Validity and reliability of the Korean version of the Speech Handicap Index in patients with oral cavity cancer.

The aims of this study were to evaluate the cross-cultural adaptation of the Speech Handicap Index (SHI) for Korean subjects and to determine its reliability and utility in patients with oral cavity cancer. The Korean version of the SHI was administered to 50 healthy subjects and 56 patients with speech problems resulting from treatment for oral cavity cancers. The content and construct validity, internal consistency, and test-retest reliability were examined. Healthy subject and patient group scores were compared, and the Mann-Whitney U-test was used to determine discriminatory ability. The Korean version of the SHI had high internal consistency (Cronbach's alpha=0.99) and test-retest reliability for the total and subscales: total (T) 0.98, speech (S) 0.99, and psychosocial (P) 0.97. Mean scores in the healthy group were 0.5 (T), 0.2 (S), and 0.2 (P), whereas those in the patient group were 34.3 (T), 16.6 (S), and 15.5 (P). The scores differed significantly between the groups (P<0.05). The Korean version of the SHI can be a useful tool to evaluate a patient's self-perception of their speech dysfunction in daily life and to better understand postoperative speech disorders in patients with oral cavity cancer.

Long-term subjective tongue function after partial glossectomy.

There have been limited studies of subjective tongue function over long-term follow-up in spite of swallowing and articulation disorders are common complications of glossectomy. To assess long-term subjective swallowing and articulation function after partial glossectomy. A total of 63 patients with the mobile tongue cancer who underwent partial glossectomy without reconstruction were interviewed to score their swallowing and articulation function on a 100-point scale. The relation of this subjective scoring to the perioperative data was subjected to multivariate analysis. The mean patient age was 53·4 (19-81) years, and the mean follow-up duration was 78·9 (14-277) months. Mean swallowing and articulation function score was 87·7 ± 6·1 and 88·6 ± 5·4. Age, follow-up duration, T stage and resection volume were significantly correlated with swallowing function (P = 0·026, 0·029, 0·016, 0·002, respectively); follow-up duration was correlated with articulation function (P = 0·039). Patients who undergo partial glossectomy without reconstruction generally demonstrate good function on long-term follow-up. Subjective dysfunction was correlated with larger resection volume, older age and shorter follow-up duration.

The Korean version of the University of Washington Quality of Life Questionnaire for Patients with head and neck cancer, and its use in an initial validation study of 56 patients.

The University of Washington Quality of Life (UW-QOL) questionnaire is often used to assess health-related quality of life (HRQOL) of head and neck cancer patients. The aim of this study was to translate the UW-QOL version 4 into the Korean language and to carry out an initial validation study. A recognized methodology for translation of questionnaires was used. The validation study used the final Korean version between March and September 2009. Adult patients were recruited, with a confirmed diagnosis of head and neck cancer, therapy completed and disease-free for at least 1 year. The UW-QOL was successfully translated into Korean. 56 patients completed Korean versions of UW-QOL, the Beck Depression Inventory and the World Health Organization Quality of Life-BREF and various expected correlations were confirmed first between the two UW-QOL subscales (Spearman 0.54 p<0.001) and then of these subscales with the other concurrent measures. Lower (worse) UW-QOL scores were seen for later stage patients in all 12 domains. The Korean version of UW-QOL is ready for use in the assessment of HRQOL for Korean patients. Validation work needs to be continued to further establish psychometric properties of the questionnaire for use in this population.

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells.

Soluble TRAIL and adenovirus (ad)-TRAIL exhibit a strong antitumor effect by inducing apoptosis. Vorinostat is the histone deacetylase (HDAC) inhibitor that induces cell death in cancer cell lines and regulates the expression of epigenetically silenced genes, such as Coxackie adenoviral receptor (CAR), the receptor for adenoviral entry. We propose a new strategy in which vorinostat will induce high expression of ad-TRAIL and a strong antitumor response, and investigated the mechanism involved. The effect of vorinostat on transcription and expression of TRAIL from ad-TRAIL-transduced lung cancer cells were confirmed by reverse transciption-PCR (RT-PCR), quantitative real time-PCR and western blot assay. Anti-tumor effects were measured after cotreatment of vorinostat and ad-TRAIL, and the drug interactions were analyzed. After combined treatment of vorinostat and ad-TRAIL, apoptosis and western blot assays for Akt, Bcl-2 and caspase were performed. Vorinostat increased the expression of CAR in lung cancer cell lines and increased the expression of luciferase (luc) from ad-luc-transduced cells and TRAIL from ad-TRAIL-transduced cells. RT-PCR and quantitative real time-PCR, after sequential vorinostat treatment, revealed that vorinostat may enhance TRAIL expression from ad-TRAIL by increasing transduction through enhanced CAR expression and increasing adenoviral transgene transcription. Combined vorinostat and ad-TRAIL treatment showed the synergistic anti-tumor effect in lung cancer cell lines. Combined vorinostat and ad-TRAIL induced stronger apoptosis induction, suppression of NF-κB activation and breakdown of the anti-apoptotic molecule Bcl-2. In conclusion, the vorinostat synergistically enhanced the anti-tumor effect of ad-TRAIL by (1) increasing adenoviral transduction through the increased expression of CAR and (2) increasing adenoviral transgene (TRAIL) transcription in lung cancer cell lines.

