Cholesterotic Fibrous Histiocytoma in a Patient with Metabolic Syndrome.

Among the many variants of dermatofibroma, dermatofibroma with cholesterol cleft (cholesterotic fibrous histiocytoma) is extremely rare. Here, we describe the case of a 50-year-old male patient with a cholesterotic fibrous histiocytoma on his left lower leg. He presented with a hyperkeratotic nodule 6 mm in diameter with a brown surface on the extensor surface of his left lower leg. The lesion had developed over the course of a few years without any tendency to heal. A skin biopsy performed on the tumor showed histopathological findings compatible with those of dermatofibroma. Interestingly, the lesion included many cholesterol clefts, as well as foamy histiocytes and multinucleated giant cells around them. He had had metabolic syndrome for years. To the best of our knowledge, this is the first report of a cholesterotic fibrous histiocytoma in a patient with metabolic syndrome. We conclude that the altered microenvironment caused by metabolic syndrome, as well as hyperlipoproteinemia itself, may play a role in the pathogenesis of this rare case.

Successful Treatment of Two Cases of Squamous Cell Carcinoma on the Ear with Intra-Arterial Administration of Peplomycin through a Superficial Temporal Artery.

Cutaneous squamous cell carcinoma (SCC) is the second most common non-melanoma skin cancer and tends to develop in sun-exposed cosmetic areas, including the ear. In this report, we describe two cases of SCC on the ear successfully treated with intra-arterial administration of peplomycin through a superficial temporal artery. In addition to this selective chemotherapy, we administered oral tegafur, which achieved complete remission of the tumor. These findings suggest that intra-arterial administration of peplomycin with tegafur is one of the optimal therapies for the treatment of SCC developing on the ear.

Acute pancreatitis in patients with ulcerative colitis.

Twenty-two patients (13 men and 9 women; median age, 34 years; range, 15-64 years) with ulcerative colitis (UC) were evaluated to determine the incidence of acute pancreatitis with UC at the First Department of Internal Medicine, Mie University School of Medicine, during 1989-2001. Among these, three patients (14%) were diagnosed as having had episodes of acute pancreatitis during the mean follow-up period of 6 years. One patient presented with acute pancreatitis and UC simultaneously. Two patients had drug-induced pancreatitis (one due to azathioprine and the other due to 5-ASA). In conclusion, acute pancreatitis is not a frequent, but an occasional extraintestinal manifestation of UC.

Long-term follow-up of patients with liver cirrhosis after endoscopic esophageal varices ligation therapy: comparison with ethanol injection therapy.

BACKGROUND/AIMS: Esophageal variceal hemorrhage is the most dreaded complication of liver disease. Prevention or emergency therapy of bleeding is important. METHODOLOGY: A group of 217 patients underwent endoscopic esophageal variceal therapy including endoscopic ethanol injection, endoscopic esophageal variceal ligation, or a combination of the two. RESULTS: Esophageal varices were eradicated by endoscopic esophageal variceal ligation with the least sessions required, and associated complications with endoscopic esophageal variceal ligation therapy were lower than with the other two approaches. However, the cumulative recurrence-free period of esophageal varices was significantly higher after endoscopic ethanol injection than after endoscopic esophageal variceal ligation and in some cases F3 varices were observed post-endoscopic esophageal variceal ligation hemorrhage. A combined endoscopic esophageal variceal ligation and endoscopic ethanol injection therapy had no advantage with respect to cumulative recurrence-free rate, session number, or complication frequency, relative to either therapy alone. CONCLUSIONS: While the combined observations indicate that endoscopic esophageal variceal ligation is safe and simple, we should consider additional therapy to achieve complete mucosal fibrosis of the esophagus after endoscopic esophageal variceal ligation.

Hepatocellular carcinoma presenting with obstructive jaundice: a clinicopathological study of eight cases.

BACKGROUND/AIMS: The prognosis of icteric type hepatocellular carcinoma is extremely poor, not only because of obstructive jaundice, but also because of difficulties for early diagnosis. The aim of this study is to evaluate characteristics of icteric hepatocellular carcinoma for early diagnosis. METHODOLOGY: Eight patients with icteric hepatocellular carcinoma among 326 patients with hepatocellular carcinoma in our hospitals were retrospectively examined by laboratory data, image studies and pathology studies. RESULTS: Most cases were already advanced, with a portal tumor thrombus at the time of diagnosis. Imaging studies fail to reveal tumors because this type of hepatocellular carcinoma has an irregular faint margin and has lost the characteristic pattern of hepatocellular carcinoma, such as capsular formation or early enhancement. Pathology observations demonstrated poorly or moderately differentiated hepatocellular carcinoma in all our cases. CONCLUSIONS: This type of hepatocellular carcinoma should be considered in cirrhotic patients with obstructive jaundice or in patients with high tumor marker levels even if image studies fail to reveal tumors. For better prognosis, combination therapies such as biliary drainage, support for portal flow as well as treatment for the hepatocellular carcinoma, are necessary.

