Comparing the Efficacy and Safety of Gemcitabine plus Nab-Paclitaxel versus Gemcitabine Alone in Older Adults with Unresectable Pancreatic Cancer.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. PATIENTS AND METHODS: In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. RESULTS: GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. CONCLUSION: GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.

Effects of Encircled Abdominal Compression Device in Colonoscopy: A Meta-Analysis.

: Background and Aim: The efficacy of encircling abdominal compression devices in colonoscopies is inconsistent. We performed a meta-analysis of randomized controlled trials (RCTs) in which encircling abdominal compression devices were compared with control in colonoscopies. METHODS: We systematically searched RCTs published in the Cochrane Library, PubMed, and the Igaku-Chuo-Zasshi database. The data from the eligible RCTs were combined using the random-effects model. The weighted mean differences (WMDs), pooled odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. RESULTS: Five RCTs were included in this meta-analysis. Compared to the control group, encircling abdominal compression devices significantly reduced the caecal intubation time (WMD: -1.31, 95% CI: -2.40 to -0.23, p = 0.02). Compared to the control group, encircling abdominal compression devices significantly decreased the frequency of postural change (OR 0.30, 95% CI: 0.22 to 0.41, p < 0.00001). Compared to the control group, the use of encircling abdominal compression devices significantly reduced the need for abdominal compression (OR: 0.35, 95% CI: 0.17 to 0.70, p = 0.003). CONCLUSIONS: Encircling abdominal compression devices in colonoscopies was found to reduce the caecal intubation time and the frequency of abdominal compression.

Complete remission of peritoneal dissemination of colon cancer by alternate-day S-1 and oxaliplatin plus bevacizumab treatment and maintenance chemotherapy comprising alternate-day S-1 plus bevacizumab: A case report.

A 56-year-old man diagnosed with sigmoid colon cancer underwent sigmoid colectomy. Nine months later, his serum carcinoembryonic antigen (CEA) level had increased, and the diagnosis of recurrent peritoneal dissemination was made based on positron emission tomography/computed tomography (PET/CT) findings. Although systemic chemotherapy comprising S-1 and oxaliplatin (SOX) plus bevacizumab was initiated, severe diarrhea occurred on day 4 of the second cycle despite reduction in S-1 dose. By changing the daily oral intake schedule for S-1 to an alternate-day intake from the third cycle (modified SOX plus bevacizumab), the patient was able to continue undergoing chemotherapy without any adverse gastrointestinal effects. All tumors disappeared after four cycles, and the patients received eight cycles of modified SOX plus bevacizumab followed by maintenance chemotherapy comprising alternate-day S-1 plus bevacizumab. Maintenance chemotherapy was discontinued after 17 cycles owing to adverse events, including thrombocytopenia, corneal and lacrimal duct disorders, and hyperbilirubinemia. The patient has been radiographically confirmed to be in remission for 5 years without any recurrence, and his serum CEA level has been within normal range for >3 years. To conclude, compared with the conventional consecutive treatment, alternate-day SOX plus bevacizumab treatment may reduce the adverse effects of these chemotherapeutic drugs.

Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.

In the present study, the immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination combined with docetaxel (DCDOC) in advanced esophageal cancer patients who had already received first-line chemotherapy was investigated. Ten HLA-A*2402 patients were treated with docetaxel (50 mg/m2) on day 1 and WT1 peptide-pulsed DC vaccination (1×107 cells) on days 15 and 22 (repeated every 4 weeks for 3 cycles). The delayed-type hypersensitivity skin test, HLA tetramer assay and interferon-γ enzyme-linked immunospot (ELISPOT) assay were used to evaluate the induction of a WT1-specific immune response. Median overall survival was 5 months (range, 1.1-11.6). The clinical effect of DCDOC therapy was not observed and only 1 patient could complete the protocol therapy. Disease progression was observed in 9 patients and 1 patient succumbed to fatality during the second cycle of therapy. As a pilot study, it was not possible to evaluate the safety of WT1 peptide-pulsed DCDOC therapy for esophageal squamous cell cancer. However, a WT1-specific response in 6 patients, as indicated by the ELISPOT or HLA/WT1-tetramer assay, was demonstrated. The results suggested that the positive immune response had significant relevance on the low percentage of CD11b+ and CD66b+ granulocytic myeloid-derived suppressor cells in CD15+ cells. Furthermore, DCDOC elicited a WT1-specific immune response regardless of the myelosuppression associated with docetaxel. The present findings support future studies and further work to assess DCDOC as an adjuvant therapy for esophageal cancer will be performed. The present clinical trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry on November 11th, 2011, no. UMIN000006704.