Class III beta-tubulin, but not ERCC1, is a strong predictive and prognostic marker in locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Recent researches revealed that class III beta-tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in head and neck squamous cell carcinoma (HNSCC) is not defined yet. We analyzed the significance of TUBB3 expression along with p53 and ERCC1 in locally advanced HNSCC patients receiving cisplatin-based induction chemotherapy. MATERIALS AND METHODS: Retrospective review of medical records at Seoul National University Hospital between 1998 and 2007 was carried out. Immunohistochemical stain of TUBB3, p53, and ERCC1 was done in paraffin-embedded tumor tissue. We assessed response to treatment, progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). RESULTS: Eighty-five patients with oropharyngeal, hypopharyngeal, and laryngeal cancers received induction chemotherapy with 5-fluorouracil (5-FU) and cisplatin (n = 55), or 5-FU, cisplatin, and docetaxel (Taxotere) (n = 30). Eighty-three received definitive treatment after induction chemotherapy, where 62 received radiotherapy and 21 received surgery. TUBB3-positive patients showed lower response rate than TUBB3-negative patients (69% versus 88%, P = 0.039). Shorter median PFS was observed in TUBB3-positive group (12 versus 47 months, P = 0.001). Shorter median OS was observed in TUBB-positive group not reaching statistical significance (30 versus 59 months, P = 0.072). TUBB3 status significantly influenced CSS (35 months versus not reached, P = 0.017). Positive p53 status was related to poorer OS and CSS. ERCC1 showed no influence on chemotherapy response, PFS, OS, and CSS. CONCLUSION: TUBB3 is a predictive and prognostic marker along with well-known p53 in HNSCC patients receiving cisplatin-based induction chemotherapy. Clinical impact of ERCC1 is not evident in this setting.

Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3K/Akt.

The E5 oncoprotein of human papillomavirus (HPV) 16 plays an important role in early cervical carcinogenesis. Vascular endothelial growth factor (VEGF) plays a central role in switching on the angiogenic phenotype during early cervical carcinogenesis. However, the relationship between E5 and VEGF has not previously been examined. To clarify the regulatory role of E5 in VEGF expression, we transferred the E5 gene into various cell types. E5 increased VEGF expression. The addition of epidermal growth factor receptor (EGFR) inhibitor significantly suppressed VEGF expression, demonstrating that E5 stimulates VEGF expression through the activation of EGFR. E5-mediated EGFR activation was accompanied by phosphorylation of Akt and ERK1/2, which are also involved in VEGF expression. Furthermore, the mRNA stability of VEGF was not affected by E5, but VEGF promoter activity could be modulated by inhibitors of the EGFR, MEK-ERK1/2 and PI3K/Akt pathways in E5-expressing cells. Collectively, these novel results suggest that HPV 16 E5 increases VEGF expression by activating EGFR, MEK/ERK1/2 and PI3K/Akt.

Volume of cervical lymph nodes using 3D ultrasonography. Differentiation of metastatic from reactive lymphadenopathy in primary head and neck malignancy.

PURPOSE: To assess the usefulness of volume measurement using 3D US for depicting metastatic cervical lymph nodes. MATERIAL AND METHODS: Thirty-five cervical lymph nodes in 13 patients with primary head and neck malignancy were included in this study. US with volume acquisition was prospectively performed with a 5-10 MHz linear mechanical volume probe. Volume measurement of the node was calculated using a 3D automatic volume calculation program. The excised nodes matched on US were examined histopathologically. RESULTS: The volume of malignant nodes ranged from 0.444 to 4.442 cm3, the volume of the benign nodes from 0.143 to 1.176 cm3. Combinations of high positive (>80%) and negative (>90%) predictive values were obtained at a cut-off value of 0.7 cm3. CONCLUSION: Volume measurement of cervical nodes using 3D US can be a useful tool for differentiating metastatic from benign nodes in patients with primary head and neck malignancy.

Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial.

Animal studies have shown that direct injection of an adenoviral vector (Adv.RSV-tk) expressing the herpes thymidine kinase gene into established tumors in the liver, followed by systemic ganciclovir administration, was effective in inducing tumor necrosis. Toxicities were minimal at therapeutically effective vector doses, although severe hepatic necroinflammation was seen at much higher supratherapeutic doses. We conducted a clinical phase I trial in patients with metastatic colorectal adenocarcinoma in the liver to assess the safety of intratumoral Adv.RSV-tk injection (escalating doses) followed by intravenous ganciclovir (fixed dose). The vector was injected into a metastatic tumor in the liver under local anesthesia by percutaneous needle placement with concurrent ultrasonographic monitoring to prevent injection or leakage into adjacent normal liver structures. We treated 16 patients in five dose level cohorts of Adv.RSV-tk, from 1.0x10(10) to 1.0x10(13) virus particles per patient. Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. Other toxicities were also transient: grade 2-3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 of 16 patients. These results indicate that Adv.RSV-tk can be safely administered by percutaneous intratumoral injection in patients with hepatic metastases at doses up to 1.0x10(13) virus particles per patient, and can provide the basis for future clinical trials involving intratumoral adenoviral vector injection.

Advanced hypopharyngeal carcinoma treatment results according to treatment modalities.

BACKGROUND: The purpose of this retrospective study is to compare the treatment results of locally advanced hypopharyngeal carcinoma according to treatment modalities. METHODS: Seventy-three patients with locally advanced hypopharyngeal carcinoma treated at the Department of Therapeutic Radiology, Seoul National University Hospital, between August 1979 and July 1997 were retrospectively analyzed. Twenty-three patients were treated with radiotherapy (RT) alone, 18 patients were treated with surgery and postoperative RT, and 32 patients were treated with neoadjuvant chemotherapy (CTx) and RT. Median follow-up period was 28 months. RESULTS: The overall 5-year survival rates were 15.7% for the RT alone group, 46.8% for surgery and postoperative RT group, and 43.0% for neoadjuvant CTx and RT group. The 5-year disease-free survival rates were 13.9%, 47.4%, and 30.7%, respectively. Surgery and postoperative RT or neoadjuvant CTx and RT showed superiority over RT alone in terms of both overall survival and disease-free survival rates. No significant differences were found in overall and disease-free survival rates between the surgery and postoperative RT group and neoadjuvant CTx and RT group (p =.15, p =.13). In the neoadjuvant CTx and RT group, 12 patients (38%) retained their larynx more than 5 years. CONCLUSION: Neoadjuvant CTx and RT is an effective strategy to achieve organ preservation without compromising the survival of patients with locally advanced hypopharyngeal carcinoma.

Association of p53 and BCL-2 expression with Epstein-Barr virus infection in the cancers of head and neck.

BACKGROUND: Reports that have both evaluated the site-specific Epstein-Barr virus (EBV) infection and compared it with the expression of the EBV-related proto-oncogenes and tumor suppressor genes in the various cancers of head and neck are scarce. METHODS: Thirty-eight nasopharyngeal carcinoma (NPC) cases, 32 oropharyngeal or hypopharyngeal carcinoma (OPC/HPC) cases, and 93 laryngeal carcinoma (LC) cases were evaluated with in situ hybridization on EBV-encoded small RNA (EBER) and immunohistochemical assessments of the p53, bcl-2, and epidermal growth factor receptor (EGFR) by use of formalin-fixed paraffin-embedded tissue array slides. RESULTS: The expression of viral EBERs was observed in more than two thirds (71.1%) of the NPC cases. In contrast, only 1 case of OPC and none of the HPC or LC cases exhibited EBV positivity. In the nonkeratinizing NPC, the EBV positivity was significantly associated with both frequent p53 overexpression (p =.033) and bcl-2 expression (p =.001). In the EBV-positive nonkeratinizing NPC, a correlation between p53 overexpression and the tumor infiltration lymphocyte (TIL) density was noted (p =.012). CONCLUSIONS: A site-specific expression of viral EBER was demonstrated in the head and neck cancers, which suggests an important role for both p53 and bcl-2 in the carcinogenesis of an EBV-infected NPC. The correlation between p53 overexpression and the TIL density in the EBV-infected NPC suggests that the product of a lymphoepithelial interaction, such as A20, can induce a dysfunctional p53 protein.

