Otolaryngologists
20 years of experience
Video profile
Accepting new patients
Medical Center
Karmanos Cancer Center - Bone Marrow Transplant
4100 John R St
Detroit, MI 48201
800-527-6266
Locations and availability (2)

Education ?

Medical School Score Rankings
University of Kansas (1990)
  • Currently 3 of 4 apples
Top 50%

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Head and Neck Cancer (Head and Neck Neoplasm)
Squamous Cell Carcinoma
Hour Detroit Magazine's TOP DOCS+
Hour Detroit Magazine's TOP DOCS: 2010, 2011, 2012
Voted Best Doctors 2011-2012
Castle Connolly America's Top Doctors® (2009, 2013 - 2014)
Castle Connolly America's Top Doctors® for Cancer (2014)
Associations
American Head and Neck Society
American Academy of Otolaryngology: Head and Neck Surgery
American College of Surgeons
American Board of Otolaryngology

Affiliations ?

Dr. Yoo is affiliated with 21 hospitals.

Hospital Affilations

Score

Rankings

  • St. John Hospital & Medical Center
    Otolaryngology
    22101 Moross Rd, Detroit, MI 48236
    • Currently 4 of 4 crosses
    Top 25%
  • Harper University Hospital
    Otolaryngology
    3990 John R St, Detroit, MI 48201
    • Currently 3 of 4 crosses
    Top 50%
  • Rehabilitation Institute of Michigan
    Otolaryngology
    261 Mack Ave, Detroit, MI 48201
    • Currently 3 of 4 crosses
    Top 50%
  • St John Detroit Riverview Hospital
    7733 E Jefferson Ave, Detroit, MI 48214
    • Currently 3 of 4 crosses
    Top 50%
  • St. John Macomb-Oakland Hospital (Oakland Center)
    27351 Dequindre Rd, Madison Heights, MI 48071
    • Currently 3 of 4 crosses
    Top 50%
  • DMC - Sinai-Grace Hospital
    Otolaryngology
    6071 W Outer Dr, Detroit, MI 48235
    • Currently 3 of 4 crosses
    Top 50%
  • Detroit Receiving Hospital & University Health Center
    Otolaryngology
    4201 Saint Antoine St, Detroit, MI 48201
    • Currently 3 of 4 crosses
    Top 50%
  • John D Dingell Va Medical Center
  • Hutzel Hospital
  • Detroit Receiving Hospital
  • Harper Hospital
  • Detroit Receiving - UHC
  • Detroit Receiving
  • Children's Hospital of Michigan
    3901 Beaubien St, Detroit, MI 48201
  • Rehabilitation
  • Hutzel Women's Hospital
    3980 John R St, Detroit, MI 48201
  • Sinaigrace Hospital
  • Karmanos Cancer Center
    4100 John R St, Detroit, MI 48201
  • Sinai-Grace Hospital
    6071 W Outer Dr, Detroit, MI 48235
  • Grace Hospital
  • Sinai-Grace
  • Publications & Research

    Dr. Yoo has contributed to 61 publications.
    Title Xrp6258-induced Gene Expression Patterns in Head and Neck Cancer Carcinoma.
    Date July 2010
    Journal The Laryngoscope
    Excerpt

    XRP6258 is a novel taxoid, which has antitumor activity in preclinical mouse orthotopic and human xenograft cancer models. However, limited XRP6258 studies have been performed in head and neck squamous cell carcinoma cells (HNSCC). The objective of this study is to identify the antitumor activity of XRP6258 in HNSCC cell line models.

    Title Intratumoral Delivery of Docetaxel Enhances Antitumor Activity of Ad-p53 in Murine Head and Neck Cancer Xenograft Model.
    Date May 2010
    Journal American Journal of Otolaryngology
    Excerpt

    The aim of this study is to determine the ability of intratumorally delivered docetaxel to enhance the antitumor activity of adenovirus-mediated delivery of p53 (Ad-p53) in murine head and neck cancer xenograft model.