The PPARgamma ligand, 15-Deoxy-Delta12,14-PGJ2, regulates apoptosis-related protein expression in cholangio cell carcinoma cells.

PPARgamma is known to induce apoptosis in malignant tumor cells, but the mechanism of this induction is not well understood. We investigated induction of apoptosis with 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a PPARgamma ligand, in cholangio cell carcinoma (CCC) cells (RBE, ETK-1 or HuCCT-1). Apoptosis was induced in RBE and ETK-1 cells with 15d-PGJ2, but not in HuCCT-1 cells, although PPARgamma was expressed in all CCC cells. Apoptosis-related proteins were also expressed, including FLIP, bclx, Apaf-1 and XIAP, but expression levels differed among the three cell lines. RBE cells treated with 15d-PGJ2 showed caspase activation, and it appeared that PPARgamma-induced apoptosis was dependent on caspase activation. However, neither ETK-1 nor HuCCT-1 cells showed significant activation of caspase-8 or -3 with 15d-PGJ2 treatment, raising the possibility of a caspase-independent apoptosis induction pathway. XIAP was down-regulated by 15d-PGJ2 in all three CCC cell lines. Therefore, 15d-PGJ2 induces apoptosis in CCC cells via caspase-dependent or independent pathways. 15d-PGJ2 may also induce down-regulation of XIAP and may promote caspase cascade activation through TNF-family receptor signaling pathways.

12E2: a cloned murine dermal cell with features of dermal dendrocytes and capacity to produce pathologic changes resembling early Kaposi's sarcoma.

Factor XIIIa-positive dendrocytes are abundant within the dermis and have been implicated in the pathogenesis of various disorders, including AIDS-related Kaposi's sarcoma. Purified cultures of factor XIIIa-positive normal dermal dendrocytes have not as yet been achieved. 12E2 is a cloned cell line derived from superficial murine dermis where factor XIIIa-positive dendrocytes are abundant. Subconfluent cultures of 12E2 demonstrate polydendritic cell contours with thin, elongated membranous projections. These cells express Factor XIIIa and VCAM-1 by immunohistochemistry and by Western blot analysis of 12E2 cell lysates. 12E2 cells also constitutively express the Langerhans-cell-related epitope DEC-205, detected by NLDC-145 antibody and the CD80 co-stimulatory molecule, as well as Ia antigen on exposure to interferon-gamma. Cells so treated exhibit significant ability to present alloantigens in vitro. 12E2 cells are shown to express mRNA for numerous cytokines, including interleukin (IL)-1alpha, IL-1beta, IL-5, IL-6, IL-7, tumor necrosis factor-alpha and granulocyte macrophage-colony stimulating factor, by reverse-transcriptase polymerase chain reaction followed by Southern blot hybridization. Microinjection of 12E2 cells, but not 3T3control fibroblasts, into footpads of syngeneic and SCID mice results in lesions that mimic the histology and immunohistochemistry of human Kaposi's sarcoma. In aggregate, these data indicate that 12E2 cells 1) share lineage characteristics with factor XIIIa-positive dermal dendrocytes, 2) produce mRNA for numerous cytokines and are cytokine responsive to interferon-gamma, and 3) behave in vivo in a manner that resembles Kaposi's sarcoma, a condition known to involve proliferation of human dermal dendrocytes.

Clinical characteristics and prognostic indicators of drug-induced fulminant hepatic failure.

