[Adult Gianotti-Crosti syndrome caused by hepatitis B].

A 42-year-old man was admitted to our hospital with a lower extremity rash, general fatigue, and abdominal discomfort. Laboratory findings revealed elevated serum transaminases as well as positivity for the hepatitis B surface antigen and the immunoglobulin M type anti-hepatitis B core antibody. He was diagnosed with a rash typical of Gianotti-Crosti syndrome due to acute infection with hepatitis B virus, genotype A. After admission, the rash gradually decreased; however, serum transaminases and jaundice increased. Entecavir therapy was initiated on day 11 of admission, and his liver function subsequently improved over two weeks. Gianotti-Crosti syndrome is rarely seen in adult patients. It may be important to pay attention to the typical rash of Gianotti-Crosti syndrome because it may provide an important clue to an otherwise asymptomatic acute hepatitis B infection.

Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells.

BACKGROUND: Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that regulates apoptosis sensitivity in a variety of cell types. Here we evaluate the roles of Mcl-1 in chemotherapy-associated apoptosis in gastric cancer cells. In addition, our study examined whether Mcl-1 contributed to apoptosis resistance in so-called cancer stem cell (CSC)-like populations in gastric cancer. METHODS: Seven gastric cancer cell lines were used. The expression of Mcl-1 was assessed by either real-time polymerase chain reaction or Western blot analysis. Apoptosis was quantitated by morphological observation and caspase activity measurement. Adenovirus-mediated RNA interference (RNAi) technology was used to knockdown the expression of Mcl-1. The release of cytochrome c was evaluated by subcellular fractionation and immunoblot analysis. To identify and isolate the CSC-like populations, we used the CSC-associated cell surface marker CD44 and flow cytometry. RESULTS: Six out of the 7 gastric cancer cell lines overexpressed Mcl-1 protein. These Mcl-1-expressing cell lines were relatively resistant to chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin (CDDP). Depletion of Mcl-1 protein by RNAi technology effectively sensitized the cells to anticancer drug-induced mitochondrial cytochrome c release, caspase activation, and apoptosis. In addition, vast amounts of Mcl-1 mRNA were expressed in CD44-positive CSC-like cells. Mcl-1 suppression enhanced the apoptosis in CD44-positive cells to a level equivalent to that in CD44-negative cells, suggesting that Mcl-1 mediates chemotherapy resistance in CSC-like populations. CONCLUSION: These results suggest that Mcl-1 mediates the resistance to apoptosis in gastric cancer cells by blocking the mitochondrial pathway of cell death. Mcl-1 depletion appears to be an attractive strategy to overcome chemotherapy resistance in gastric cancer cells.

Chemoresistance is associated with cancer stem cell-like properties and epithelial-to-mesenchymal transition in pancreatic cancer cells.

BACKGROUND: The aim of this study was to evaluate whether apoptosis-resistant cancer cells have cancer stem cell (CSC)-like properties. MATERIALS AND METHODS: Panc-1 pancreatic cancer cells were incubated in the presence of 5-fluorouracil (5-FU) for 24 h, and further incubated without 5-FU for 28 days. To assess the capacity of self-renewal, surviving cells were planted for sphere-forming assay. Epithelial-to-mesenchymal transition (EMT) was induced with TGF-ß, then mRNA expression was evaluated by real-time PCR for E-cadherin, SNAIL, and vimentin. The E-Cadherin protein levels were also examined by immunoblot analysis. The Local invasion ability was analyzed by Matrigel invasion assay. RESULTS: The frequency of cells that were capable of initiating spheres was higher in 5-FU-pre treated cells, which also overexpressed stem cell marker genes, OCT4 and NANOG. Matrigel invasion activity of apoptosis-resistant Panc-1 cells was greater than that of control Panc-1 cells. CONCLUSION: Apoptosis-resistant cancer cells have CSC-like properties, i.e., able to initiate sphere formation, express stem cell genes, and respond to EMT stimulation.

