDR mRNA and protein, and 4 cell lines (AsPC-1, Capan-1, T3M4 and PANC-1) expressed flt-1 mRNA transcripts. Binding studies with (125)I-labeled VEGF165 indicated that only Capan-1 cells exhibited high levels of specific binding. Furthermore, VEGF enhanced the growth of Capan-1 cells but was without effect in the other cell lines. VEGF also enhanced mitogen-activated protein kinase (MAPK) phosphorylation and c-fos induction in Capan-1 cells, whereas the MAPK kinase inhibitor PD98059 abolished the growth-stimulatory effect of VEGF. These data indicate that human pancreatic cancers have the capacity to over-express VEGF and its receptors and suggest that in some instances VEGF may directly promote pancreatic cancer growth via the MAPK pathway.

Epithelial cell proliferation activity of the biliary ductal system with congenital biliary malformations.

Congenital biliary malformations such as anomalous arrangement of the pancreaticobiliary ductal system (AAPB), congenital cystic dilatation of the common bile duct (CCDB), and congenital biliary strictures at the hepatic hilum (CBSH) are newly designated disease entities and are frequently found in adult patients with biliary malignancy such as gallbladder carcinoma, common bile duct carcinoma, and intrahepatic bile duct carcinoma. In the present study, the relationship of these malformations and biliary malignancy was investigated. We studied 61 gallbladders of patients with AAPB and 56 gallbladders of patients without AAPB; 16 common bile ducts of patients with CCDB (12 with AAPB and 4 without AAPB) and 11 gallbladders of patients without CCDB; and 17 intrahepatic bile ducts of patients with CBSH and 6 intrahepatic bile ducts of patients without CBSH. Tissue sections from the mucosa of the gallbladder, common bile duct, and intrahepatic bile duct were stained for proliferating cell nuclear antigen (PCNA). The PCNA labeling indexes of patients with these malformations were significantly higher than those of patients without these malformations (P < 0.05). Cell proliferation of the epithelia in the biliary ductal system in patients with these congenital biliary malformations was accelerated. Consequently, these congenital malformations appear to be an important risk factor for the occurrence of biliary malignancy.

Increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival.

Cyclin D 1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. In the present study we characterized cyclin D1 expression in 6 cultured human pancreatic cancer cell lines and in normal and cancerous human pancreatic tissues. A 4.4-kb cyclin D1 mRNA transcript was present in all cell lines and in all pancreatic tissues. Cyclin D1 mRNA levels were 2.1-fold higher in the pancreatic cancers than in normal pancreatic tissues (p < 0.0002). Cancer patients with lower cyclin D1 levels (n=16) had a median survival of 15.5 months whereas patients with higher levels (n=16) had a median survival of 6.5 months (p < 0.007). These data indicate that cyclin D1 expression may serve as a predictor of postoperative survival in pancreatic cancer patients, and raise the possibility that treatment modalities blocking cyclin D1 activity may have a future role in the therapy of these patients.

Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression.

Vascular endothelial growth factor (VEGF) is an angiogenic polypeptide that has been implicated in cancer growth. In the present study, we characterized VEGF expression in cultured human pancreatic cancer cell lines and determined whether the presence VEGF in human pancreatic cancers is associated with enhanced neovascularization or altered clinicopathological characteristics. VEGF mRNA transcripts were present in all six tested cell lines (ASPC-1, CAPAN-1, MIA-PaCa-2, PANC-1, COLO-357, and T3M4). Immunoblotting with a highly specific anti-VEGF antibody revealed the presence of VEGF protein in all of the cell lines. Northern blot analysis of total RNA revealed a 5.2-fold increase in VEGF mRNA transcript in the cancer samples in comparison with the normal pancreas. Immunohistochemical and in situ hybridization analysis confirmed the expression of VEGF in the cancer cells within the tumor mass. Immunohistochemical analysis of 75 pancreatic cancer tissues revealed the presence of strong VEGF immunoreactivity in the cancer cells in 64% of the cancer tissues. The presence of VEGF in these cells was associated with increased blood vessel number, larger tumor size, and enhanced local spread but not with decreased patient survival. These findings indicate that VEGF is commonly overexpressed in human pancreatic cancers and that this factor may contribute to the angiogenic process and tumor growth in this disorder.