    Title A Phase 2 Trial of Surgery with Perioperative Ingn 201 (ad5cmv-p53) Gene Therapy Followed by Chemoradiotherapy for Advanced, Resectable Squamous Cell Carcinoma of the Oral Cavity, Oropharynx, Hypopharynx, and Larynx: Report of the Southwest Oncology Group.
    Date October 2009
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    To assess the feasibility of treating patients with high-risk stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx with perioperative adenovirus-p53 (INGN 201) gene therapy along with surgery and chemoradiotherapy.

    Title Fine Needle Aspiration of Head and Neck Masses in the Operating Room: Accuracy and Potential Benefits.
    Date August 2008
    Journal Diagnostic Cytopathology
    Excerpt

    Fine needle aspiration (FNA) in the operating room is a convenient optional diagnostic approach. Our objective of this study was to evaluate the accuracy and study the potential benefits of fine needle aspiration in the operating room.Retrospective review of all intraoperative FNA that were requested and performed by pathologists over 20-month period was carried out. Immediate smears were interpreted by the cytopathology team after staining with Diff Quik stain. All cases were reviewed and correlation with subsequent tissue diagnosis was done. Accuracy was calculated and potential benefits were discussed. The number of aspirates was 32. Adequate material for immediate and final interpretation was achieved in 31 cases (sensitivity 97%). In 20 cases (63%), malignancy was diagnosed while a benign diagnosis was rendered in 12 (37%). All cases had a follow up tissue diagnosis. No false-positive cases were identified (specificity 100%). The information gained from this approach was considered helpful to the surgeons. We concluded that FNA of head and neck masses in the operating room is an accurate and sensitive diagnostic approach. The service provides helpful information to surgeons and is an additional optional diagnostic approach.

    Title Effect of Docetaxel on the Surgical Tumor Microenvironment of Head and Neck Cancer in Murine Models.
    Date July 2008
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVES: To identify the antitumor activity and wound-healing effect of docetaxel delivered in the surgical tumor microenvironment of head and neck squamous cell carcinoma (HNSCC). DESIGN: Control and experimental series. SETTING: Academic medical center. SUBJECTS: BALB/c and severe combined immunodeficiency mice. INTERVENTION: Intrawound (IW) docetaxel therapy was tested in 3 HNSCC xenograft and 2 taxane-resistant models. Intratumoral (IT) docetaxel therapy was further tested in the 2 taxane-resistant models. MAIN OUTCOME MEASURES: Tumor size, survival, and wound toxic effects were measured. The effect of docetaxel on various factors involved in wound healing and tumor growth within the surgical tumor microenvironment was also analyzed. RESULTS: In a pilot study using BALB/c mice, IW docetaxel therapy was not associated with problems in wound healing. Using the HN6, HN12, and HN30 HNSCC xenograft model, IW docetaxel prevented tumor growth and improved survival when compared with controls. No local or systemic toxic effect or wound-healing problem was noted. Using taxane-resistant xenograft lung cancer (H460/T800) and syngeneic salivary cancer (BALB/c mucoepidermoid carcinoma) models, IW therapy did not delay tumor growth. An antitumor effect was detected with repeated docetaxel injections in the H460/T800 taxane-resistant model but not in the BALB/c mucoepidermoid carcinoma model. Docetaxel inhibited the expression of growth factors and receptors in tumor cells; however, it did not inhibit the level of wound-healing growth factors in the surgical tumor microenvironment. CONCLUSIONS: These preclinical results support further testing of IW docetaxel treatment in HNSCC. Docetaxel appears to exert antitumor activity without affecting factors involved in wound healing in the tumor microenvironment.

    Title Autoantibody Approach for Serum-based Detection of Head and Neck Cancer.
    Date May 2008
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Excerpt

