Fang-Jung Yu

Multiple Molecular Markers as Predictors of Colorectal Cancer in Patients with Normal Perioperative Serum Carcinoembryonic Antigen Levels

Purpose: In this study, a high-sensitivity colorimetric membrane array method was used to detect circulating tumor cells (CTC) in the peripheral blood of colorectal cancer (CRC) patients with normal perioperative serum carcinoembryonic antigen (CEA) levels. This membrane array method was evaluated as a potential diagnostic and postoperative surveillance tool. Study Design: Membrane arrays consisting of a panel of mRNA markers that include human telomerase reverse transcriptase, cytokeratin-19, cytokeratin-20, and CEA mRNA were used to detect CTCs in the peripheral blood of 157 postoperative CRC patients with normal perioperative serum CEA levels and in 80 healthy individuals. Digoxigenin-labeled cDNA were amplified by reverse transcription-PCR from the peripheral blood samples, which were then hybridized to the membrane array. The sensitivity, specificity, and accuracy of membrane arrays for the detection of CTCs were then calculated. Results: Using the four markers in combination, expression of any three markers or all the four markers in this panel was significantly correlated with the clinicopathologic characteristics, including depth of tumor invasion, lymph node metastasis, tumor-node-metastasis stage, and postoperative relapse (all P < 0.05). The interval between the detection of all four positive molecular markers and subsequent elevated CEA ranged from 3 to 8 months (median 6 months). The expression of all four mRNA markers was an independent predictor for postoperative relapse. CRC patients with all four mRNA markers expression showed a significantly poorer survival rate than those with less than four positive markers. Conclusions: The constructed membrane array method was helpful in the early prediction of postoperative relapse in CRC patients with normal perioperative serum CEA levels.

Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors in metastatic colorectal cancer patients treated with cetuximab.

Objective:Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), has been proven to be efficient in metastatic colorectal cancer (mCRC); however, the therapeutic response is variable and markers predictive of response are urgently required. This study was conducted to determinate the predictive values of KRAS mutation status and EGFR expression in mCRC patients treated with cetuximab plus chemotherapy. Summary Background Data:Clinical benefit with EGFR-targeting antibodies seems to be restricted to a particular subgroup of mCRC patients. Therefore, the identification of reliable predictive factors for mCRC patients is imperative before the introduction of targeted chemotherapy. Methods:Ninety-five mCRC patients receiving cetuximab plus the FOLFIRI or FOLFOX-4 chemotherapy were enrolled into the present study. KRAS mutation status/EGFR expression levels were analyzed using direct sequencing, immunohistochemistry (IHC), and reverse transcription-polymerase chain reaction (RT-PCR) assay, respectively. The association between clinical response, progression-free survival (PFS) and overall survival (OS) as well as KRAS mutation status/EGFR expression levels were evaluated. Results:Of 95 mCRC patients, KRAS mutations were identified in 41 cases, and EGFR overexpression (protein or mRNA levels) were observed in 78 patients. Among 41 tumors with KRAS mutation, 33 were found to be activating mutants at codons 12, 13, 15 or 18, while 8 were nonactivating mutants at codons 20, 30, or 31. Fifty-five patients responded to cetuximab plus chemotherapy, 49 were EGFR overexpression and 46 were wild-type KRAS tumor status. Patients with tumors that express high EGFR levels or harbor wild-type KRAS are more likely to have a better PFS and OS when treated with cetuximab plus chemotherapy (all P < 0.05). Furthermore, patients with nonactivating KRAS mutants in tumors had a significantly better PFS and OS than patients with activating KRAS mutants (both P < 0.05). However, for patients with wild-type KRAS tumor status, EGFR expression remains a relevant predictor of clinical response. Conclusions:The study suggests that activating KRAS mutants is a particularly important independent predictive marker in mCRC patients treated with cetuximab plus chemotherapy, of which combing activating KRAS mutants and EGFR could help to identify the subgroup of patients who are most likely to respond to cetuximab plus chemotherapy.