Bifid epiglottis associated with Joubert's syndrome.

This report presents the case of a 2-year-old boy who had a bifid epiglottis associated with Joubert's syndrome. He had episodic tachypnea and apnea, inspiratory stridor, aspiration, and growth and mental retardation. Direct laryngoscopy demonstrated agenesis of the right half of the epiglottis and hypertrophied mucosa over the arytenoid cartilage. After the hypertrophied mucosa was partially vaporized with a CO2 laser, the inspiratory stridor soon improved and the aspiration was alleviated. Brain magnetic resonance imaging showed cerebellar vermian agenesis and enlargement of the fourth ventricle.

Enhancement of adenoviral transduction with polycationic liposomes in vivo.

Although the high transfection efficiency with adenovirus in vitro is well documented, it is still not clear whether adenoviral vectors are effective in vivo in solid tumor models. In our preliminary experiment, transduction of tumor tissue was limited to just around the injection site after intratumoral injection of the adenoviral vector. To improve the transduction efficiency in vivo, we tried a combination of adenoviral vector and liposome in our animal model. Adenovirus carrying human placental alkaline phosphatase (AdALP) and Lipofectamine or 1,3-di-oleoyloxy-2-(6-carboxyspermyl)-propylamide were used as a marker gene and the cationic liposome, respectively. A >15-fold increase in the transfection efficiency was observed in CT26 tumor cell lines with the combination of AdALP adenovirus carrying murine granulocyte-macrophage colony-stimulating factor (AdmGM-CSF), and liposome compared with adenovirus alone, showing the feasibility of the combination treatment. In the animal model, with the combination of liposome and AdALP, deeper and wider distribution of the marker gene in the tumor mass was shown. We conclude that the limitations of direct application of adenoviral vectors in a solid tumor model could be overcome by the use of cationic liposomes. This approach will facilitate the more effective delivery of adenoviral vectors in a clinical trial setting.

Effect of GM-CSF and IL-2 co-expression on the anti-tumor immune response.

We evaluated the effect of potential therapeutic genes, GM-CSF and IL-2 respectively, or in combination of both cytokines, on the activation of systemic antitumor responses. CT26 tumor cells were modified to secrete GM-CSF and/or IL-2. The growth rate of the modified tumor cells versus the parental CT26 cells did not show any difference. When we implanted the CT26 tumor cells which secrete either GM-CSF or IL-2, delayed and suppressed tumorigenicity was observed. However, another CT26 cell line which expresses both GM-CSF and IL-2 (CT26/GMCSF/IL-2) did not form any tumor mass in the immunocompetent syngeneic Balb/c mice, showing the potential immune responses. Immunohistochemical examination of the modified tumor masses implanted with the cells expressing GM-CSF or IL-2 showed increased necrosis and infiltration of NK (CD56+) lineage cells and macrophage/monocytes. In the vaccination model, the growth of rechallenged wild-type CT26 was more suppressed int he mice which were injected with GM-CSF or IL-2, however, the wild-type CT26 tumor formed normal tumor mass in the mice vaccinated with CT26/GM-CSF/IL-2 showing acute non-T-cell mediated immune response. As a treatment, we injected those modified tumor cells into the established tumor. There we could find tumor growth suppression by the injection of cytokine-modified CT26 cells, especially by the CT26/GM-CSF/IL-2. In the present study we could induce the eradication of tumorigenicity by the transfection of both GM-CSF and IL-2 genes and a potent role in the growth suppression of an established tumor.

Cationic liposome-enhanced adenoviral gene transfer in a murine head and neck cancer model.

The effect of combining adenoviral vector and cationic liposomes on the efficiency of gene transfer to head and neck tumor cells was investigated. Two human and two murine cell lines were used for the screening of gene transfer efficiency using an adenoviral vector. Cationic liposome-enhanced gene transfer was checked using a murine squamous carcinoma cell line, SCCVII/SF. A considerable difference in the efficiency of gene transduction was observed among the cell lines. The combination of DOSPER and adenoviral vector containing human alkaline phosphatase showed a remarkable enhancing effect in gene transfer in vitro and in vivo, compared to the adenovirus alone or control groups. With an improvement in the efficiency of gene transfer, it may be possible not only to enhance the expression of transduced genes, but also to deliver a smaller amount of virus, as a result, reducing toxicity and the immune response against adenovirus.

Therapeutic dilemmas in the management of thyroid cancer with laryngotracheal involvement.

