[Primary effusion lymphoma-like lymphoma transformed to diffuse large B-cell lymphoma].

A rare kind of malignant lymphoma, called primary effusion lymphoma (PEL) is associated with human herpesvirus 8 (HHV-8), and characterized by lymphomatous effusion in the bodily cavities. Although the initial clinical presentation of primary effusion lymphoma-like lymphoma (PEL-LL) is similar to that of PEL, PEL-LL is HHV-8 negative and has a favorable prognosis. A PEL-LL diagnosis was made after an 88-year-old man was admitted to our hospital with a pleural effusion. His disease regressed after effusion drainage. He demonstrated disease progression to diffuse large B-cell lymphoma after two years and ten months. Our example demonstrates that aggressive B-cell lymphoma can develop from PEL-LL.

[MIC2 (CD99) as a diagnostic marker for TdT-negative B lymphoblastic lymphoma].

Lymphoblastic lymphoma (LBL) is a rare hematologic malignancy that originates from immature lymphocytes and usually expresses terminal deoxynucleotidyl transferase (TdT). Here, we report a case of TdT-negative B-LBL. A 71-year-old male patient presented to a hospital with shortness of breath. His chest computed tomography showed a mediastinal mass. Tumor cells did not express TdT but expressed MIC2, which led to LBL diagnosis. MIC2 is a useful marker for LBL diagnosis.

Acquired Amegakaryocytic Thrombocytopenia Associated With Autoimmune Hemolytic Anemia.

Acquired amegakaryocytic thrombocytopenia (AATP) is a thrombocytopenic disorder characterized by a decrease in megakaryocytes in the bone marrow. AATP is effectively treated with immunosuppressive therapy. We report a case of a 68-years-old male referred to us due to purpuric lesions on the extremities and was noted to be thrombocytopenic. Bone marrow biopsy showed AATP with autoimmune hemolytic anemia (AIHA). Only two cases of AATP associated with AIHA have been reported. AATP should be differentiated carefully from other causes of peripheral destruction of platelets, such as immune thrombocytopenia (ITP).

Radiofrequency ablation for the treatment of hepatocellular carcinoma with decompensated cirrhosis.

BACKGROUND: Radiofrequency ablation (RFA) is used to treat early-stage hepatocellular carcinoma (HCC), but is sometimes avoided in patients with decompensated liver cirrhosis because of the possible side effect of deterioration of liver function. AIMS: In this study, we report the safety and effects of RFA for treating HCC patients with Child-Pugh B/C liver cirrhosis. METHODS: Sixty-six consecutive HCC patients with Child-Pugh B/C cirrhosis, who were treated by RFA, were enrolled in this study. We analyzed patient outcomes, the complications of RFA, and changes in liver function and tumor markers. RESULTS: Fifty-six patients were classified as Child-Pugh class B, and 10 were classified as class C. The overall survival rates in patients with Child-Pugh B and C cirrhosis were 82 and 83% at 1 year and 47 and 31% at 3 years, respectively. Serum total bilirubin (T.Bil), albumin, prothrombin time, ascites, and encephalopathy were unchanged at 1, 3, and 6 months after RFA in patients with Child-Pugh B cirrhosis; however, serum T.Bil levels increased significantly at 6 months after RFA in 6/10 (60%) patients with Child-Pugh C cirrhosis. Hemothorax and rupture of esophageal varices were observed in 2 patients; however, there were no complications related to poor liver function. CONCLUSION: RFA is a useful modality for treating HCC in patients with poor liver function such as Child-Pugh B and C, but careful monitoring after RFA must be needed.

Oral administration of taurine improves experimental pancreatic fibrosis.