Colon neoplastic cells do not originate from bone marrow-derived cells after sex-mismatched bone marrow transplantation.

BACKGROUND: Although previous studies indicate that gastrointestinal (GI) cancer may originate from cells recruited from bone marrow (BM) in mice, whether similar phenomena occur in humans is controversial. In the current study, we evaluated two female patients who developed colonic adenocarcinoma more than 10 years after gender-mismatched BM transplantation, and followingly underwent successful endoscopic mucosal resection. MATERIALS AND METHODS: Fluorescent in situ hybridization (FISH) analysis was used to determine whether the tumours contained donor-derived BM cells. RESULTS: Approximately 1.2% of the tumour cells contained Y-chromosome-positive signals, and a comparable percentage of normal colonic epithelial cells close to the tumour also contained Y-chromosome-positive signals. CONCLUSION: These results do not support the concept that GI cancer can originate from BM-derived cells.

[A case of hepatic artery aneurysm that had formed asymptomatically and penetrated into the duodenum].

A 41-year-old man was admitted to our hospital with gastrointestinal bleeding. Esophagogastroduodenoscopy revealed a submucosal protrusion with erosion in the duodenal bulb which was thought to be the bleeding source. Dynamic CT scan, ultrasonography and angiography of the abdomen revealed a hepatic artery aneurysm and a dilated celiac artery that dissected from its origin. Although we considered percutaneous transcatheter arterial embolization with metallic coils, we chose surgical resection and vascular reconstruction to prevent hepatic ischemia resulting from interruption of collateral circulation. On the 8(th) day, hepatic artery aneurysmectomy and revascularization with a great saphenous vein was carried out without any severe complication. The pathological specimen demonstrated segmental arterial mediolysis.

[Advanced gallbladder cancer that showed complete response to gemcitabine plus S-1 chemotherapy].

A 57-year-old man with advanced gallbladder cancer and accompanying hepatic, colonic and duodenal invasion and para-aortic lymph node metastasis was referred to our hospital. Gemcitabine plus S-1 administration was chosen. Gemcitabine was administered intravenously at a dose of 1000 mg/m(2) on days 1 and 15, and repeated every 4 weeks. S-1 was administered orally at a dose of 40 mg/m(2) b.i.d. on days 1-14. Chemotherapy was effective for the primary gallbladder tumor and lymph node metastasis. The primary tumor and metastatic lymph nodes were shown to have disappeared by a FDG-PET CT study after 10 courses of chemotherapy. Informed consent was obtained prior to performing surgery of the primary lesion. Pathological examination showed fibrosis and a small focus of residual cancer in the resected gallbladder. Complete resection was achieved as all the margins were negative. The findings suggest that gemcitabine plus S-1 treatment may be effective against advanced gallbladder cancer.

[A case of metastatic esophageal cancer - endoscopic resection of the primary site following systemic chemotherapies].

A 64-year-old male presented with discomfort in the chest. His endoscopic examination and CT scan showed esophageal cancer with multiple liver metastases. A total of ten courses of systemic chemotherapy by 5-fluorouracil (5-FU) (800 mg for five days) and cisplatin (CDDP) (80 mg/day on the first day of the week for four weeks) were performed, and liver and lymph node metastases disappeared. The primary lesion was the only site detected positive by PET scan. After a concurrent chemoradiation therapy, salvage endoscopic mucosal resection (EMR) was performed on the remainder of the primary site and the patient gained a complete response (CR). We report this case because, although the mean survival time of advanced esophageal cancer is less than one year, this patient responded to chemotherapy and gained complete response by salvage EMR. This patient has had no recurrence for four years since his initial diagnosis.

Gemcitabine as first-line chemotherapy in elderly patients with unresectable pancreatic carcinoma.

