Yih-Huei Uen

Bio: Yih-Huei Uen is an academic researcher from National Taiwan University. The author has contributed to research in topics: Circulating tumor cell & Cancer. The author has an hindex of 13, co-authored 23 publications receiving 679 citations. Previous affiliations of Yih-Huei Uen include Taipei Medical University & Kaohsiung Medical University.

Prognostic significance of multiple molecular markers for patients with stage II colorectal cancer undergoing curative resection.

Abstract: Objective: The aim of this study was to determine whether our constructed high-sensitivity colorimetric membrane-array method could detect circulating tumor cells (CTCs) in the peripheral blood of stage II colorectal cancer (CRC) patients and so identify a subgroup of patients who are at high risk for relapse. Summary Background Data: Adjuvant chemotherapy is not routinely recommended in patients diagnosed with UICC stage II CRC. However, up to 30% of patients with stage II disease relapse within 5 years of surgery from recurrent or metastatic disease. The identification of reliable prognostic factors for high-risk stage II CRC patients is imperative. Methods: Membrane-arrays consisting of a panel of mRNA markers that included human telomerase reverse transcription (hTERT), cytokeratin-19 (CK-19), cytokeratin-20 (CK-20), and carcinoembryonic antigen (CEA) mRNA were used to detect CTCs in the peripheral blood of 194 stage II CRC patients who underwent potentially curative (R0) resection between January 2002 and December 2005. Digoxigenin (DIG)-labeled cDNA were amplified by RT-PCR from the peripheral blood samples, which were then hybridized to the membrane-array. All patients were followed up regularly, and their outcomes were investigated completely. Results: Overall, 53 of 194 (27.3%) stage II patients were detected with the expression of all 4 mRNA markers using the membranearray method. After a median follow up of 40 months, 56 of 194 (28.9%) developed recurrence/metastases postoperatively. Univariately, postoperative relapse was significantly correlated with the depth of invasion (P 0.001), the presence of vascular invasion (P 0.001), the presence of perineural invasion (P 0.048), the expression of all 4 mRNA markers (P 0.001), and the number of examined lymph nodes (P 0.031). Meanwhile, using a multivariate logistic regression analysis, T4 depth of tumor invasion (P 0.013), the presence of vascular invasion (P 0.032), and the expression of all 4 mRNA markers (P 0.001) were demonstrated to be independent predictors for postoperative relapse. Combination of the depth of tumor invasion, vascular invasion, and all 4 mRNA markers as predictors of postoperative relapse showed that patients with any 1 positive predictor had a hazard ratio of about 27-fold to develop postoperative relapse (P 0.001; 95% CI 11.42‐64.40). The interval between the detection of all 4 positive molecular markers and subsequently developed postoperative relapse ranged from 4 to 10 months (median: 7 months). Furthermore, the expression of all 4 mRNA markers in all stage II CRC patients, or either stage II colon or rectal cancer patients were strongly correlated with poorer relapse-free survival rates by survival analyses (all P 0.001). Conclusions: The pilot study suggests that the constructed membrane-array method for the detection of CTCs is a potential auxiliary tool to conventional clinicopathological variables for the prediction of postoperative relapse in stage II CRC patients who have undergone curative resection.

Persistent presence of postoperative circulating tumor cells is a poor prognostic factor for patients with stage I-III colorectal cancer after curative resection.

Abstract: Aim To detect pre- and postoperative circulating tumor cells (CTCs) in stage I–III colorectal cancer (CRC) patients undergoing curative resection and so identify a subgroup of patients who are at high risk for relapse.

Activating KRAS Mutations and Overexpression of Epidermal Growth Factor Receptor as Independent Predictors in Metastatic Colorectal Cancer Patients Treated With Cetuximab

Abstract: 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.

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

Abstract: 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 re- verse 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.

Circulating tumor cells as a surrogate marker for determining clinical outcome to mFOLFOX chemotherapy in patients with stage III colon cancer

Abstract: This study was aimed to detect post-chemotherapeutic circulating tumour cells (CTCs) in stage III colon cancer patients and identify those who were at high risk of relapse. We used human telomerase reverse transcriptase, cytokeratin-19, cytokeratin-20, and carcinoembryonic antigen (CEA) as the biomarkers to detect CTCs in 90 stage III colon cancer patients undergoing curative resection followed by mFOLFOX chemotherapy. Post-chemotherapeutic relapse occurred in 30 (33.3%) patients. By univariate analysis and multivariate proportional hazards regression analysis, perineural invasion (hazard ratio (HR): 2.752; 95% confidence interval (CI): 1.026–7.381), high post-chemotherapeutic serum CEA levels (HR: 2.895; 95% CI: 1.143–7.333) and persistent presence of post-chemotherapeutic CTCs (HR: 6.273; 95% CI: 2.442–16.117) were independent predictors of post-chemotherapeutic relapse. In addition, the persistent presence of post-chemotherapeutic CTCs strongly correlated with reduced disease-free survival and overall survival. Accuracy of detecting relapse in post-chemotherapeutic stage III colon cancer patients by analysing the persistent presence of post-chemotherapeutic CTCs was higher than that by post-chemotherapeutic CEA levels (odds ratio: 50.091 vs 5.211). The persistent presence of post-chemotherapeutic CTCs is a potential powerful surrogate marker for determining clinical outcome in stage III colon cancer patients receiving adjuvant mFOLFOX chemotherapy.

Clinical practice guidelines in oncology

Abstract: Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Abstract: Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

Detection, clinical relevance and specific biological properties of disseminating tumour cells

Abstract: Most cancer deaths are caused by haematogenous metastatic spread and subsequent growth of tumour cells at distant organs. Disseminating tumour cells present in the peripheral blood and bone marrow can now be detected and characterized at the single-cell level. These cells are highly relevant to the study of the biology of early metastatic spread and provide a diagnostic source in patients with overt metastases. Here we review the evidence that disseminating tumour cells have a variety of uses for understanding tumour biology and improving cancer treatment.

Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

Abstract: Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53), and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects.

Long-term patient survival in ANCA-associated vasculitis

Abstract: Background Wegener9s granulomatosis and microscopic polyangiitis are antineutrophil cytoplasm antibodies (ANCA)-associated vasculitides with significant morbidity and mortality. The long-term survival of patients with ANCA associated vasculitis treated with current regimens is uncertain. Objective To describe the long-term patient survival and possible prognostic factors at presentation in an international, multicentre, prospectively recruited representative patient cohort who were treated according to strictly defined protocols at presentation and included the full spectrum of ANCA-associated vasculitis disease. Methods Outcome data were collected for 535 patients who had been recruited at the time of diagnosis to four randomised controlled trials between 1995 and 2002. Trial eligibility was defined by disease severity and extent, covered the spectrum of severity of ANCA-associated vasculitis and used consistent diagnostic criteria. Demographic, clinical and laboratory parameters at trial entry were tested as potential prognostic factors in multivariable models. Results The median duration of follow-up was 5.2 years and 133 (25%) deaths were recorded. Compared with an age- and sex-matched general population there was a mortality ratio of 2.6 (95% CI 2.2 to 3.1). Main causes of death within the first year were infection (48%) and active vasculitis (19%). After the first year the major causes of death were cardiovascular disease (26%), malignancy (22%) and infection (20%). Multivariable analysis showed an estimated glomerular filtration rate Conclusion Patients with ANCA-associated vasculitis treated with conventional regimens are at increased risk of death compared with an age- and sex-matched population.