Clinical significance of human intestinal spirochetosis: a retrospective study.

The clinical and pathological features of human intestinal spirochetosis (HIS) are not well known. Here we report 55 patients with HIS who were diagnosed at our institution during the past 5 years. Seven patients presented with symptoms such as abdominal pain or diarrhea, while the others were incidentally diagnosed during screening colonoscopy. Most patients had non-specific endoscopic findings, including intestinal edema or erosion. The diagnosis of HIS was histologically confirmed via hematoxylin and eosin staining, periodic acid-Schiff staining, and/or immunohistochemistry using anti-Treponema pallidum antibody. Among the 55 patients, five were diagnosed with diseases other than HIS (amoebic colitis, three;ulcerative colitis, one). Sixteen patients were treated with either amoxicillin or metronidazole;only metronidazole proved to be effective. The clinical significance of asymptomatic HIS remains unknown. Some case reports suggest a risk for increased severity in patients with immunodeficiency and/or sexually transmitted diseases. Therefore, aggressive treatment for HIS should be considered, particularly in high-risk patients.

[Hepatocyte nuclear factor 1α-inactivated hepatocellular adenomatosis in a patient with maturity-onset diabetes of the young type 3: case report and literature review].

A 19-year-old Japanese woman had been diagnosed with diabetes at the age of 9 years. She had a strong family history of diabetes, and genetic screening showed she had maturity-onset diabetes of the young type 3 (MODY3). Ultrasonography of the liver and magnetic resonance imaging showed multiple nodules consistent with hepatocellular adenoma (HA). Biopsy of the liver tumors revealed hepatocyte nuclear factor (HNF) 1α-inactivated HA. HA is known as a MODY3-related disease due to mutations in HNF1α. We present the first report of HA associated with MODY3 in Japan.

Endoscopic snare papillectomy for a solitary Peutz-Jeghers-type polyp in the duodenum with ingrowth into the common bile duct: Case report.

Solitary duodenal Peutz-Jeghers (PJ)-type hamartomatous polyps are rare and considered a different disease entity than classic PJ syndrome. We describe the case of an 89-year-old man admitted to our emergency department with symptoms of acute cholangitis, liver dysfunction, and slight jaundice. Magnetic resonance imaging showed multiple signal voids, reflecting choledocholithiasis, and an oval-shaped tumor in the common bile duct (CBD). Following endoscopic retrograde cholangiopancreatography, the patient was diagnosed with a lower CBD tumor 20 mm in diameter. Endoscopic sphincterotomy was performed for choledocholithotomy, resulting in the expulsion of a large tumor with a stalk connected to the papilla of Vater. The tumor was successfully excised en bloc by endoscopic snare papillectomy. Histopathologic examination showed that the tumor was a PJ-type hamartomatous polyp. No mucocutaneous pigmentation of the skin was evident and the patient's family history was negative. Solitary duodenal PJ-type hamartomatous polyps are usually diagnosed incidentally during endoscopy for other indications because most of these tumors are asymptomatic or have nonspecific presentations. To our knowledge, this is the first reported solitary PJ-type polyp with intra-CBD growth treated by endoscopic snare papillectomy.

Ampullary Adenoma Treated by Endoscopic Double-Snare Retracting Papillectomy.

We report herein improved methods for the safe and successful completion of endoscopic papillectomy (EP). Between January 2008 and November 2011, 12 patients underwent double-snare retracting papillectomy for the treatment of lesions of the major duodenal papilla. The main outcomes were en bloc resection rates, pathological findings, and adverse events. All of the patients (mean age, 60.1 years; range, 38 to 80 years) were diagnosed with ampullary adenoma by endoscopic forceps biopsies prior to endoscopic snare papillectomy. En bloc resection by double-snare retracting papillectomy was successfully performed for all lesions (median size, 12.3 mm), comprising six tubular adenomas, one tubulovillous adenoma, three cases of epithelial atypia, one hamartomatous polyp, and one case of duodenitis with regenerative change. Significant hemorrhage and pancreatitis were observed in one case after EP. Adenoma recurrence occurred in three patients during follow-up (median, 28.5 months) at a mean interval of 2 months postoperatively (range, 1 to 3 months). No serious adverse events were observed. Double-snare retracting papillectomy is effective and feasible for treating lesions of the major duodenal papilla. Further treatment experience, including a single-arm phase II study, needs to be accumulated before conducting a randomized controlled study.

Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.

This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).

TGF-ß1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression.