    Currently, no effective tool exists for screening or early diagnosis of head and neck squamous cell carcinoma (HNSCC). Here, we describe an approach for cancer detection based on analysis of patterns of serum immunoreactivity against a panel of biomarkers selected using microarray-based serologic profiling and specialized bioinformatics. We biopanned phage display libraries derived from three different HNSCC tissues to generate 5,133 selectively cloned tumor antigens. Based on their differential immunoreactivity on protein microarrays against serum immunoglobulins from 39 cancer and 41 control patients, we reduced the number of clones to 1,021. The performance of a neural network model (Multilayer Perceptron) for cancer classification on a data set of 80 HNSCC and 78 control samples was assessed using 10-fold cross-validation repeated 100 times. A panel of 130 clones was found to be adequate for building a classifier with sufficient sensitivity and specificity. Using these 130 markers on a completely new and independent set of 80 samples, an accuracy of 84.9% with sensitivity of 79.8% and specificity of 90.1% was achieved. Similar performance was achieved by reshuffling of the data set and by using other classification models. The performance of this classification approach represents a significant improvement over current diagnostic accuracy (sensitivity of 37% to 46% and specificity of 24%) in the primary care setting. The results shown here are promising and show the potential use of this approach toward eventual development of diagnostic assay with sufficient sensitivity and specificity suitable for detection of early-stage HNSCC in high-risk populations.

    Title Gefitinib Prevents Cancer Progression in Mice Expressing the Activated Rat Her2/neu.
    Date March 2008
    Journal International Journal of Cancer. Journal International Du Cancer
    Excerpt

    We tested the efficacy of gefitinib in the prevention of HER2/neu-mediated breast cancer development in BALB-NeuT transgenic mice. Oral administration of gefitinib to female transgenic mice from 5 to 14 weeks of age reduced tumor multiplicity from 9.6 +/- 0.82 to 0.58 +/- 1.1 (83%). We observed a decrease in the number and size of lobules and lobular nodules in treated mice with a reduction in the overall disease burden per gland. Normal duct development in the mammary glands was not affected by gefitinib. The development of acinic cell carcinoma in the parotid glands of these animals was also reduced coincident with decreased stromal involvement during progression. Gefitinib eliminated phosphorylation of HER2 and HER3 and signaling through MAPK and Akt in lobular hyperplasias and carcinomas. At the same time MAPK activity and cytokine production in splenocytes and lymph nodes was increased in gefitinib-treated animals coincident with an increase in lymph node size. Delaying gefitinib treatment until mammary glands exhibited atypical lobular hyperplasias reduced efficacy. These studies demonstrate the critical role of HER2 signal transduction in the onset and progression of HER2/neu-dependent breast cancer and suggest a role for specific inhibitors to prevent the outgrowth of early hyperplastic disease.

    Title Bms-275183-induced Gene Expression Patterns in Head and Neck Carcinoma.
    Date January 2008
    Journal American Journal of Otolaryngology
    Excerpt

    PURPOSE: BMS-275183 is an orally bioavailable taxane that has antitumor activity in preclinical cancer models. However, limited BMS-275183 studies have been performed in head and neck squamous cell carcinoma (HNSCC) cell lines. The purpose of this study is to identify the biological activity of BMS-275183 on HNSCC. MATERIALS AND METHODS: Head and neck squamous cell carcinoma cell lines, HN6, HN12, and HN30, were exposed to BMS-275183. BMS-275183-induced growth suppression, cell-cycle arrest, and apoptosis were measured. Then, expression of selected proteins that were induced by BMS-275183 was determined by Western blot analysis. RESULTS: BMS-275183 suppressed proliferation and induced G(2)M arrest and apoptosis in all HNSCC cell lines tested. BMS-275183 altered the expression of cell-cycle regulators, such as cyclin A and cyclin B1. The expression of E2F and p27 was decreased and increased, respectively, in all HNSCC cell lines. Cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) were increased in HN6 and HN12 cells. epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) expression were decreased by BMS-275183 in HN6 and HN30 cell lines, whereas phosphorylated epidermal growth factor receptor (pEGFR) was decreased in only HN6 cells. CONCLUSIONS: BMS-275183 induced cellular apoptosis, cell-cycle arrest, and altered gene expression in HNSCC via molecular pathways similar to other taxanes. These preclinical experiments suggest that BMS-275183 may be useful in treating HNSCC and that the aforementioned genes can potentially be used as surrogate end-point biomarkers.