BACKGROUND/AIMS: In most cases of drug-induced liver injury, it is difficult to diagnose whether these cases would progress to fulminant hepatic failure. We investigated the characteristics of non-viral and suspiciously drug-induced fulminant hepatic failure by comparing clinical data between cases that progressed and those that did not progress to fulminant hepatic failure. METHODOLOGY: Ninety-five cases of suspicious drug-induced liver injury including 22 cases that had been treated at our hospital, and subsequently progressed to fulminant hepatic failure were involved in this study. We investigated the characteristics of drug-induced fulminant hepatic failure by a comparison of non-fulminant and fulminant cases, and simultaneously of survivors and fatal cases in the group of fulminant cases. RESULTS: Many of the clinical variables were significantly deteriorated in fulminant cases. The latent period, which means the duration of drug administration, correlated with the severity of drug-induced liver injury including fulminant hepatic failure. Suspicious cases of drug-induced liver injury where the bilirubin level at the time of definite diagnosis stayed over 13 mg/dL for more than one month were likely to progress to fulminant hepatic failure. CONCLUSIONS: Our results suggest that the latent period and the peak level of total bilirubin would be prognostic factors for the severity of drug-induced fulminant hepatic failure. Early preparation of liver transplantation should be recommended by referring these characteristics.

Long-term follow-up of patients with liver cirrhosis after endoscopic ethanol injection sclerotherapy for esophageal varices.

BACKGROUND/AIMS: Esophageal variceal hemorrhage is a severe complication of liver cirrhosis, and therapy for acute bleeding and prevention of hemorrhage are important. In this study, we evaluated the long-term cumulative survival rate of patients with esophageal varices after treatment with endoscopic ethanol injection sclerotherapy (EIS group) or pharmacological therapy (non-EIS group). METHODOLOGY: All 110 patients were treated for their esophageal varices and their prognosis and complications were analyzed during the follow-up period. RESULTS: The cumulative survival rate in the primary preventive EIS group was superior to that in the non-EIS group. The preventive EIS group had greater long-term survival rate than those treated on an emergency group. With respect to emergency therapy, the EIS group had better survival rates than the non-EIS group during the two-year follow-up period after esophageal variceal therapy. CONCLUSIONS: We conclude that primary preventive EIS is an effective therapy for survival of patients with esophageal varices over a long-term period.

Cellular FLICE/caspase-8-inhibitory protein as a principal regulator of cell death and survival in human hepatocellular carcinoma.

Human hepatocellular carcinomas (HCCs) show resistance to apoptosis mediated by several death receptors. Because cellular FLICE/caspase-8-inhibitory protein (cFLIP) is a recently identified intracellular inhibitor of caspase-8 activation that potently inhibits death signaling mediated by all known death receptors, including Fas, TNF-receptor (TNF-R), and TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs), we investigated the expression and function of cFLIP in human HCCs. We found that cFLIP is constitutively expressed in all human HCC cell lines and is expressed more in human HCC tissues than in nontumor liver tissues. Metabolic inhibitors, actinomycin D (ActD) or cycloheximide (CHX), dramatically rendered HCC cells sensitive to Fas-mediated apoptosis. Neither caspase-8 nor caspase-3 was activated by agonistic anti-Fas antibody alone, but both caspases were activated by Fas stimulation in the presence of ActD or CHX, indicating the importance of caspase-8 inhibitors that are sensitive to metabolic inhibitors. Actually, cFLIP expression was decreased in ActD or CHX treatment. cFLIP down-regulation induced by cFLIP antisense oligodeoxynucleotides sensitized HLE cells to Fas, TNF-R, and TRAIL-R-mediated apoptosis. Furthermore, cFLIP over-expression activated nuclear factor (NF)-kappaB and cFLIP down-regulation attenuated NF-kappaB activation induced by TNF-alpha or TRAIL. Pretreatment with pan-caspase-inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD-fmk), restored NF-kappaB activity attenuated by cFLIP down-regulation. cFLIP expression was increased by TNF-alpha, TRAIL, or vascular endothelial growth factor but decreased by wortmannin, indicating that cFLIP expression is regulated by both the NF-kappaB and phosphatidylinostiol-3 kinase (PI-3)/Akt pathways. These results suggest that cFLIP plays an important role in cell survival not simply by inhibiting death-receptor-mediated apoptosis but also by regulating NF-kappaB activation in human HCCs.

Low-dose chemotherapy of cisplatin and 5-fluorouracil or doxorubicin via implanted fusion port for unresectable hepatocellular carcinoma.

