Jehn-Chuan Lee

Treatments and outcomes of malignant tumors of external auditory canal

PURPOSE Primary cancer of the external auditory canal (EAC) is a rare disease with poor prognosis. Because of the rarity of this entity, there is no large series for staging, treatments, and outcomes. The purpose of this study is to evaluate the treatment modalities and outcomes for malignant tumors of EAC at our institute, comparing with other studies. METHODS We retrospectively reviewed the patients treated for primary cancer of EAC between 1991 and 2002 at our hospital, which is a tertiary referral center. Ten males and 2 females were enrolled in this study. The median follow-up period was 56.5 months. The interventions included sleeve resection, radical mastoidectomy, or lateral temporal bone resection combined with neck dissection or parotidectomy. Adjuvant radiotherapy was performed in case of incomplete resection. All patients were staged according to the Pittsburgh staging system. RESULTS Ten patients had squamous cell carcinoma and 2 had adenoid cystic carcinoma (ACC). Five patients had stage I disease, 2 with stage II, 1 with stage III, and 4 with stage IV. All patients (n = 7) with early stage (I or II) were disease-free, but only 1 of 5 patients with late stage (III or IV) was disease-free. The recurrences occurred in 50% (2/4) of patients with incomplete resection, despite of the adjuvant radiotherapy. Only one patient with complete resection had recurrence and the histologic diagnosis of this particular patient was ACC. CONCLUSIONS Patients with early-stage cancer can benefit from less aggressive surgical interventions without significant morbidity or mortality. No recurrence occurred in patients with complete resection except the one with ACC. The result of our institute was comparable or superior to those of other studies in early-stage disease. However, patients with advanced cancer had high recurrence rate despite of adjuvant radiotherapy, suggesting more aggressive surgical approach for complete resection was necessary.

Upregulation of B-cell translocation gene 2 by epigallocatechin-3- gallate via p38 and ERK signaling blocks cell proliferation in human oral squamous cell carcinoma cells

Oral squamous cell carcinoma (OSCC) is a well-known malignancy that accounts for the majority of oral cancers. B-cell translocation gene 2 (BTG2) is an important regulator of cell cycle dynamics in cancer cells. However, the role of BTG2 in OSCC cells and the influences of epigallocatechin-3-gallate (EGCG) on BTG2 gene expressions have not been well evaluated. The objectives of this study were to examine the effect of EGCG-induced BTG2 expression and the potential signal pathways involved. The (3)H-thymidine incorporation and Western-blot assays revealed cell proliferation was attenuated by EGCG via upregulation of BTG2 expression causing cell cycle G1 phase arrest in OSCC cells. BTG2 overexpression decreased tumor cell growth, while BTG2 knockdown illuminated the opposite effect in xenograft animal studies. Overexpressed BTG2 arrested the cell cycle at the G1 phase and downregulated protein expressions of cyclin A, cyclin D, and cyclin E. Western-blot assays indicated that EGCG induced phosphorylation of p38, JNK, and ERK. However, pretreatments with selective mitogen-activated protein kinase (MAPK) inhibitors, SB203580 (p38 inhibitor) and PD0325901 (ERK1/2 inhibitor), significantly suppressed the activation of EGCG on BTG2 expression. Our results indicate that EGCG attenuates cell proliferation of OSCC cells by upregulating BTG2 expression via p38 and ERK pathways.

N-myc downstream-regulated gene 1 downregulates cell proliferation, invasiveness, and tumorigenesis in human oral squamous cell carcinoma1

Oral squamous cell carcinoma (OSCC) is the most common phenotype of oral cancer. N-myc downstream regulated gene 1 (NDRG1) is a modulator for cell proliferation, differentiation, and invasion. The role and function of NDRG1 in OSCC cells remain inconclusive. The (3)H-thymidine incorporation and in vitro matrigel invasion assays revealed NDRG1-knockdown significantly enhanced OSCC cell proliferation and invasion. Overexpressed NDRG1 arrested the cell cycle at the S-phase, thus attenuated cell proliferation in OECM-1 cells. The NDRG1-knockdown enhanced tumorigenesis of OECM-1 cells in the xenograft animal model. Western-blot and zymographic assays revealed that NDRG1 downregulated the gelatinase activities and protein levels of metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9). NDRG1 modulated epithelial-mesenchymal transition (EMT) through upregulation of the E-cadherin expression, but downregulation of the N-cadherin, Vimentin, Snail-1, and Slug. Immunofluorescence staining indicated knockdown of NDRG1 enhanced F-actin expression and polymerization. Our results indicated NDRG1 attenuated OSCC cell growth in vitro and in vivo. The downregulation of EMT, MMP-2, and MMP-9 may explain the role of anti-invasion of NDRG1 in human OSCC cells. The experiments recognize that NDRG1 is an antitumor gene in OSCC cells.