    Title Investigation of the Air Kerma Response of Spherical Ionization Chambers for Unfolded Pulse Height Distributions of (60)co and (137)cs Using the Egs4 Monte Carlo Code.
    Date December 2007
    Journal Journal of Radiation Research
    Excerpt

    Data required for the determination of the absolute air kerma rate for (60)Co and (137)Cs gamma-rays using spherical cavity chambers were calculated using the EGS4 Monte Carlo system. Mass energy-absorption coefficient ratio and the stopping power ratio were calculated for a 10 cm(3) primary standard graphite-walled ionization chamber from the unfolded energy pulse height distributions of (60)Co and (137)Cs sources. Wall correction factors and non-uniformity correction factors for two graphite and one air equivalent plastic walled ionization chambers were also calculated with EGS4 code. The wall correction factors were compared with those determined by an experimental extrapolation method. To check the accuracy of the calculations the results were compared with those obtained from other primary standard laboratories such as NIST and NRCC. For a 10 cm(3) graphite ionization chamber, the mass energy-absorption coefficient ratios were 0.99917 for (60)Co and 1.0004 for (137)Cs. The values differed by 0.02-0.05 % for (60)Co and 0.11 % for (137)Cs from those of two laboratories. The stopping power ratios were 0.99984 for (60)Co and 1.0087 for (137)Cs. Comparison with NIST values showed differences of 0.06 % for (60)Co and 0.04 % for (137)Cs. The wall correction factors were obtained and they were different by 0.6-1.1 % for (60)Co and (137)Cs compared to the experimental linear extrapolation method. These values were compared with Monte Carlo derived values from other laboratories. The non-uniformity correction factors were also calculated and they differed from unity, the traditional value used in most standard national metrology laboratories.

    Title Transoral Carbon Dioxide Laser Supraglottic Laryngectomy and Irradiation in Stage I, Ii, and Iii Squamous Cell Carcinoma of the Supraglottic Larynx: Report of Southwest Oncology Group Phase 2 Trial S9709.
    Date October 2007
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To evaluate feasibility, functional outcome, and disease control of endoscopic surgery and irradiation in patients with squamous cell carcinoma of the supraglottic larynx. DESIGN: Prospective, single-arm, phase 2 multi-institutional trial. SETTING: Southwest Oncology Group trial S9709. PATIENTS: Thirty-four patients diagnosed as having stage I, stage II, or selected stage III (T1-2N1M0) supraglottic laryngeal carcinoma enrolled from September 15, 1997, to December 1, 2001. INTERVENTIONS: Transoral supraglottic laryngectomy by carbon dioxide laser followed by planned postoperative radiotherapy. MAIN OUTCOME MEASURES: Three-year progression-free survival, proportion of patients requiring tracheostomy as a result of surgery, and time to adequate oral intake. RESULTS: All 34 patients underwent surgery without major protocol deviation. Thirty-two patients (94%) completed planned postoperative radiotherapy without major deviation. At the time of analysis, only 1 patient (3%) had documented local disease recurrence at the primary disease site and required salvage total laryngectomy, and 2 patients (6%) had documented regional recurrence and required salvage neck dissection. Estimated 3-year progression-free survival and overall survival were 79% and 88%, respectively. No subjects required tracheostomy as a direct consequence of endoscopic resection. Patients who required tracheostomy before endoscopic resection due to either obstructive tumor bulk or unfavorable anatomy that precluded safe intubation (4 patients [12%]) were all decannulated in the early postoperative period (<or=1 week). Of the 34 patients, 24 (71%) recovered adequate oral intake (no longer requiring supplemental intravenous fluids or tube feeding) in the early postoperative period (before hospital discharge) (median time, 2 days; range, 1-7 days), with an additional 7 patients (21%) achieving delayed recovery (2.7-9.8 months). Three patients (9%) remained dependent on a feeding tube at last documented follow-up. CONCLUSIONS: Transoral endoscopic carbon dioxide laser excision of supraglottic tumors combined with postoperative radiotherapy appears feasible in a multi-institutional setting, with reasonable disease control. Although timing was variable, most patients recovered adequate swallowing in the early postoperative period.

    Title Dissecting the Akt/mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative.
    Date September 2007
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma. EXPERIMENTAL DESIGN: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array. RESULTS: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR. CONCLUSIONS: These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.