BACKGROUND AND AIM: The mechanism of pancreatic fibrosis is unclear. Taurine is used in the clinical treatment of a wide variety of diseases, but its effect on improving pancreatic fibrosis is unknown. We examined whether a diet with added taurine improves pancreatic fibrosis induced by dibutyltin dichloride (DBTC) in an experimental chronic pancreatitis rat model. In addition, we examined the influence of taurine on pancreatic stellate cells. METHODS: Pancreatic fibrosis was induced by DBTC. Rats were fed a taurine-containing diet or a normal diet and were killed at 4 weeks. Pancreatic stellate cells were isolated from male Wistar rats. Cultured pancreatic stellate cells were incubated with or without taurine chloramine. Type I collagen and transforming growth factor-beta1 secretion was evaluated by ELISA, and matrix metalloproteinase activity was assessed by gelatin zymography. Interleukin-6, interleukin-2, and transforming growth factor-beta1 levels in the supernatants of pancreatic tissue homogenates were measured. RESULTS: Pancreatic fibrosis induced by DBTC was improved remarkably by the oral administration of the taurine-containing diet. Taurine chloramine decreased type I collagen, transforming growth factor-beta1, and matrix metalloproteinases 2 of the pancreatic stellate cell culture supernatant. Increased interleukin-6 and decreased interleukin-2 were found in the supernatants of the pancreatic tissue homogenates of DBTC-induced pancreatitis rats compared with other groups. CONCLUSION: The oral administration of taurine improves pancreatic fibrosis. Taurine chloramine inhibits transforming growth factor-beta1 produced from activated pancreatic stellate cells and improves pancreatic fibrosis.

Heparanase regulates esophageal keratinocyte differentiation through nuclear translocation and heparan sulfate cleavage.

Heparanase is an endo-beta-glucuronidase that specifically cleaves heparan sulfate (HS) chains. Heparanase is involved in the process of metastasis and angiogenesis through the degradation of HS chains of the extracellular matrix and cell surface. Recently, we demonstrated that heparanase was localized in the cell nucleus of normal esophageal epithelium and esophageal cancer, and that its expression was correlated with cell differentiation. However, the nuclear function of heparanase remains unknown. To elucidate the role of heparanase in esophageal epithelial differentiation, primary human esophageal cells were grown in monolayer as well as organotypic cultures, and cell differentiation was induced. Expression of heparanase, HS, involucrin, and p27 was determined by immunostaining and Western blotting. SF4, a novel pharmacological inhibitor, was used to specifically inhibit heparanase activity. Upon esophageal cell differentiation, heparanase was translocated from the cytoplasm to the nucleus. Such translocation of heparanase appeared to be associated with the degradation of HS chains in the nucleus and changes in the expression of keratinocyte differentiation markers such as p27 and involucrin, whose induction was inhibited by SF4. Furthermore, these in vitro observations agreed with the expression pattern of heparanase, HS, involucrin, cytokeratin 13, and p27 in normal esophageal epithelium. Nuclear translocation of heparanase and its catalytic cleavage of HS may play a critical role in the differentiation of esophageal epithelial cells. Our study provides a novel insight into the role of heparanase in an essential differentiation process.

Xanthine oxidase-derived free radicals directly activate rat pancreatic stellate cells.

BACKGROUND AND AIM: Free radicals are reported to be associated with fibrosis in the pancreas. It is generally accepted that pancreatic stellate cells (PSC) play an important role in pancreatic fibrosis. However, the exact role of free radicals in activation of PSC has not been fully elucidated. In the present study, using a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DDC) with cultured PSC, we investigated how free radicals act on the activation of PSC. METHODS: PSC were isolated from male Wister rats. Cultured rat PSC were incubated with DDC for 48 h. Intracellular SOD activity and lipid peroxidation were examined in DDC-treated PSC. Activation of PSC was examined by determining the expression of alpha-smooth muscle actin (alpha-SMA) by immunocytochemistry. The number of PSC using a hemocytometer, type I collagen secretion with ELISA and matrix metalloproteinases (MMP) activities with gelatin zymography were also examined. Secretion of transforming growth factor-beta1 (TGF-beta1) was evaluated by ELISA. The effects of the allopurinol, a xanthine oxidase (XOD) inhibitor, on PSC were also examined. RESULTS: DDC decreased SOD activity and increased lipid peroxidation products in PSC. DDC activated PSC, increasing the number of alpha-SMA positive cells, enhancing secretion of type I collagen and MMP, inhibiting PSC proliferation. Secretion of TGF-beta1, which is known to activate PSC, was increased by DDC treatment. These alterations were prevented by allopurinol. CONCLUSION: These results suggest that free radicals generated by XOD might directly activate PSC.

Pneumatosis cystoides intestinalis after alpha-glucosidase inhibitor treatment in a patient with interstitial pneumonitis.