Ileocolic free flap reconstruction, concomitant chemotherapy and radiotherapy and assessment of speech and swallowing function during management of advanced cancer of the larynx and hypopharynx: preliminary report.

Conclusion The new technique of ileocolic free flap reconstruction provides a better quality of life in terms of swallowing and speech for patients who have undergone laryngopharyngectomy with concomitant chemotherapy and radiotherapy (CCRT). Objectives To compare and contrast the swallowing and speech outcomes of patients who underwent total laryngopharyngectomy with ileocolic free flap reconstruction and to analyze the survival rate after surgery and CCRT. Material and methods This was a follow-up study of 12 patients with advanced (stages III, IVA and IVB) laryngeal and hypopharyngeal cancer who underwent major surgery, CCRT (with one exception) and ileocolic free flap reconstruction. Results All patients were able to tolerate single-stage combined management comprising total laryngopharyngectomy with or without radical neck dissection plus ileocolic free flap reconstruction and postoperative CCRT (with one exception), without immediate morbidity or mortality. Eleven patients were diagnosed with hypopharyngeal cancer and one with laryngeal cancer. The mean interval between surgery and CCRT was 34.1 days. The mean follow-up period was 16.5 months. Four patients died during the follow-up period as a result of local recurrence (n=2), distant metastasis (n=1) and suicide (n=1). One patient was alive with disease despite neck recurrence.

The Iron Chelator, Dp44mT, Effectively Inhibits Human Oral Squamous Cell Carcinoma Cell Growth in Vitro and in Vivo

Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment.

Radiation-induced squamous cell carcinoma of the external auditory canal.

Radiation treatment of nasopharyngeal carcinoma (NPC) may induce malignancy in the external ear or mastoid (1Y4), occurring with an incidence of approximately 0.15% (1). Modified criteria (1) for the diagnosis of radiation-induced malignancy include a previous history of irradiation, followed by development of a new malignancy in the radiation field diagnosed no less than 2 years after the radiotherapy and which is proven to differ histologically from the original malignancy. En bloc resection including lateral subtotal or total temporal resection is usually recommended for removal of a primary ear malignancy.

Voice and speech outcomes with radial forearm free flap-accompanied phonation tube after total pharyngolaryngectomy of hypopharyngeal cancer.

Abstract Conclusions: Radial forearm free flap (RFFF)-accompanied phonation tube (PT) for voice and speech restoration after pharyngolaryngectomy is promising, especially in phonation efficacy and intelligibility. It offers not only another safe surgical option but also a satisfactory result for such patients with advanced hypopharyngeal cancer. Objectives: We use RFFF with RFFF-accompanied PT for one-stage reconstruction both for tissue defect and voice reconstruction in patients undergoing total pharyngolaryngectomy. Methods: Eight male patients with advanced hypopharyngeal cancer underwent total pharyngolaryngectomy. Voice restoration was done with RFFF-accompanied PT. Phonation outcomes and speech outcomes of the patients were evaluated and scored. Results: The mean follow-up time was 13.7 months. All free flaps were successful without perioperative mortality. All the patients were able to produce sound. Phonation efficacy ranged from 70% to >90% postoperatively and 40% to >90% at the last follow-up. The speech intelligibility was graded as moderately good.

Multiple analyses of factors related to complications in endoscopic sinus surgery.

Background This study was undertaken to evaluate whether endoscopic sinus surgery (ESS) with a microdebrider had an impact on complication rates, and to facilitate the determination of factors associated with complications in patients who underwent ESS at a tertiary referral center in Taiwan. Methods This investigation was a retrospective study and literature review. We analyzed 997 consecutive patients who underwent ESS at Mackay Memorial Hospital in Taipei, Taiwan from January 2006 through February 2010. All data including those of patient medical information, and peri‐ and postoperative complications were provided by the surgeons involved in patient medical care. We analyzed the complication rates using the following 10 variables by univariate analysis and multivariate logistic regression: sex, age, Lund–Mackay score, polyp grading, previous sinonasal surgery, surgeon skill, adjunctive sinonasal surgery, mesenteric type of anterior ethmoid artery, Keros skull base type, and the use of a microdebrider. Results Of the 997 patients in our study, 78 (7.8%) had complications. Major complications occurred in five patients (0.5%): two with cerebrospinal fluid rhinorrhea, one with medial rectus muscle damage, and two with retrobulbar hematoma. Minor complications were found in 73 patients (7.3%), which included 32 patients with perioperative estimated blood loss > 15% of the total estimated blood volume, 26 with lamina papyracea damage, two with orbital cellulitis, and 13 with postoperative bleeding. Univariate analysis showed that risk factors related to complication rate were advanced Lund–Mackay scores (scores 19–24), advanced polyp grading (Grades 2 and 3), inexperienced surgeon (resident), and microdebrider usage. However, multivariate analysis revealed that complication rate was linked to advanced Lund–Mackay scores (Scores 19–24), mesenteric type of anterior ethmoid artery, and inexperienced surgeon. Conclusion Overall, the results of our study showed that the ESS complication rate was 7.8%, with risk factors including advanced Lund–Mackay scores (19–24, odds ratio 10.4) and inexperienced surgeon. It was also noted that ESS with a microdebrider had no impact on complication rates, although the presence of a mesenteric type of anterior ethmoid artery proved to be a protective factor.