    Title Breast Cancer Expressing the Activated Her2/neu is Sensitive to Gefitinib in Vitro and in Vivo and Acquires Resistance Through a Novel Point Mutation in the Her2/neu.
    Date August 2007
    Journal Cancer Research
    Excerpt

    The HER2/neu oncogene is an important diagnostic and prognostic factor and therapeutic target in breast and other cancers. We developed and characterized a breast cancer cell line (Bam1a) that overexpresses the activated HER2/neu and ErbB-3 and has a gene expression profile consistent with the ErbB-2 genetic signature. We evaluated the effects of the epidermal growth factor receptor (EGFR)/HER2 inhibitor, gefitinib, on this breast tumor line in vitro and in vivo. We characterized the effects of gefitinib on EGFR, HER2, and ErbB-3 phosphorylation by Western blot and determined the effects on downstream signaling through growth, survival, and stress pathways and the effect on proliferation, cell cycle, and apoptosis. Gefitinib treatment diminished phosphorylation of the ErbB-3 > EGFR > HER2/neu and signal transducers and activators of transcriptions in a dose-dependent fashion. Downstream mitogenic signaling through mitogen-activated protein (MAP)/extracellular signal regulated kinase kinase, p44/42 MAP kinase (MAPK) and stress signaling through c-Jun-NH(2)-kinase (JNK) 1 and c-Jun was impaired (1 micromol/L, 4-24 h), leading to cytostasis and cell cycle arrest within 24 h by decreased cyclin D1, cyclin B1, and p(Ser795)Rb and increased p27. Proliferation and colony formation were inhibited at 0.5 and 1 micromol/L, respectively, and correlated with altered gene expression profiles. Diminished survival signaling through Akt, induction of bim, loss of connexin43, and decreased production of vascular endothelial growth factor-D preceded caspase-3 and poly(ADP)ribose polymerase (PARP) cleavage and apoptosis (>50% 2 micromol/L, 48 h). Oral administration of gefitinib was able to prevent the outgrowth of Bam1a tumor cells from palpable lesions, shrink established tumors, eliminate HER2 and HER3 phosphorylation, and decrease MAPK and Akt signaling in vivo. A variant of the Bam1a cell line, IR-5, with acquired ability to grow in 5 micromol/L gefitinib was developed and characterized. IR-5 bears a novel point mutation in the HER2/neu that corresponds to a L726I in the ATP-binding pocket and correlates with a log decrease in sensitivity to gefitinib, increased heterodimerization with EGFR and HER3, and impaired down-regulation. Gene expression profiling of IR-5 showed increased expression of EMP-1, NOTCH-1, FLT-1, PDGFB, and several other genes that may contribute to the resistant phenotype and sustain signaling through MAPK and Akt. This model will be useful in understanding the differences between intrinsic drug sensitivity and acquired resistance in the context of therapeutic strategies that target oncogene addicted diseases.

    Title Benefit of Postoperative Chemoradiotherapy for Patients with Unknown Primary Squamous Cell Carcinoma of the Head and Neck.
    Date January 2007
    Journal Head & Neck
    Excerpt

    BACKGROUND: Postopertative adjuvant chemoradiotherapy recently became an established modality for patients with selected high-risk locally advanced head and neck cancers. The optimal treatment of unknown primary squamous cell cancer of the head and neck (SCCHN) continues to be controversial, since major randomized studies excluded those patients. METHODS: We conducted a retrospective review of patients treated during 1995 to 2002 for unknown primary SCCHN. All patients were treated with a neck dissection followed by concurrent high-dose cisplatin (100 mg/m(2)) and bilateral neck radiotherapy. RESULTS: Thirty-seven patients were identified with nodal disease distribution of N1 (5%), N2a (22%), N2b (41%), N2c (8%), N3 (22%), and Nx (3%). Modified neck dissection was done on the majority (30/37 = 81%) of patients. With a median follow-up of 42 months among the survivors, very few patients had regional recurrence (5%) or distant failure (11%), and 89% of patients were alive. The actuarial 5-year overall survival rate could not be estimated because there were no deaths beyond 20 months after surgery. Substantial yet acceptable acute and late morbidities were demonstrated in this cohort of patients. CONCLUSIONS: Postoperative chemoradiotherapy is of potential benefit to patients with unknown primary SCCHN by improving survival and reducing failures. This treatment warrants further prospective evaluation.