Amphiregulin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor-targeted therapy.

Human pancreatic cancers overexpress the epidermal growth factor (EGF) receptor (EGFR) and all 5 ligands that bind to this receptor, including amphiregulin. It is not known, however, whether amphiregulin contributes in an autocrine manner to enhance pancreatic cancer cell growth. Therefore, we used an amphiregulin antisense oligonucleotide (AR-AS) to suppress amphiregulin expression in T3M4 human pancreatic cancer cells. These cells express high levels of EGFR and amphiregulin. AR-AS abolished amphiregulin immunoreactivity in T3M4 cells, decreased amphiregulin release into the medium and inhibited cell growth in a dose-dependent manner. Exogenous amphiregulin reversed AR-AS-mediated growth inhibition. A random oligonucleotide (AR-R) did not alter either cell growth or cellular amphiregulin immunoreactivity. AR-AS also increased cellular EGFR protein levels and enhanced the growth-inhibitory actions of TP40, a chimeric protein consisting of transforming growth factor-alpha coupled to Pseudomonas exotoxin that internalizes into cells via EGFR. These findings indicate that there is an important EGFR/ amphiregulin autocrine loop in T3M4 cells and raise the possibility that modalities aimed at abrogating amphiregulin action may prove useful in pancreatic cancer, especially when used in conjunction with EGFR-targeted therapy.

[Congenital dilatation and stricture of the bile duct as a cause of primary intrahepatic calculi].

Further studies on image techniques and hepatobiliary scintigraphy for diagnosis of biliary diseases revealed details of the whole biliary ductal system and appeared some kinds of biliary malformation, which are clinically important and had been unknown yet, such as anomalous arrangement of the pancreatico-biliary ductal system, congenital biliary strictures and congenital dilatation of the intrahepatic bile duct associated with choledochal cyst. We had 42 cases with primary intrahepatic calculi for these 12 years and they had Alonso-Lej Type I cysts with dilatation of the intrahepatic bile duct and congenital biliary strictures in the-hepatic hilum. Furthermore, we had 30 cases with both the biliary malformations, but without intrahepatic stones. Consequently, coexistence of both these anomalies of the bile duct is thought to be the basis for the formation of primary intrahepatic calculi.

A Case of Ductal Carcinoma In Situ (DCIS:noncomedo type)Detected by Ultrasonography: Demonstration of Occult Multiple Foci.

We report a case of ductal carcinoma in situ (DCIS) of the breast detected by ultrasonographic mass screening in a 51-year-old woman. In a mass screening program for breast cancer, physical examination with inspection and palpation, and ultrasonography (US) were performed. A hypoechoic mass with a slightly irregular margin was detected by US in the lateral upper quadrant of the right breast, at a distance 2 cm from the edge of the nipple. The mass was not detected by physical examinations or by mammography (MMG). The mass, which measured 0.8 x 0.5 cm and was examined by fine needle aspiration biopsy (FNAB) under US guidance, was cytologically diagnosed as class X. Modified radical mastectomy (Auchincloss method) was performed with the patient's consent. Pathological examination of the resected specimen revealed DCIS (noncomedo type) and occult multiple foci of malignancy which was considered tracking centripetally underneath the nipple. This case suggests that US and FNAB performed under US guidance are useful in the detection and diagnosis, respectively, of a breast mass. We should take multifocality into consideration, particularly with tendency tracking to the nipple, in the treatment of small breast cancers such as DCIS.

Two Cases of Choroidal Metastasis from Breast Cancer.

We report two cases of choroidal metastasis from breast cancer. The first case was a 41-year-old woman with loss of her right upper visual area in whom right breast cancer accompained by lung and choroidal metastases were detected simultaneousyl. She died without having received radiation therapy for the affected eye 6 months after mastectomy and oophorectomy. The second case was a 34-year-old woman in whom choroidal metastasis causing right visual disturbance was diagnosed 3 years after mastectomy for breast cancer. She received radiation therapy following oophorectomy and her visual acuity completely recovered. She dies 7 months later. Radiation therapy improved her quality of life despite her short survival, because her visual acuity was maintained until death. In general, the life span of patients with choroidal metastases is short because of multiple organ metastases, but to obtain a better quality of life, active treatment of the affected eye is necessary.