Quadruple rescue therapy for Helicobacter pylori infection after two treatment failures.

Background A standard third‐line therapy for Helicobacter pylori infection is lacking, and antimicrobial sensitivity data for patients who failed eradication therapy are often unavailable in clinical practice. We therefore designed the prospective study to assess the efficacy of levofloxacin, amoxicillin, bismuth and rabeprazole quadruple therapy as a third‐line treatment for H. pylori infection.

Rabeprazole- versus Esomeprazole-Based Eradication Regimens for H. pylori Infection

Background:  Different kinds of proton pump inhibitor‐based triple therapies could result in different Helicobacter pylori eradication rates.

CYP2C19 polymorphism influences Helicobacter pylori eradication

The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.

Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients

The current study was to investigate the interaction between Helicobacter pylori and human dendritic cells (DCs). Whether impaired DC function can influence the outcome of H. pylori infections. Human monocyte-derived DCs (MDDCs) from five gastric cancer patients and nine healthy controls were stimulated with H. pylori. Maturation markers of MDDC were examined by flow cytometry. IL-10 and TNF-α released by MDDCs and IL-17 produced by T cells were measured by ELISA. Regulatory signaling pathways of IL-10 were examined by ELISA, western blotting, and chromatin immunoprecipitation assay. The results showed that as compared with healthy individuals, the maturation marker CD40 in MDDCs, IL-17A expression from T cells, and IL-10 expression from MDDCs were significantly lower in gastric cancer patients. Blocking DC-SIGN, TLR2, and TLR4 could reverse H. pylori-associated IL-10 production. Activation of the p38 MAPK and NF-kB signaling pathways concomitant with decreased tri-methylated H3K9 and increased acetylated H3 accounted for the effect of H. pylori on IL-10 expression. Furthermore, upregulated IL-10 expression was significantly suppressed in H. pylori-pulsed MDDCs by histone acetyltransferase and methyltransferase inhibitors. Taken together, impaired DC function contributes to the less effective innate and adaptive immune responses against H. pylori seen in gastric cancer patients. H. pylori can regulate IL-10 production through Toll-like and DC-SIGN receptors, activates p-p38 MAPK signaling and the transcription factors NF-kB, and modulates histone modification.

Differentiation between Malignant and Benign Gastric Ulcers: CT Virtual Gastroscopy versus Optical Gastroendoscopy

PURPOSE To retrospectively compare computed tomographic virtual gastroscopy (VG) and conventional optical gastroendoscopy for the differentiation of malignant and benign gastric ulcers. MATERIALS AND METHODS The institutional review board approved this study and confirmed that informed consent was not required. Gastric ulcers in 115 patients (mean age, 64.7 years; range, 31-86 years; 61 men, 54 women) were evaluated by using endoscopy and VG. Ulcer shape, base, and margin and periulcer folds were evaluated by two independent reviewers. Malignant gastric ulcers were identified by irregular, angulated, or geographic shape; uneven base; irregular or asymmetric edges; and disrupted or moth-eaten appearance of periulcer folds near the crater edge and/or clubbed or fused folds. Benign gastric ulcers were identified by smooth and regular shapes, even bases, clearly demarcated and regular edges, and folds that tapered and converged toward the ulcer. The performance of VG and endoscopy for the diagnosis of benign and malignant gastric ulcers was evaluated by using histopathologic results as the reference standard. The McNemar test was used to compare VG and endoscopic data. A P value less than .05 was considered to indicate a significant difference. RESULTS At histopathologic examination, 39 gastric ulcers were benign, while 76 were malignant. VG and endoscopy had sensitivities of 92.1% (70 of 76) and 88.2% (67 of 76), respectively, for overall diagnosis of malignant gastric ulcers, and specificities of 91.9% (34 of 37) and 89.5% (34 of 38), respectively, for overall diagnosis of malignant gastric ulcers. Endoscopy was more sensitive in depicting malignancy according to ulcer base (85.5% [65 of 76] vs 68.4% [52 of 76]) (P = .034), and VG was more specific in depicting malignancy according to ulcer margin (78.4% [29 of 37] vs 63.2% [24 of 38]) (P = .034). CONCLUSION VG and endoscopy were almost equally useful in distinguishing between malignant and benign gastric ulcers. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/2522081249/DC1.