    Title A Novel Mutation W252x in the Was Gene in a Korean Patient with Wiskott-aldrich Syndrome.
    Date December 2006
    Journal International Journal of Hematology
    Excerpt

    Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder characterized by recurrent infection, eczema, and microthrombocytopenia. WAS is inherited in an X-linked recessive pattern, and various mutations in the WAS gene on the X chromosome are the genetic basis of WAS. A 7-month-old Korean boy presented with recurrent bloody diarrhea, eczema, and persistent thrombocytopenia with small platelets. Direct sequence analysis of the entire coding region of the WAS gene showed a novel nonsense mutation with a G-to-A substitution at the nucleotide position 756 on exon 8, leading to a premature termination at codon 252 (c.756G>A; p.W252X). Family study revealed that neither of the parents had the mutation, indicating the de novo occurrence of the mutation.

    Title Iressa Induces Cytostasis and Augments Fas-mediated Apoptosis in Acinic Cell Adenocarcinoma Overexpressing Her2/neu.
    Date July 2006
    Journal International Journal of Cancer. Journal International Du Cancer
    Excerpt

    Understanding the role of signal transduction in regulating pathways responsible for cell growth, survival and apoptosis is critical for cancer therapy. We developed and characterized a HER2/neu and Fas overexpressing cell line (BNT.888 ACA2) from a salivary gland adenocarcinoma that arose in a HER2/neu transgenic mouse. We evaluated the effects of Iressa on signal transduction networks downstream of the activated HER2 and the impact on proliferation, cell cycle and apoptosis. Iressa treatment diminished phosphorylation of the HER2/neu and EGFR. Phosphorylation of STAT-3 also decreased and mitogenic signaling through the MAPK pathways was greatly reduced. Cyclin D1 levels decreased, and cells were arrested in G0 and failed to enter S-phase because of hypophosphorylation of Rb and to traverse the G2M checkpoint because of degradation of cyclin B1. Cytostasis occurred within 48 hr at 250-500 nM Iressa. Levels of proapoptotic factors (bim and bax) increased and levels of antiapoptotic factors (bcl-2 and bcl-xL) decreased in a dose-dependent manner. Higher doses of Iressa diminished phosphorylation of Akt slightly, but failed to induce apoptosis. Fas antibody was a potent agonist of apoptosis. Pretreatment with Iressa (1 microM, 24 hr) greatly enhanced Fas-mediated apoptosis as determined by Annexin V binding, cleavage of caspase-3 and PARP. Augmentation of apoptosis was associated with increased Fas expression and membrane localization. Iressa pretreatment increased bid activation, cleavage of caspases -3, -9 and -12 and stress signaling via c Jun. These data showing that Iressa induces cytostasis and primes the extrinsic (Fas) and intrinsic (mitochondrial and endoplasmic reticulum) apoptotic pathways should lead to the development of novel therapeutic targets and strategies.

    Title Application of Unfolding Technique to Hpge Detector Using Response Functions Calculated with the Egs4 Monte Carlo Code.
    Date May 2006
    Journal Journal of Radiation Research
    Excerpt

