Pen-Yuan Chu

MicroRNA-200c attenuates tumour growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells†

MicroRNA‐200c (miR200c) is emerging as an important regulator of tumourigenicity and cancer metastasis with a strong capacity for inducing epithelial–mesenchymal transitions. However, the role of miR200c in head and neck squamous cell carcinoma (HNSCC) and HNSCC‐associated cancer stem cells (HNSCC‐CSCs) is unknown. In this study, the expression of miR200c in the regional metastatic lymph node of HNSCC tissues was significantly decreased, but BMI1 expression was increased as compared to parental tumours. Importantly, site‐directed mutagenesis with a luciferase reporter assay showed that miR200c targeted the 3′ UTR of BMI1 in HNSCC cells. Isolated HNSCC‐derived ALDH1+/CD44+ cells displayed CSC‐like tumour initiating and radio‐resistant properties. The expression levels of miR200c were significantly down‐regulated while BMI1 was increased in HNSCC‐ALDH1+/CD44+ compared to the other subsets of HNSCC cells. Furthermore, increased miR200c expression or knockdown of BMI1 could significantly inhibit the malignant CSC‐like properties of ALDH1+/CD44+ cells. miR200c over‐expression further down‐regulated the expressions of ZEB1, Snail and N‐cadherin, but up‐regulated E‐cadherin expression in ALDH1+/CD44+ cells. Finally, a xenotransplantion study confirmed that over‐expression of miR200c or BMI1 knockdown effectively inhibited the lung metastatic ability and prolonged the survival rate of ALDH1+/CD44+‐transplanted mice. In summary, miR200c negatively modulates the expression of BMI1 but also significantly inhibits the metastatic capability of epithelial–mesenchymal transitions in malignant HNSCC by reducing the expression of BMI1/ZEB1. Restoration of miR200c in HNSCC and CSCs may be a promising therapeutic approach. Copyright

Risks and clinical implications of perineural invasion in T1‐2 oral tongue squamous cell carcinoma

Risks of perineural invasion (PNI) in T1‐2 oral tongue squamous cell carcinoma (SCC) have not been specifically elucidated.

BNCT for locally recurrent head and neck cancer: preliminary clinical experience from a phase I/II trial at Tsing Hua Open-Pool Reactor.

To introduce our preliminary experience of treating locally and regionally recurrent Head and Neck cancer patients at Tsing Hua Open-Pool Reactor in Taiwan, four patients (M/F=3/1, median age 68 Y/O) were enrolled. BNCT with BPA (400 mg/kg) injected in 2 phases and prescription dose of 12-35 Gy (Eq.)/fraction for 2 fractions at 30 day interval can be given with sustained blood boron concentration and tolerable early toxicities for recurrent H & N cancer.

Effectiveness of narrow band imaging in patients with oral squamous cell carcinoma after treatment

We evaluated the effectiveness of narrow band imaging (NBI) in patients with oral squamous cell carcinoma (OSCC) after treatment.

Positron emission tomography in surveillance of head and neck squamous cell carcinoma after definitive chemoradiotherapy.

We assessed the role of 18F‐fluoro‐deoxy‐glucose positron emission tomography (PET) in detecting head and neck squamous cell carcinoma (HNSCC) after definitive chemoradiotherapy (CRT).

Persistent Krüppel-like factor 4 expression predicts progression and poor prognosis of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is one prevalent human cancer worldwide. No molecular markers are presently used for predicting prognosis in HNSCC. Krüppel‐like factor 4 (KLF4) is a transcription factor with diverse physiological functions, and possesses opposing roles in different human cancers. The expression and roles of KLF4 in HNSCC remain to be elucidated. In this study, immunohistochemical (IHC) analysis of KLF4 in 62 HNSCC was firstly performed. IHC results demonstrated that 42 (67.7%) had decreased KLF4 expression compared with surrounding normal epithelium, while persistent KLF4 expression was demonstrated in 20 (32.3%). The IHC results were further verified by Western blot and real‐time PCR analyses to confirm the robustness of staining and interpretation. Interestingly, persistent KLF4 expression independently correlated with a worse disease‐specific survival (P = 0.005), especially in patients with advanced disease. In consistent with clinical observation, all five HNSCC cell lines tested revealed a low level of baseline KLF4 expression. Moreover, enforced KLF4 expression in cell line SAS significantly increased in vitro migration/invasion abilities, multi‐drug resistance, and in vivo tumorigenicity. These results clearly illustrate that persistent KLF4 expression predicts poor prognosis and confers aggressiveness in HNSCC. Our data therefore provides valuable information that HNSCC with persistent KLF4 expression might require intensified combination treatment in future practice. (Cancer Sci 2011; 102: 895–902)

Second Primary Malignancies in Squamous Cell Carcinomas of the Tongue and Larynx: An Analysis of Incidence, Pattern, and Outcome

Background: Head and neck cancer patients have a higher risk of developing a second primary malignancy (SPM) than the general population. This study was conducted to identify the characteristics of SPM and its impact on survival in patients with squamous cell carcinoma of the tongue (TSCC) and larynx (LSCC). Methods: A retrospective study was conducted of 538 patients who were treated by surgery primarily for TSCC (n = 146) and LSCC (n = 392) from 1990 to 2000. The incidence, site, and overall survival of SPMs were evaluated. Results: Seventy‐seven patients developed SPM during the follow‐up period (median, 73 months), including 18 (12%) with TSCC and 59 (15%) with LSCC. Fifty‐six percent of SPMs of the TSCC group appeared in the oral cavity. Among the SPMs of LSCC patients, 54% developed in the lung (31%) and larynx (24%). The 5‐year overall survival after the diagnosis of SPM in the head and neck was 39%, compared to 29% for SPM in other areas (p = 0.010). Conclusion: SPMs after treatment of TSCC and LSCC are similar in incidence but distinct in pattern. SPMs within the head and neck are associated with a better prognosis than those outside this area.

