Jonathan C. Irish

Identification of a microRNA signature associated with progression of leukoplakia to oral carcinoma

MicroRNAs (miRs) are non-coding RNA molecules involved in cancer initiation and progression. Deregulated miR expression has been implicated in cancer; however, there are no studies implicating an miR signature associated with progression in oral squamous cell carcinoma (OSCC). Although OSCC may develop from oral leukoplakia, clinical and histological assessments have limited prognostic value in predicting which leukoplakic lesions will progress. Our aim was to quantify miR expression changes in leukoplakia and same-site OSCC and to identify an miR signature associated with progression. We examined miR expression changes in 43 sequential progressive samples from 12 patients and four non-progressive leukoplakias from four different patients, using TaqMan Low Density Arrays. The findings were validated using quantitative RT-PCR in an independent cohort of 52 progressive dysplasias and OSCCs, and five non-progressive dysplasias. Global miR expression profiles distinguished progressive leukoplakia/OSCC from non-progressive leukoplakias/normal tissues. One hundred and nine miRs were highly expressed exclusively in progressive leukoplakia and invasive OSCC. miR-21, miR-181b and miR-345 expressions were consistently increased and associated with increases in lesion severity during progression. Over-expression of miR-21, miR-181b and miR-345 may play an important role in malignant transformation. Our study provides the first evidence of an miR signature potentially useful for identifying leukoplakias at risk of malignant transformation.

Atypical clinical behavior of p16-confirmed HPV-related oropharyngeal squamous cell carcinoma treated with radical radiotherapy.

PURPOSE To report atypical clinical behavior observed in human papillomavirus (HPV)-related oropharyngeal carcinoma (OPC) treated with radiotherapy. METHODS AND MATERIALS A retrospective cohort study was conducted for all newly diagnosed OPC cases treated with radiotherapy on July 1, 2003 to April 30, 2009. HPV positivity was determined by p16 immunostaining in tumors. The incidence of additional malignancies and the pattern of distant metastases (DMs) were compared between the HPV-positive (HPV+) and HPV-negative (HPV-) cohorts. RESULTS HPV status was evaluated in 318 of 613 consecutive OPC cases (52%), showing 236 HPV+ and 82 HPV- patients. Compared with HPV-, HPV+ cases were less likely to have additional malignancies (prior: 11% vs. 20%, p = 0.038; synchronous: 1% vs. 9%, p = 0.001; metachronous: 6% vs. 16%, p = 0.003). Whereas the majority (10 of 12) of HPV- additional head-and-neck (HN) mucosal malignancies were in the oral cavity, there was none (0 of 7) in the HPV+ cohort (p < 0.001). HPV+ synchronous HN second primaries (SPs) were in the supraglottis, post-cricoid, and nasopharynx; metachronous HN SPs were in the glottis, supraglottis, and ethmoid plus glottis/post-cricoid region. All SPs that could be tested were HPV+. There was no difference in DM rate (10% vs. 15%, p = 0.272), but HPV+ DMs were more likely to involve multiple organs (46% vs. 0%, p = 0.005) and unusual sites. CONCLUSIONS This study reports atypical clinical behavior seen in HPV+ OPC, including multicentric lesions in HN mucosa and DM to multiple organs and unusual sites. The frequency of these events is low, but they may have clinical implications. The routine assessment of HPV status for all OPC is warranted.

The free iliac crest and fibula flaps in vascularized oromandibular reconstruction: comparison and long-term evaluation.

A variety of free flaps have been successfully used for mandible reconstruction. This study compared the short‐ and long‐term results of using the free iliac crest and fibula flaps.

Postlaryngectomy Voice Rehabilitation: State of the Art at the Millennium

Total laryngectomy or laryngopharyngectomy remains the procedure of choice for advanced laryngeal/hypopharyngeal carcinoma, either as a primary procedure or as salvage following irradiation alone or concurrent chemoradiation therapy. Over the past 25 years there has been significant improvement in the rehabilitation of these patients, with speech restoration that has dramatically altered and improved their quality of life. This article reviews postlaryngectomy voice rehabilitation with a historical background as well as the present state-of-the-art tracheoesophageal shunt voice with an artificial valve. Finally, this article reviews and compares artificial valve prostheses as to their voice characteristics, patient satisfaction, complications associated with the procedure, and devices used at a center in Europe (The Netherlands Cancer Institute, Amsterdam) and a North American center (The Wharton Head and Neck Center, Princess Margaret Hospital, University of Toronto, Canada).

Investigation of C‐Arm Cone‐Beam CT‐Guided Surgery of the Frontal Recess

Objective/Hypothesis: A cone‐beam CT (CBCT) imaging system based on a mobile C‐arm (Siemens PowerMobil) incorporating a high‐performance flat‐panel detector (Varian PaxScan) has been developed in our laboratory. We hypothesize that intraoperative C‐arm CBCT provides image quality and guidance performance sufficient to assist surgical approach to the frontal recess.