BACKGROUND: The efficacy of continuous arterial infusion chemotherapies via a subcutaneously implanted port has been reported in unresectable HCC cases. However, the regimens for this therapy are still controversial. Among these regimens, cisplatinum (CDDP) + 5-fluorouracil (5-FU) or epirubicin have been reported to have favorable effects. PATIENTS AND METHODS: The efficacies of these two regimens are compared with regard to size of tumor, a tumor marker and survival rate in patients with unresectable HCC. RESULTS: Treatments with both the epirubicin (epirubicin group) and the CDDP + 5-FU (CDDP group) demonstrated significant tumoricidal effects as compared with conservative therapies (control group). Furthermore, the tumoricidal effects observed in the CDDP group were superior to that in the epirubicin group, despite a higher incidence of portal tumor thrombus in the CDDP group. Additionally, a longer survival was observed in the CDDP group relative to the epirubicin group. CONCLUSION: Arterial infusion chemotherapy using CDDP + 5-FU may be the superior regimen for advanced HCC, even with portal tumor thrombus complications.

Hepatocellular carcinoma development in sustained viral responders to interferon therapy in patients with chronic hepatitis C.

The incidence of hepatocellular carcinoma (HCC) tends to decrease in sustained responders (SR) to interferon (IFN) therapy for chronic hepatitis C rather than in non-responders (NR). However, some SR develop HCC and their details and prognosis are not well-known, so we investigated such cases. Among 462 patients who underwent IFN therapy and were available for follow-up, 142 patients (30.7%) were SR and six of these (4.2%) developed HCCs. The interval between interferon therapy and diagnosis of HCC was 32-99 months (average 59.2 months). Five of the six cases were single HCCs sized 20-125 mm. The remainder was multiple HCCs. After initial treatment, five patients (83.3%) relapsed and three patients (60%) died due to the HCC. The interval between initial treatment and recurrence was 2-14 months (average 5.8 months). Among the three fatal cases, the interval between initial treatment and their death was 11-66 months (average 29.3 months). Though the prognosis of the one patient who did not relapse after initial treatment was good, the other five patients relapsed and three of them died due to the HCC. These results suggest that the prognosis of sustained responders who develop HCC after IFN therapy is not necessarily good, so close follow-up remains necessary, despite their response to IFN therapy.

The usefulness of digital subtraction imaging with Levovist in the diagnosis of focal hepatic tumors.

This study was designed to evaluate digital subtraction imaging (DSI) with Levovist in the diagnosis of hepatocellular carcinoma (HCC), metastatic hepatocellular carcinoma, and hepatic hemangioma. The subjects in this study were 70 patients with 76 nodules of hepatic tumors (48 nodules in 46 cases of hepatocellular carcinoma, 20 nodules in 16 cases of metastatic hepatocellular carcinoma, and 8 nodules in 8 cases of hepatic hemangioma). Contrast enhancement of tumors acquired in the early, portal, and late phases with DSI were compared to classify the tumors. DSI of HCC showed contrast enhancement of 40 nodules (82.2%). High contrast enhancement in the early phase, which was maintained in the portal phase, changed to images with no contrast enhancement with partial persistence of contrast enhancement in the late phase. DSI of metastatic hepatic carcinomas demonstrated contrast enhancement of tumor of 18 nodules (90%) to a high degree in the early and portal phases, which changed to images with no contrast enhancement in the late phases. DSI of hepatic hemangioma maintained high contrast enhancement on tumor margins of 5 nodules (62.5%) and on the entire tumor of 3 nodules (37.5%) in the early, portal, and late phases. DSI of hepatic tumors (hepatocellular carcinoma, metastatic hepatocellular carcinoma, and hepatic hemangioma) provided characteristic findings of contrast enhancement in the early, portal, and late phases, and contribute to differential diagnosis.

Clinicopathological analysis of liver abscess in Japan.

Currently, pyogenic liver abscess is not frequent, but it is a severe infectious disease. However a strategy for the effective treatment of liver abscess is not established. We analyzed 75 cases of liver abscess over an eight year period and evaluated their prognosis, any associated underlying disease, or the effect of percutaneous transhepatic abscess drainage (PTAD). For all 75 cases, laboratory data were analyzed and imaging studies were performed. Next, PTAD and antibiotic administration were started on these cases as first choice treatments. These treatments were continued until the laboratory data of the patient were restored to within the normal range. Those cases that were PTAD non-effective or required operation for underlying diseases, underwent operations. Of the total 75 cases, 63 survived after treatment and 12 cases died. Bacteria were detected in 50 cases and Klebsiella pneumoniae was detected in 31 of these 50 cases, but 25 out of 75 cases were negative. The biliary system was the main route of infection. PTAD was effective, especially in cases that were complicated with disseminated intravascular coagulation (DIC) or acute renal failure (ARF). PTAD is an effective treatment for liver abscess, it is especially useful in the restoration of severe general conditions as indicated by this study.