Perineural invasion in T1 oral squamous cell carcinoma indicates the need for aggressive elective neck dissection.

Observation or elective neck dissection (END) for cN0 neck remains controversial for the treatment of T1-2 oral squamous cell carcinoma (OSCC). Perineural invasion (PNI) has been recognized as a poor prognostic factor for OSCC. However, its significance in T1 OSCC remains unclear. A detailed histologic reevaluation of PNI was carried out in 307 patients with T1-2 OSCC who received surgical treatment between June 2001 and January 2009. We found that the presence of PNI correlated with cervical lymph node metastasis in both T1 and T2 OSCC, with a lower PNI-positive rate in T1 (17.1% vs. 36.6%; P<0.001). Importantly, observation for cN0 neck was used twice as often in T1 than in T2 patients (47.4% vs. 22.8%; P<0.001). Although patients with T1 OSCC achieved significantly better outcomes, PNI correlated with neck recurrence and poor disease-specific survival (DSS) only in T1 (P<0.001 and P<0.0001) but not in T2 patients (P=0.399 and 0.1478). Of the 146 patients with T1 OSCC, PNI independently predicted cervical lymph node metastasis, neck recurrence, and poor DSS. END significantly reduced neck recurrence of T1 OSCC in PNI-positive (P=0.001) but not in PNI-negative (P=0.114) patients. In addition, END improved the 5-year DSS of T1 OSCC more in PNI-positive than in PNI-negative patients (16.2% vs. 5.4%). Our results indicate that PNI independently predicts a poor prognosis in T1 OSCC patients who are potentially curable but tend to be treated conservatively. For its efficacy in improving treatment outcomes, aggressive END is indicated for T1 OSCC patients at the presence of PNI.

Synergistic effects of carboxymethyl-hexanoyl chitosan, cationic polyurethane-short branch PEI in miR122 gene delivery: accelerated differentiation of iPSCs into mature hepatocyte-like cells and improved stem cell therapy in a hepatic failure model.

MicroRNA122 (miR122), a liver-specific microRNA, plays critical roles in homeostatic regulation and hepatic-specific differentiation. Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but it remains unknown whether non-viral vector-mediated miR122 delivery can enhance the differentiation of iPSCs into hepatocyte-like cells (iPSC-Heps) and rescue thioacetamide-induced acute hepatic failure (AHF) in vivo. In this study, we demonstrated that embedment of miR122 complexed with polyurethane-graft-short-branch polyethylenimine copolymer (PU-PEI) in nanostructured amphiphatic carboxymethyl-hexanoyl chitosan (CHC) led to dramatically enhanced miR122 delivery into human dental pulp-derived iPSCs (DP-iPSCs) and facilitated these DP-iPSCs to differentiate into iPSC-Heps (miR122-iPSC-Heps) with mature hepatocyte functions. Microarray and bioinformatics analysis further indicated that CHC/PU-PEI-miR122 promoted the gene-signature pattern of DP-iPSCs to shift into a liver-specific pattern. Furthermore, intrahepatic delivery of miR122-iPSC-Heps, but not miR-Scr-iPSC-Heps, improved liver functions and rescued recipient survival, and CHC-mediated delivery showed a better efficacy than that using phosphate buffered saline as a delivery vehicle. In addition, these transplanted miR122-iPSC-Heps remained viable and could produce circulatory albumin for 4 months. Taken together, our findings demonstrate that non-viral delivery of miR122 shortens the time of iPSC differentiation into hepatocytes and the delivery of miR122-iPSC-Heps using CHC as a vehicle exhibited promising hepatoprotective efficacy in vivo. miR122-iPSC-Heps may represent a feasible cell source and provide an efficient and alternative strategy for hepatic regeneration in AHF.

Cisplatin-based chemotherapy versus cetuximab in concurrent chemoradiotherapy for locally advanced head and neck cancer treatment.

Background and Purpose. This study aimed to analyze survival, clinical responses, compliance, and adverse effects in locally advanced head and neck cancer (LAHNC) patients treated with split-dose cisplatin-based concurrent chemoradiation therapy (SD-CCRT) or cetuximab with concurrent radiation therapy (BioRT). Materials and Methods. We retrospectively evaluated 170 LAHNC patients diagnosed between January 1, 2009, and July 31, 2012: 116 received CCRT and 54 received BioRT. Results. Complete response rates were similar in the SD-CCRT and BioRT groups (63.8% versus 59.3%; P = 0.807), and locoregional relapse rates were 18.1% and 13.0%, respectively (P = 0.400). The 3-year relapse-free survival rate was 65.8% in the SD-CCRT group and 65.5% in the BioRT group, respectively (P = 0.647). The 3-year overall survival rate was 78.5% in the SD-CCRT group and 70.9% in the BioRT group, respectively (P = 0.879). Hematologic side effects were significantly more frequent in the SD-CCRT than in the BioRT group. Mucositis frequency was similar. Conclusions. Primary SD-CCRT and BioRT both showed good clinical response and survival. Hematologic toxicities were more frequent, but tolerable, in the SD-CCRT group. Both groups showed good compliance.