In cancer patients, sentinel lymph nodes (SLNs) are crucial in the induction of antitumor T cells. However, in many cases, SLNs and tumors appear to be in immunosuppressive condition through mechanisms yet to be elucidated. In this study, the role of tumor-derived TGF-ß1 in the generation of immunosuppressive microenvironments of tumors and SLNs was investigated. Murine colorectal carcinoma CT26 transduced with TGF-ß1 cDNA (CT26-TGF-ß1) showed enhanced tumor growth compared with mock-transduced CT26 (CT26-Mock) when implanted in syngeneic Balb/c mice, even though CT26-TGF-ß1 shows slower growth in vitro. This enhanced growth was not observed when implanted in immunodeficient mice, suggesting that TGF-ß1 enhanced tumor growth by suppressing antitumor T-cell responses. Analysis of immune cells in CT26-TGF-ß1-implanted mice revealed impairment of dendritic cells (DCs), decrease of CD8 T cells, and increase of MDSCs and Tregs in the tumors. Similarly, the SLNs of these mice showed an increase of MDSCs, Tregs, and PD-L1 DCs, and decrease of T-cell stimulatory activity of DCs accompanied by decreased CD80 expression and TNF-α production. In addition, induction of tumor antigen-specific T cells from SLNs of the CT26-TGF-ß1-implanted mice was significantly reduced. These results demonstrate that overproduction of TGF-ß1 is critical for the generation of immunosuppressive microenvironments in both tumors and SLNs, which may result in suppression of spontaneous antitumor CD8 T-cell responses. Therefore, TGF-ß1 is an attractive target for restoration of immunosuppressive condition in cancer patients.

CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion.

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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.

Mesenchymal stem cells regulate epithelial-mesenchymal transition and tumor progression of pancreatic cancer cells.

Cancer-associated fibroblasts contribute to cancer progression that is caused by epithelial-mesenchymal transition (EMT). Recently, mesenchymal stem cells (MSCs) were found to be the major candidate involved in the development of tumor-promoting cancer stroma. Here we report that α-smooth muscle actin-positive myofibroblast-like cells originating from MSCs contribute to inducing EMT in side population cells of pancreatic cancer. More importantly, MSC-derived myofibroblasts function to maintain tumor-initiating stem cell-like characteristics, including augmenting expression levels of various stemness-associated genes, enhancing sphere- forming activity, promoting tumor formation in a mouse xenograft model, and showing resistance to anticancer drugs. Furthermore, both γ-secretase inhibitor and siRNA directed against Jagged-1 attenuated MSC-associated E-cadherin suppression and sphere formation in pancreatic cancer side population cells. Thus, our results suggest that MSC-derived myofibroblasts play important roles in regulating EMT and tumor-initiating stem cell-like properties of pancreatic cancer cells through an intermediating Notch signal.

Activated hepatic stellate cells mediate the differentiation of macrophages.

AIM: Liver macrophages play integral roles in both the progression and resolution of hepatic inflammation and fibrosis, comprising opposing functions that largely coincide with the activation state of nearby hepatic stellate cells (HSC). While cross-talk between HSC and macrophages may be essential at various stages of inflammation and fibrogenesis, many facets of this interaction have yet to be thoroughly explored. Here, we examine the potential roles of HSC-derived signaling molecules as mediators of liver macrophage differentiation. METHODS: Human peripheral blood mononuclear cells (PBMC) were differentiated to macrophages in the presence or absence of cultured HSC-derived conditioned media. The phenotype of resulting macrophages was characterized by examination of cell surface marker expression, antigen-presenting capabilities and cytokine secretion. RESULTS: Conditioned media from activated human HSC promoted the differentiation of a unique set of macrophages that differed in morphology and function from both classical (M1) and alternative (M2) macrophages, expressing increased levels of CD14 and CD16, as well as a distinct interleukin (IL)-6(high) /IL-10(low) /transforming growth factor (TGF)-ß(high) expression profile. These macrophages expressed high levels of CD206, CD209, CD80 and human leukocyte antigen DR, though no significant increases in antigen presentation were apparent. HSC-derived macrophages exhibited specific activation of p38 mitogen-activated protein kinase, and inhibition of this activation by p38 inhibitors during differentiation effectively reversed increases in IL-6 and TGF-ß. CONCLUSION: The present results suggest that HSC-derived signaling molecules promote differentiation of liver macrophages with both pro-inflammatory and profibrotic functions. Furthermore, these effects appear to be mediated, at least partially, in a p38-dependent manner.