BACKGROUND: Gemcitabine (GEM) is the key drug for the chemotherapy of unresectable pancreatic cancer. However, the efficacy and safety of GEM has not been established in elderly patients. We retrospectively examined the prognosis of elderly pancreatic cancer patients treated with GEM. METHODS: Sixty-six patients with unresectable pancreatic cancer (pathologically identified) and no prior chemotherapy were divided into three groups. Group A: patients aged 70 years or more who received standard GEM (1000 mg/m(2)) on days 1, 8, and 15 and rest on day 21; Group B: patients less than 70 years old who received standard GEM therapy; and Group C: patients under best supportive care. RESULTS: Median survival times (MSTs) (days) were 311 in group A (p < 0.05 vs. group C), 292 in group B (p < 0.05 vs. group C), and 127 in group C. Among the patients who received GEM, 23% patients in group A and 16% patients in group B obtained partial responses. The response rates and MSTs were similar in groups A and B, as well as in more aged (≥75 years) patients. Bone marrow suppression was more frequently seen in elderly patients. Cox's hazard model in patients aged 70 years or more revealed that GEM therapy reduced the hazard ratio for death (hazard ratio: 0.683, p = 0.041). CONCLUSIONS: Chemotherapy with GEM appears to be effective and safe in elderly patients as well as in younger patients. Patients with unresectable pancreatic carcinoma should receive GEM therapy even if they are aged 70 or more, even if they are aged 75 or more.

Granulocyte and monocyte adsorption apheresis therapy modulates monocyte-derived dendritic cell function in patients with ulcerative colitis.

The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and monocyte-derived dendritic cell (moDC) function after GMA therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled: 14 patients were responders, and 4 patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after GMA therapy. Flow cytometric analysis for monocyte markers (CD14/CD16) was then performed. Monocyte-derived dendritic cells were obtained and alterations in their phenotype were analyzed by flow cytometry. Their function was also analyzed in a mixed lymphocyte reaction assay between allo-naïve T lymphocytes. Flow cytometric analysis for intracellular interferon (IFN)-gamma (T-helper 1 cells) and interleukin (IL)-4 (T-helper 2 cells) was then performed for the stimulated T lymphocytes. In patients who responded to GMA, the average numbers of monocytes, especially CD16(+) monocytes, were significantly decreased after therapy (P < 0.05). In responders, post-GMA moDCs expressed significantly lower CD80 and B7-DC, which are one of the stimulation and maturation markers of dendritic cells, compared to pre-GMA moDCs. CD83, CD86 and human leukocyte antigen-DR also showed a tendency to decrease. In responders, naïve T lymphocytes stimulated with post-GMA moDCs produced significantly less IFN-gamma and IL-4 compared to those stimulated with pre-GMA moDCs. The results of our study show that some of the immunosuppressive effects of GMA therapy may be associated with the modulation of monocyte subsets and moDC function.

Side population of pancreatic cancer cells predominates in TGF-beta-mediated epithelial to mesenchymal transition and invasion.

We report here side population (SP) cells, a cancer stem cell enriched fraction from pancreatic cancer cell line, have enormous superior potential of the epithelial to mesenchymal transition (EMT), invasion, and metastasis. In an isolated SP cell culture, the cells rapidly expressed and up-regulated E-cadherin, an epithelial phenotypic marker, and the cells formed tightly contacted cell cluster, which is a representative epithelial phenotypic appearance. When the SP cells were incubated in the presence of TGF-beta, SP cells changed their shape into mesenchymal-like appearance including spindle shaped assembly. This alteration was associated with significant reduction of E-cadherin expression level. TGF-beta induced EMT-associated gene alteration such as reduction of E-cadherin mRNA and induction of Snail mRNA and matrixmetalloproteinase (MMP)-2 mRNA. Finally, SP cells exerted notable matrigel invasion activity in response to TGF-beta treatment, whereas MP cells did not respond to TGF-beta-mediated invasion. In conclusion, these results suggest that SP cells from pancreatic cancer cell line possess superior potentials of phenotypic switch, i.e., EMT/MET, micro-invasion, and in vivo metastasis, as compared to MP cells. Because micro-invasion and metastasis are key mechanisms of cancer malignant potential, SP cells would be the attractive target for preventing cancer progression.

Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients.

OBJECTIVE: The clinical significance of cytomegalovirus (CMV) reactivation complicating ulcerative colitis (UC) patients has been uncertain. It has therefore remained undetermined whether or not CMV reactivation should be treated in UC patients under immunosuppression. The aim of the study was to clarify the natural history of CMV reactivation in UC patients. METHODS: Sixty-nine UC patients with moderate to severe activity were enrolled in the study. All of the patients were treated with prednisolone, and/or immunosuppressants such as cyclosporine A. We sequentially monitored CMV reactivation every 2 wk up until 8 wk using the CMV antigenemia (Ag) assay and plasma quantitative real-time polymerase chain reaction (PCR) assay for CMV. RESULTS: Immunoglobulin (Ig) G for CMV was positive in 48 patients (69.6%) and negative in 21 patients (30.4%). CMV was reactivated in 25 patients out of the 48 seropositive patients (52.1%) during the study period. The CMV Ag and PCR values were low and none of the patients showed any evidence of CMV infection on biopsy specimens by hematoxylin and eosin staining. While gancylovir (GCV) was not used except in two patients, clinical outcomes including rates of remission and colectomy were not significantly different among the CMV reactivation-positive, -negative, and CMV IgG negative groups. Furthermore, CMV disappeared without GCV in most of the CMV reactivation-positive patients. CONCLUSIONS: CMV is frequently reactivated in active UC patients; however, it disappears without antiviral agents. Therefore, antiviral therapies should not be necessary for most UC patients with only CMV reactivation as long as CMV Ag values are low.

[A case of intrahepatic cholangiocarcinoma effectively treated by hepatic arterial infusion chemotherapy].

The patient was a 50-year-old woman who suffered from gastric discomfort. She was first diagnosed as intrahepatic cholangiocarcinoma with hepatic, paraaortic lymphnodal and bone metastasis. Initial systemic chemotherapy using gemcitabine (GEM) and 5-FU failed to control the disease activity. Then she was given GEM and cisplatin (CDDP) combination chemotherapy. The response was assessed as stable disease (SD), but grade 4 leukopenia was seen. Then systemic therapy using GEM, and hepatic arterial infusion therapy with CDDP, l-leucovorin and 5-FU were continued biweekly. Partial response (PR) was achieved six months later, and her disease status was maintained as SD. This hepatic arterial infusion chemotherapy would be safe and feasible as therapy for inoperable intrahepatic cholangiocarcinoma.

[A case of advanced gastric cancer with lymphangitis carcinomatosa after operation of Krukenberg tumor treated by TS-1 plus CPT-11 as third-line chemotherapy].

Chemotherapies for recurrent gastric cancer have not yet been established. Here we report a case of type 4 gastric cancer associated with lymphangitis carcinomatosis which became refractory to the previous chemotherapies. The case was a 40-year-old woman. She had been diagnosed with gastric cancer after a Krukenberg tumor operation. Chemotherapies (TS-1 plus CDDP as first-line, and TS-1 plus taxanes as second-line) were performed, and a partial response was achieved. Disease activity has been well controlled until this time. Since recurrence of left pleural effusion and lymphangitis carcinomatosis was recognized, we changed the chemotherapy TS-1 plus CPT-11. Pleural effusion decreased and lymphangitis carcinomatosis improved. The serum CA 19-9 level rose transiently after CPT-11 administration, and tended to fall at the second week of chemotherapy. However, the patient died 2 years 4 months after the onset. TS-1 plus CPT-11 combination chemotherapy would be effective for lymphangitis carcinomatosis and also useful as third-line chemotherapy for recurrent gastric cancer.