A 56-year-old woman was admitted to our hospital for treatment of non-specific interstitial pneumonitis (NSIP). The patient started prednisone treatment, but one month later treatment with voglibose, an alpha-glucosidase inhibitor (alpha-GI), was started because of prednisone-induced diabetes mellitus. One week later, a massive volume of free air below the diaphragm was detected by a chest X-ray examination. An abdominal CT examination demonstrated pneumatosis coli and the patient was diagnosed with pneumatosis cystoides intestinalis (PCI). Voglibose was discontinued and parenteral nutrition and oxygen inhalation were initiated. Radiographic findings of PCI disappeared within 7 days. We encountered a rare case of PCI, that was associated with alpha-GI treatment.

Successful treatment of a patient with gastric and duodenal metastases from large cell carcinoma of the lung with carboplatin and gemcitabine.

A 62-year-old man with large cell carcinoma of the lung underwent a right upper lobectomy and four months later demonstrated a relapse in the stomach and duodenum. He received systemic chemotherapy consisting of carboplatin and gemcitabine. After the first cycle of chemotherapy, the duodenal lesion disappeared, however, the gastric lesion demonstrated no response. Considering the risk of bleeding or perforation, a partial gastroduodenal resection was therefore performed. Subsequently, he received adjuvant chemotherapy with the same regimen. He has since been doing well for 24 months after the recurrence. Although the prognosis for patients with gastrointestinal metastases from lung cancer tends to be extremely poor, treatment with chemotherapy and a metastasectomy have resulted in this patient, achieving a long survival.

Pancreatic enzyme supplement improves dysmotility in chronic pancreatitis patients.

BACKGROUND AND AIMS: Impaired gallbladder contraction and rapid gastric emptying in patients with chronic pancreatitis may be the result of depleted pancreatic exocrine function. The authors tested whether oral pancreatic enzymes can improve the dysmotility or not. METHODS: Study subjects consisted of 15 patients with chronic pancreatitis and 18 healthy controls. The gastric emptying time and gallbladder contraction were studied. All patients were initially studied using a test meal without pancreatic enzymes, followed on separate days by a test meal with a single and a triple dose of pancreatic enzymes. Blood samples were taken before and 2 h after the test meal to determine the pancreatic polypeptide levels. RESULTS: In patients with chronic pancreatitis, gallbladder contraction at 15 min after the meal was impaired. The gastric emptying time was faster and the ratio of pre- to postprandial pancreatic polypeptide levels was enhanced. A single dose and a triple dose of oral enzymes further improved the gastric emptying time and the pancreatic polypeptide ration, but did not improve the gallbladder contraction rate at 15 min. CONCLUSIONS: It was demonstrated that the oral pancreatic enzymes improved the gastric dysmotility, confirming the previous findings that suggested the depleted pancreatic enzyme output caused the dysmotility.

EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes.

The epidermal growth factor receptor (EGFR) activates several signaling cascades in response to epidermal growth factor stimulation. One of these signaling events involves tyrosine phosphorylation of signal transducer and activator of transcription (STAT), whereas another involves activation of the phosphatidylinositol 3-OH kinase pathway. Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion with the functional consequence of enhanced cell migration, which can be abolished by use of a JAK-specific inhibitor, AG-490. We determined the mechanisms underlying the signal transduction pathway responsible for increased cell migration. Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. In addition, we found that activation of this signaling pathway results in matrix metalloproteinase-1 (MMP-1) activity. By contrast, Akt activation does not impact the EGFR-STATs-JAKs complex formation and nuclear translocation of the STATs with subsequent MMP-1 activity, although Akt activation may contribute to cell migration through an independent mechanism. Taken together, we find that the recruitment of the STAT-JAK complex by EGFR is responsible for keratinocyte migration that, in turn, might be mediated by MMP-1 activation.

Combination chemotherapy with continuous 5-fluorouracil and low-dose cisplatin infusion for advanced hepatocellular carcinoma.

BACKGROUND: In this study we evaluated the efficacy and toxicities of combination chemotherapy consisting of continuous 5-fluorouracil (5-FU) infusion and low-dose cisplatin infusion (low-dose FP therapy) in the treatment of advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Thirty-eight patients with advanced HCC in whom local treatment was not indicated were enrolled. The low-dose FP therapy consisted of 5-FU (170 mg/m2/day on days 1 to 7/week, continuous infusion) and cisplatin (3 mg/m2/day in 100 ml normal saline, infusion more than 30 minutes, on days 1 to 5/weeks). The patients were treated for 4 consecutive weeks with a subsequent one-week rest period. RESULTS: Thirty-seven of the 38 patients (97%) completed this therapy. A partial response was obtained in 18 (47%), no change in 10 and progressive disease in 9. The time to progression was 211 days. The most common toxicity was nausea/vomiting (13.2%). CONCLUSION: Low-dose FP therapy has a substantial effect on low-grade toxicity in long-term treatment. Low-dose FP therapy is useful for the treatment of advanced HCC.

Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.

Epidermal growth factor receptor (EGFR) overexpression is observed in a number of malignancies, especially those of esophageal squamous cell origin. However, little is known about the biological functions of EGFR in primary esophageal squamous epithelial cells. Using newly established primary human esophageal squamous epithelial cells as a platform, we overexpressed EGFR through retroviral transduction and established novel three-dimensional organotypic cultures. Additionally, EGFR was targeted in a cell type- and tissue-specific fashion to the esophageal epithelium in transgenic mice. EGFR overexpression in primary esophageal keratinocytes resulted in the biochemical activation of Akt and STAT pathways and induced enhanced cell migration and cell aggregation. When established in organotypic culture, EGFR-overexpressing cells had evidence of epithelial cell hyperproliferation and hyperplasia. These effects were also observed in EGFR-overexpressing transgenic mice and the esophageal cell lines established thereof. In particular, EGFR-induced effects upon aggregation appear to be mediated through the relocalization of p120 from the cytoplasm to the membrane and increased interaction with E-cadherin. EGFR modulates cell migration through the up-regulation of matrix metalloproteinase 1. Taken together, the functional effects of EGFR overexpression help to explain its role in the initiating steps of esophageal squamous carcinogenesis.

Matrix metalloproteinase-2 in pancreatic juice for diagnosis of pancreatic cancer.

INTRODUCTION: Matrix metalloproteinase-2 (MMP-2) has an activity to degrade type IV collagen and is associated with invasion angiogenesis of malignant tumor. AIM: A diagnostic value of MMP-2 in pancreatic juice was studied in the diagnosis of pancreatic cancer. METHODOLOGY: Using gelatin zymography, active MMP-2 and proMMP-2 were determined in pancreatic juice obtained endoscopically from 12 patients with pancreatic cancer, 11 with chronic pancreatitis, and 7 control subjects. RESULTS: ProMMP-2 was detected in 12 of 12 patients (100%) with pancreatic cancer, 6 of 11 (54.5%) with chronic pancreatitis, and 3 of 7 (42.9%) controls. Active MMP-2 was detected in 11 patients (91.6%) with pancreatic cancer, 2 (18.2%) with chronic pancreatitis, and none of the control subjects. An activation ratio of MMP-2 (active MMP-2/total MMP-2) in pancreatic juice is significantly higher in pancreatic cancer (23.4 +/- 4.4%, mean +/- SE) than in chronic pancreatitis (2.1 +/- 1.7%) and controls (0%) (p < 0.01). Active MMP-2 was also detected in pancreatic juice from three cases of small pancreatic cancer (tumor <2 cm in diameter). CONCLUSION: Our observation suggests that detection of active MMP-2 in pancreatic juice using gelatin zymography may be useful for the diagnosis of pancreatic cancer.

Wnt-1 but not epidermal growth factor induces beta-catenin/T-cell factor-dependent transcription in esophageal cancer cells.

beta-Catenin plays an important role in signal transduction pathways that regulate cellular differentiation and proliferation. The increased concentration of this protein in the cytoplasm favors its binding to the T-cell factor (TCF) family of DNA-binding proteins, and it subsequently translocates to the nucleus, where it induces transcription of specific genes. We explored mechanisms that lead to activation of beta-catenin/TCF-dependent transcription in esophageal squamous cell carcinoma (ESCC) independent of adenomatous polyposis coli and beta-catenin mutation. Electrophoresis mobility shift assay demonstrated that TCF4 and beta-catenin form a complex and have DNA binding activity. However, there was no constitutive activation of beta-catenin/TCF-dependent transcription. Coculture experiments demonstrated that Wnt-1, but not Wnt-5A and Wnt-7A, activated the TCF reporter gene. Additionally, when cultured with Wnt-1-conditioned media, ESCC cell lines showed an accumulation of beta-catenin in the cytoplasm. Although both Wnt and epidermal growth factor inactivate glycogen synthase kinase 3beta, activation of epidermal growth factor receptor did not stabilize beta-catenin. A comparison of extracellular stimuli suggests that specific Wnt family members stabilize beta-catenin with resulting activation of TCF-dependent transcription in ESCC.