Comparison of the efficacy and toxicity of two dose levels of cisplatin/5-fluorouracil as the chemoradiotherapy regimen for the treatment of locally advanced squamous cell carcinoma of the head and neck

Abstract Conclusion: The low-dose regimen brought less grade 3–4 neutropenia and mucositis with similar treatment efficacy. It should be further investigated in prospective randomized clinical trials to confirm its effectiveness and tolerability. Objectives: This nonrandomized study compared the efficacy and toxicity profiles of two dose levels of cisplatin/5-fluorouracil (5-FU) as the chemoradiotherapy regimen for the treatment of locally advanced squamous cell carcinoma of the head and neck. Methods: Concurrent chemotherapy consisted of two dose levels: a low dose (cisplatin 12 mg/m2 + 5-FU 600 mg/m2 per day) or a high dose (cisplatin 15 mg/m2 + 5-FU 750 mg/m2 per day). Both were administered as a 5-day continuous infusion in week 1 and week 5 during radiotherapy. Results: With a median follow-up of 44 months, the overall survival and disease-free survival were 35 months and 22 months (n = 67) for the low-dose group and 36 months and 33 months for the high-dose group (n = 96). The 2-year locoregional control rate was 67.2% for the low-dose and 66.8% for the high-dose group. No statistically significant differences were demonstrated in the treatment efficacy end points. The high-dose regimen resulted in significantly more grade 3–4 neutropenia (31.5% vs 10.9%, p = 0.003) and a trend towards more mucositis (62.1% vs 49.3%, p = 0.066).

EGF and EGFR genetic polymorphisms predict prognosis in locally advanced pharyngolaryngeal squamous cell carcinoma patients receiving postoperative concurrent chemoradiotherapy

Background Epidermal growth factor (EGF) and its receptor (EGFR) are part of an important signaling pathway that is involved in the pathogenesis of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that EGF/EGFR genetic polymorphisms might have a prognostic impact on disease-free survival and overall survival (OS) in locally advanced SCCHN. Materials and methods The patient group included a consecutive cohort of 180 patients with locally advanced SCCHN who underwent postoperative concurrent chemoradiotherapy between 2002 and 2010. DNA from formalin-fixed, paraffin-embedded tumor tissues was genotyped for the single nucleotide polymorphism (SNP) of EGF A61G A>G, EGFR R521K G>A and G-216T. The log-rank test was applied to evaluate the impact of SNPs on the outcomes. Survival was estimated using the Kaplan–Meier statistical method. Results We demonstrated that EGF/EGFR SNPs might predict prognosis in patients with primary pharyngolaryngeal tumors, but not in those with oral cavity tumors. In pharyngolaryngeal tumor subgroup, EGF61 G/G genotype led to worse 5 year OS rate when compared to G/A or A/A genotypes (13.3% versus 34.3% versus 50.0%, P=0.017). The 5 year OS of patients with EGFR R521K G/G (11.1%) and G/A (15.9%) were lower than the A/A (62.5%) genotype (P=0.054). Patients carrying one or two unfavorable alleles had worse 5 year OS than those without unfavorable allele (not available versus 20% versus 71.4%, P=0.002). Multivariate analysis revealed that the highest risk of death was associated with the coexistence of two unfavorable genotypes (hazard ratio 25.7, 95% confidence interval =3.4–193.4; P=0.002). Conclusion In this study, we were able to demonstrate that the EGF A61G and EGFR R521K genetic polymorphisms might be important prognostic factors in patients with locally advanced primary pharyngolaryngeal squamous cell carcinoma who underwent postoperative concurrent chemoradiotherapy.