Invasion of the larynx and trachea by thyroid cancer is an uncommon but difficult problem. There is no consensus on indication for or extent of surgery, particularly when there is a requirement for airway reconstruction. From 1989 through 1996, we treated 22 patients with thyroid carcinoma with invasion of the larynx and trachea. Seventeen of these patients had recurrent disease. We applied radioactive iodine therapy after regional ablative surgery to resectable tumors with or without lung metastasis, larynx-preserving surgery to extraluminal or small intraluminal tumors restricted to the short segment of trachea, or total laryngectomy to recurrent tumors deeply invading the cartilage framework of the larynx. We performed arytenoid adduction or thyroplasty in one stage if the recurrent laryngeal nerve was paralyzed or resected intraoperatively. We could get relatively good survival and functional results by aggressive surgical treatment in 20 patients, but the disease was inoperable in 2 patients. It is stressed that head and neck surgeons who have to deal with cancer of the thyroid should not only be familiar with various techniques of airway reconstruction and voice rehabilitation but also must be aware of the biologic behavior of the thyroid carcinoma.

Pyriform sinus fistula: management with chemocauterization of the internal opening.

A branchial remnant originating in the pyriform sinus causes a recurrent fistula or abscess in the neck. In spite of excision, recurrence may result from inadequate removal of the fistula tract. We attempted chemocauterization of the internal opening of the fistula tract with trichloroacetic acid (TCA) on direct endoscopy. This is a 6-year review of 18 patients with pyriform sinus fistula. Medical history, barium esophagography, computed tomography scans, operative findings, and treatment results were analyzed. By direct endoscopy, all patients were found to have a fistula opening in the pyriform sinus, exclusively on the left side. In only 9 patients, the fistula tract was identified by barium esophagography before operation. Computed tomography revealed a suspicious fistula tract originating from the pyriform sinus in 8 of 10 patients. Sixteen patients were initially managed by TCA chemocauterization. There were no serious intraoperative or postoperative complications. Four patients had recurrent masses, which were managed by simple excision in 2 patients and repeated TCA cauterization in the other 2 patients with unobliterated internal openings. We recommend barium swallow study and direct endoscopy for all patients presenting with a recurrent lateral neck abscess, especially on the left side. Our results suggest that initial chemocauterization of the internal opening can be a reasonable alternative procedure for the management of pyriform sinus fistula.

Reconstruction of human hard-palate mucosal epithelium on de-epidermized dermis.

Artificial hard-palate mucosa equivalents were reconstructed using keratinocytes derived from normal human hard-palate and de-epidermized dermis. Reconstructed hard-palate mucosal epithelium formed in three-dimensional culture was compared to native hard-palate mucosal epithelium and reconstructed oral buccal mucosal epithelium with regard to keratin expression. Artificial hard-palate mucosal epithelium reconstructed in medium with delipidized serum showed a differentiation pattern similar to that of hard-palate epithelium in vivo. The present study also confirmed that keratinocytes derived from hard-palate mucosa are intrinsically different from those of nonkeratinizing oral surfaces.

Neoadjuvant chemotherapy and radiation therapy compared with radiation therapy alone in advanced nasopharyngeal carcinoma.

PURPOSE: To analyze the impact of neoadjuvant chemotherapy on the treatment of locoregionally advanced nasopharyngeal carcinoma and to assess the outcomes of patients receiving such treatment. METHODS AND MATERIALS: We analyzed 137 previously untreated and histologically confirmed advanced stage nasopharyngeal carcinoma patients treated with either radiation therapy only or combined radiation therapy and chemotherapy at the Seoul National University Hospital between 1984 and 1996. The stage distribution was as follows: AJCC Stage III-21, Stage IV-61 in the radiation therapy group (RT group); AJCC Stage III-1, Stage IV-54 in neoadjuvant chemotherapy and radiation therapy group (CT/RT group). The median follow-up for surviving patients was 48 months. RESULTS: The 5-year overall survival (OS) rates were 71% for the CT/RT group and 59% for the RT group (p = 0.04). The 5-year actuarial disease-free survival (DFS) rates were 63% for the CT/RT group and 52% for the RT group (p = 0.04). Distant metastasis (DM) incidence was significantly lower in the CT/RT group. The 5-year freedom from distant metastasis rates were 84% for the CT/RT group and 66% for the RT group (p = 0.01). The incidence of locoregional failures was also lower in the CT/RT group, although this difference did not reach statistical significance (69% vs. 56%, p = 0.09) CONCLUSION: While not providing conclusive evidence, historical evidence from this institution suggests that neoadjuvant chemotherapy significantly improves both overall and the disease-free survival of patients with advanced stage nasopharyngeal carcinoma.