Comparison of the distribution and numbers of antigen-presenting cells among T-lymphocyte-mediated dermatoses: CD1a+, factor XIIIa+, and CD68+ cells in eczematous dermatitis, psoriasis, lichen planus and graft-versus-host disease.

Antigen-presenting cells (APCs) participate in the initiation of the inflammatory process in various immune-mediated dermatoses through the activation of antigen-specific T lymphocytes. The skin contains several different subsets of APCs. To investigate the role of these APCs in T-cell immune-mediated inflammation, we examined the distribution and numbers of epidermal and dermal CD1a(+) dendritic cells (DCs), factor XIIIa(+) dermal DCs, and CD68(+) macrophages in five T-cell-mediated inflammatory skin diseases. Immunohistochemistry of CD1a, factor XIIIa, and CD68 was performed using paraffin-embedded tissue obtained from a total of 51 patients with eczematous dermatitis (histologically spongiotic dermatitis), psoriasis, lichen planus, acute graft-versus-host disease (GVHD), and chronic GVHD. The numbers of positive cells for each staining were compared with those in site-matched normal skin control specimens from aged-matched subjects. In spongiotic dermatitis and lichen planus, the numbers of epidermal and dermal CD1a(+) cells and factor XIIIa(+) cells were significantly greater than in normal control skin, while in psoriasis only factor XIIIa(+) cells were significantly increased in number. Acute and chronic GVHD showed a reduced number of dermal CD1a(+) cells. Interestingly, factor XIIIa(+) cells were decreased in acute GVHD while they were increased in chronic GVHD. There was a significant reduction in epidermal CD1a(+) cells in acute GVHD, but not in chronic GVHD. The differences in the numbers of APCs in lesional skin appeared to reflect differences in the pathophysiology of these inflammatory skin diseases.

Long-term follow-up of chronic hepatitis C in Japan.

BACKGROUND/AIMS: Chronic hepatitis C which exhibits a varied natural course, is becoming a major problem worldwide. METHODOLOGY: In this study, we investigated 161 patients with chronic hepatitis C by repeated liver biopsies. From initial biopsies, we diagnosed 56 patients with chronic persistent hepatitis, 74 with chronic active hepatitis 2A, and 31 with chronic active hepatitis 2B. RESULTS: During the follow-up period, a progression from chronic hepatitis to liver cirrhosis was recognized among all stages, however the rate of progression to liver cirrhosis was less in chronic persistent hepatitis than in chronic active hepatitis 2A and chronic active hepatitis 2B. Hepatocellular carcinoma was detected in chronic active hepatitis 2A and chronic active hepatitis 2B at the initial stage, however, no tumors developed in chronic persistent hepatitis at the initial stage. Most hepatocellular carcinomas were concomitant with liver cirrhosis. CONCLUSIONS: We suggest a close follow-up of patients with chronic hepatitis C, especially those patients with chronic active hepatitis 2A or 2B and exhibiting successive active inflammation of liver.

HBV subtype as a marker of the clinical course of chronic HBV infection in Japanese patients.

Hepatitis B virus (HBV) genotype C is predominant in Japan. However, many HBV subtypes are involved in each genotype, and the clinical manifestations in the patients associated with each subtype remain unknown. Therefore, we investigated the relationship between HBV subtype and clinical aspects of chronic HBV infection. The subtype of 237 patients with chronic HBV infection, including 74 asymptomatic carriers, was determined. The subtypes of 110 HBV carriers undergoing long-term follow-up management were determined twice to detect subtypic changes. The clinical features of the patients were also studied with regard to presence or absence of subtypic change. The subtypic distribution in the 237 HBV carriers was as follows: subtype adr, 161 (68%); subtype adw, 25 (11%); subtype adwr, 12 (5%); subtype ar, 24 (10%); subtype adyr, 4 (2%); and unclassified, 8 (3%). The proportion of asymptomatic carriers in patients with subtype adw was significantly higher than those in patients with subtype adr (56% vs. 28%, P < 0.05). In addition, the proportion of HCC in patients with subtype adwr was significantly higher than those in patients with subtype adr (25% vs. 6%, P < 0.05). The prevalence of subtype adr in 74 asymptomatic carriers tended to decrease with age (82% in carriers aged < or =35 years vs 43% in those aged > or =61 years, P < 0.05). The subtypic change and the course of chronic HBV infection had no significant correlation. These results suggest that HBV subtypes are associated with the clinical course of chronic HBV infection.