Chemokine (C-C Motif) Ligand 5 is Involved in Tumor-Associated Dendritic Cell-Mediated Colon Cancer Progression Through Non-Coding RNA MALAT-1.

Tumor micro‐environment is a critical factor in the development of cancer. The aim of this study was to investigate the inflammatory cytokines secreted by tumor‐associated dendritic cells (TADCs) that contribute to enhanced migration, invasion, and epithelial‐to‐mesenchymal transition (EMT) in colon cancer. The administration of recombinant human chemokine (C‐C motif) ligand 5 (CCL5), which is largely expressed by colon cancer surrounding TADCs, mimicked the stimulation of TADC‐conditioned medium on migration, invasion, and EMT in colon cancer cells. Blocking CCL5 by neutralizing antibodies or siRNA transfection diminished the promotion of cancer progression by TADCs. Tumor‐infiltrating CD11c+ DCs in human colon cancer specimens were shown to produce CCL5. The stimulation of colon cancer progression by TADC‐derived CCL5 was associated with the up‐regulation of non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT‐1), which subsequently increased the expression of Snail. Blocking MALAT‐1 significantly decreased the TADC‐conditioned medium and CCL5‐mediated migration and invasion by decreasing the enhancement of Snail, suggesting that the MALAT‐1/Snail pathway plays a critical role in TADC‐mediated cancer progression. In conclusion, the inhibition of CCL5 or CCL5‐related signaling may be an attractive therapeutic target in colon cancer patients. J. Cell. Physiol. 230: 1883–1894, 2015.

Eradication of Helicobacter pylori Is Associated with the Progression of Dementia: A Population-Based Study.

Objective. To evaluate the effect of eradication of Helicobacter pylori (H. pylori) on the progression of dementia in Alzheimers disease (AD) patients with peptic ulcer. Methods. Participants with the diagnosis of AD and peptic ulcer were recruited between 2001 and 2008. We examined the association between eradication of H. pylori and the progression of AD using the multiple regression models. Medication shift from Donepezil, Rivastgmine, and Galantamine to Mematine is defined as progression of dementia according to the insurance of National Health Insurance (NHI) under expert review. Results. Among the 30142 AD patients with peptic ulcers, the ratio of medication shift in AD patients with peptic ulcers is 79.95%. There were significant lower incidence comorbidities (diabetes mellitus, hypertension, cerebrovascular disease, coronary artery disease, congestive heart failure and hyperlipidemia) in patients with H. pylori eradication as compared with no H. pylori eradication. Eradication of H. pylori was associated with a decreased risk of AD progression (odds ratio [OR] 0.35 [0.23–0.52]) as compared with no H. pylori eradication, which was not modified by comorbidities. Conclusions. Eradication of H. pylori was associated with a decreased progression of dementia as compared to no eradication of H. pylori in AD patients with peptic ulcers.

Occult Colon Cancer in a Patient with Diabetes and Recurrent Klebsiella Pneumoniae Liver Abscess

Klebsiella pneumoniae (Kp) is a well‐known leading cause of liver abscess in patients with diabetes, but recurrent Kp liver abscess in such patients within a period of time is seldom seen. Here, we report a patient with diabetes who experienced three episodes of Kp liver abscess within 1 year. The patient was subsequently diagnosed to have an occult sigmoid cancer. The liver abscess did not recur after resection of the colonic tumor. Occult sigmoid colonic cancer may have played an important role in the recurrent Kp liver abscess in our case. Therefore, further investigation of gastrointestinal malignancies, particularly of the colonic tract, is necessary in patients with diabetes and Kp liver abscess.