Biliary findings assist in predicting enlargement of intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND & AIMS: There is controversy over the optimal management strategy for patients with branch-duct type intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs), precursors to pancreatic cancer. We aimed to identify factors associated with the presence of BD-IPMNs and changes in their diameter. METHODS: Two separate analyses were conducted in a cohort of patients who underwent magnetic resonance cholangiopancreatography (MRCP) in a single year (2006). MRCP findings and clinical outcomes of these patients were followed for a maximum of 6 years. We evaluated initial MRCP findings and demographics associated with the presence of BD-IPMNs at baseline and increase in BD-IPMN diameter over time. RESULTS: During the follow-up period, 154 patients developed BD-IPMN and 322 patients did not. Older age, diabetes mellitus, gallbladder adenomyomatosis, and absence of gallstones were associated with the presence of BD-IPMNs at baseline. Increases in diameter of BD-IPMNs were associated with 3 baseline factors: BD-IPMN diameter greater than 17 mm, gallbladder adenomyomatosis, and a common bile duct diameter less than 5.5 mm. Patients with BD-IPMNs could be stratified into 4 groups with varying risk for the enlargement of BD-IPMNs over time: those with 3 risk factors (hazard ratio [HR], 11.4; 95% confidence interval [CI], 3.4-37.8), 2 risk factors (HR, 4.7; 95% CI, 1.7-12.8), or 1 risk factor (HR, 3.1; 95% CI, 1.2-8.2) compared with those without risk factors. CONCLUSIONS: For patients with BD-IPMNs, careful follow-up evaluation is particularly important for those with BD-IPMN >17 mm in size, common bile duct diameter <5.5 mm, or gallbladder adenomyomatosis.

Second-line chemotherapy for refractory small cell neuroendocrine carcinoma of the esophagus that relapsed after complete remission with irinotecan plus cisplatin therapy: Case report and review of the literature.

Small cell esophageal carcinoma is a type of small cell neuroendocrine carcinoma (SCNEC). SCNEC follows an aggressive clinical course and has a poor prognosis despite multidisciplinary therapies. A standard therapeutic strategy, including surgery, radiation and first-/second-line chemotherapy, has not yet been established for SCNEC. We present a case of SCNEC of the esophagus. A 66-year-old male with SCNEC as extensive disease was treated with 60 mg/m(2) cisplatin on day 1 plus 60 mg/m(2) irinotecan on days 1, 8 and 15 every 4 weeks (IP) with successful complete remission. After the sixth course of IP, increasing pro-gastrin-releasing peptide (ProGRP) and nonspecific enolase (NSE) levels and intense fluorodeoxyglucose (FDG) avidity in a lymph node around the celiac artery (SUV(max), 8.3) indicated a refractory relapse of the disease. The patient was treated with three courses of amrubicin (AMR, 35 mg/m(2)) administered intravenously for 3 consecutive days every 3 weeks as a second-line chemotherapy. The ProGRP and NSE levels returned to the normal range 1 month after the initiation of second-line chemotherapy. However, the ProGRP and NSE levels were elevated after the third course of AMR, and PET-CT revealed progressive disease with liver metastasis and extended lymph node metastasis. As the patient remained asymptomatic, paclitaxel (100 mg/m(2)) was started as third-line chemotherapy. Patients with SCNEC of the esophagus with extensive disease should be treated with aggressive chemotherapy rather than surgery or radiation monotherapy. In the present case, tumor markers such as ProGRP and NSE were predictive of relapse and PET-CT was used to detect relapse. Further research is required to identify and exploit promising agents for resistant SCNEC.

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.

5-aminosalicylic acid mediates expression of cyclooxygenase-2 and 15-hydroxyprostaglandin dehydrogenase to suppress colorectal tumorigenesis.

BACKGROUND: Cyclooxygenase-2 (COX-2) is a key enzyme that produces prostaglandin E2 (PGE2) and plays an important role in colorectal tumor growth. In addition, recent researches focused on 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades PGE2. Here we determined the effect of 5-aminosalicylic acid (5-ASA) on COX-2 and 15-PGDH expression and investigated its preventive effect for colorectal cancer (CRC). MATERIALS AND METHODS: HT-29 cells were used in the in vitro experiments. c-Ha-ras transgenic mice were employed in order to explore the chemopreventive effects. Western blotting analysis was performed and the protein expression of COX-2 and 15-PGDH was quantified. RESULTS: 5-ASA significantly suppressed COX-2 expression and induced 15-PGDH expression in HT-29 cells. In the transgenic mice, oral 5-ASA intake reduced the incidence of colorectal tumor formation and the tumor size. Furthermore, we observed a down-regulation of COX-2 and an up-regulation of 15-PGDH in the tissue from colons of these mice. CONCLUSION: 5-ASA exerts a preventive effect against colorectal tumor development through mediation of COX-2 and 15-PGDH expression.