Molecular cytogenetic analysis of head and neck squamous cell carcinoma: By comparative genomic hybridization, spectral karyotyping, and expression array analysis†

A combination of molecular cytogenetic and expression array analysis has been performed on head and neck squamous cell carcinoma (HNSCC) of the oral cavity and supraglottis. These studies were performed to identify consensus regions of chromosomal imbalance and structural rearrangement to determine whether genes located in these genomic regions are subject to alterations in gene expression. Such combinatorial studies may help to identify recurrent patterns of altered gene expression in the context of specific chromosomal changes.

Clinicopathologic and therapeutic risk factors for perioperative complications and prolonged hospital stay in free flap reconstruction of the head and neck

We aimed to determine predictors of morbidity in patients undergoing microvascular free flap reconstruction of the head and neck.

A Matched Control Study of Treatment Outcome in Young Patients With Squamous Cell Carcinoma of the Head and Neck

Objectives/Hypothesis: To determine if there is a difference in overall survival, cause‐specific survival, and relapse‐free rate between young patients (<40 years of age) with head and neck squamous cell carcinoma (HNSCC) and older patients (>40 years of age). Study design: A matched control study describing the outcome of 185 previously untreated HNSCC patients less than 40 years of age treated at the Princess Margaret Hospital, Toronto, Ontario, Canada, between 1958 and 1992. The young patient group was compared with a control group of older patients (> 40 years of age) which was selected randomly from an entire cohort of patients (n = 10,072) and matched for site, sex, and date of presentation. Methods: The medical records were reviewed and data abstracted for demographic information, tobacco and alcohol use, family history, primary site, clinical stage, primary treatment, histology, the occurrence of residual or recurrent disease, salvage treatment, development of subsequent primaries, survival, and the eventual cause of death. The patients TNM stage was reclassified according to American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) 1992 criteria on the basis of the initial clinical description and staging investigations. A multivariate regression analysis was performed. To assess the importance of age as a prognostic factor for survival, the Cox proportion hazard model was used. Smoking status was also tested in the stratified Cox proportional hazard model. Results: Tumor stage and treatment modalities were comparable in both groups. The 5‐year, cause‐specific survival in both groups was not statistically different (72% vs. 68%, P = .91). The young patient group had a significantly better 5‐year overall survival compared with the older patient group (68% vs. 49%, P = .0011). Older patients developed more subsequent primary neoplasms than the younger patient population (18% vs. 8%, P = .005). There were significantly more females, an increased incidence of oral or oropharyngeal cancer, and fewer smokers in the young patient group. Smoking, however, had an important impact on outcome with all but one patient who developed a second primary in the upper aerodigestive tract having smoked. Multivariate analysis showed that only disease stage and cancer site were significant prognostic factors for survival. Conclusions: Young patients with HNSCC do not have a worse prognosis than a matched older patient group in this case‐controlled study (power > 0.75 for a minimal detectable difference of 10% disease‐free survival between the two groups).

Oncogenes in head and neck cancer

Primary head and neck squamous cell carcinomas from 58 patients were analyzed for the presence of alterations in the K‐ras, raf, and erb‐B oncogenes. Analysis of 17 fresh tumor specimens using sequence analysis of target sequences amplified by the polymerase chain reaction showed no evidence of mutations in the K‐ras oncogene. Thirty fresh tumor specimens were analyzed for the presence of raf gene activation using Southern blot analysis. Under these conditions, no mutations in the c‐raf oncogene were detected.

Intraoperative cone-beam CT for guidance of temporal bone surgery.

OBJECTIVES: To describe our preclinical experience with Cone Beam CT (CBCT) in image-guided surgery of the temporal bone. STUDY DESIGN AND SETTINGS: A mobile isocentric C-arm (PowerMobil, Siemens Medical Systems, Erlangen, Germany) modified to include a flat-panel detector (Varian Imaging Products, Palo Alto, CA) and a motorized orbit was developed to acquire multiple projections in rotation about a subject. Initial experiments imaging steel wire in air were used to investigate the systems spatial resolution in 3D image reconstruction. Subsequently temporal bone dissection was performed on five cadaver heads using the modified C-arm as an image guidance system. RESULTS: We obtained a spatial resolution of 0.85 mm. The image acquisition time was 120 seconds and the radiation dose approximately one-tenth of a conventional CT scan. CONCLUSION: CBCT provided submillimeter accuracy at high speed with low radiation dosage to offer utility as an intraoperative imaging system. SIGNIFICANCE: CBCT offers technology that approximates “near-real-time” image guidance. EBM rating: C-4