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.

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.

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.

Microscopic colitis with granuloma which responded to steroid therapy.

We present a patient with chronic watery diarrhea and weight loss, in whom colonoscopic findings were consistent with microscopic colitis, but histopathological examination revealed granulomatous inflammation. A 67-year-old Japanese female with a several year history of chronic watery diarrhea and body weight loss was admitted to our hospital. Her laboratory data showed hypoalbuminemia and high levels of serum immunoglobulin G and C-reactive protein. Colonoscopic findings were grossly normal. Histopathology showed inflammatory cell infiltrates with non-necrotizing granulomas and multinucleated giant cells, indicating that this was not conventional microscopic colitis, lymphocytic colitis or collagenous colitis. After treatment with prednisolone her symptoms and laboratory data improved dramatically, and she went into remission without the necessity of further steroid treatment.

[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.

[Probiotics for inflammatory bowel disease].

Probiotics are defined as live microorganisms that may beneficially affect the host by improving the balance of the intestinal micro flora. In spontaneous animal models of inflammatory bowel disease (IBD), the influence of the enteric flora on gut inflammatory activity has been demonstrated, as germ free animals do not develop disease. Modification of the activity of the intestinal flora using probiotics has been investigated as a way of controlling IBD. However, there is still considerable work to be done before probiotics can be considered as part of the standard treatment of IBD. Probiotic cocktails should be carefully studied and the individual bacterial constituents evaluated in clinical settings. Several studies are currently underway to assess these issues. Further study of placebo controlled trial testing therapeutic role of probiotic bacteria in human trials is warranted.

Sensorimotor polyneuropathy as an initial clinical manifestation of sarcoidosis.

A 45 year-old Japanese woman developed numbness and tingling of both hands and feet. Electrophysiological examination revealed sensorimotor polyneuropathy. She was diagnosed as suffering from sarcoidosis on the basis of the pathological findings from dermal biopsy. Steroid therapy effectively improved the clinical symptoms. Although sarcoid neuropathy is rare, this case suggests sensorimotor polyneuropathy is an important symptom of sarcoidosis and can represent the initial clinical manifestation of the disease.