    The EGS4 Monte Carlo simulation technique was used to obtain the energy spectra of photons arriving at a detector from the pulse height distributions measured by the same detector. First, the measured pulse height distribution for incident photons from several radiation sources such as 60Co, 137Cs, 152Eu and 207Bi with a collimator are compared with those calculated using the EGS4 code to investigate the feasibility of the simulation. The comparison showed good agreement of 98.7% for 60Co, 92.5% for 207Bi on the total counts. Second, the pulse height distributions were measured in the open space and then unfolded. The measurement of the distributions was done with changing the source to detector distance (SDD) from 10 cm to 100 cm for 60Co and 137Cs respectively. In the unfolding process, response functions of a high purity Ge (HPGe) detector were calculated using the EGS4 code. The calculated pulse height distributions were then normalized to the measured ones at the peaks of the incident photon energies. The ratio of the sum of counts of the main peaks to the total count in the unfolded spectra for 60Co varied from 5.4 to 5.7 times greater than those in the measured pulse height distributions, while from 2.5 to 2.9 times for 137Cs. Electron contribution to the unfolded spectra for 137Cs decreased as the source to detector distance increased, becoming negligible above 50 cm. The pulse height distributions at the center of the reference plane at 100 cm from the 60Co and 137Cs dummy sources located inside each irradiator were also measured and unfolded to obtain the real pulse height distribution. In the unfolded spectra, the photons scattered from the surrounding materials were reduced to approximately one fourth of those measured in the open space due to the small size of apertures of the irradiators. The ratio of the sum of counts for the main peaks to the total count was larger than those in the measured pulse height distributions by the factor of 5.0 for 60Co and 3.4 for 137Cs. The uncertainties estimated in the unfolding processes were around 0.1% for 60Co and 0.07% for 137Cs.

    Title Visual Risks of Facial Fracture Repair in the Setting of Traumatic Optic Neuropathy.
    Date April 2006
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To identify whether facial fracture repair in patients with traumatic optic neuropathy results in visual deterioration. DESIGN: A retrospective analysis was performed of all patients admitted from 1992 through 1997 with the diagnosis of facial fracture and traumatic optic neuropathy. Vision was recorded before and after fracture repair using logarithm of the minimum angle of resolution measurements. Visual outcome was compared with a nonsurgically treated group of patients with a similar diagnosis. SETTING: University trauma hospital. PATIENTS: A total of 700 medical charts were reviewed, and 54 patients met study criteria. All patients received megadose corticosteroid treatment and were divided into 3 groups: (1) facial fracture repair alone, (2) optic nerve decompression (OND) + facial fracture repair, or (3) nonsurgical treatment. RESULTS: For the 16 patients in the fracture repair alone group, 12 (75%) had improved vision and 4 (25%) had no change postoperatively. For the 10 patients in the OND + fracture repair group, 3 (30%) had improved vision, 5 (50%) had no change, and 2 (20%) had worsened vision postoperatively. For the 28 patients in the nonsurgical group, 18 (64%) had improved vision, 9 (32%) had no change, and 1 (4%) had worsened vision by discharge. Facial fracture repair alone and the nonsurgical groups both demonstrated significant visual improvement by discharge. The amount of improvement was not significantly different between all 3 groups (facial fracture repair, 0.38 +/- 0.40; OND + facial fracture repair; 0.32 +/- 1.38; and nonsurgical, 0.69 +/- 1.07). CONCLUSIONS: Facial fracture repair in the setting of traumatic optic neuropathy had no adverse effect on vision. Patients requiring OND + fracture repair had a significantly worse visual prognosis.

    Title Pathological Distribution of Positive Lymph Nodes in Patients with Clinically and Radiologically N0 Oropharyngeal Carcinoma: Implications for Imrt Treatment Planning.
    Date March 2006
    Journal Cancer Journal (sudbury, Mass.)
    Excerpt

    BACKGROUND: We identified involved lymph node groups in patients with oropharyngeal carcinoma and radiologically N0 disease, aiming to define the clinical target volume, and to assess the negative predictive value of CT neck and correlate it to the tumor site, stage, and grade. METHODS AND MATERIALS: Between 1988 and 2000, we evaluated 53 patients who satisfied all of the following criteria: 1) oropharyngeal carcinoma diagnosis; 2) NO stage based on CT; 3) no prior treatment; and 4) primary surgical resection including ipsi-lateral neck dissection. The pathology reports were reviewed to identify the exact site of lymph node involvement. RESULTS: Twenty patients (37.7%) were found to have pathologically positive lymph nodes, yielding a negative predictive value of 62.3% for CT neck. Node levels II, III, and IV were the most commonly involved (26%, 17%, and 11% of all patients, respectively). Fifty percent of patients with T3 and T4 tumors had positive lymph nodes versus 20% of patients with T1 and T2 (P = 0.036). Tumor grade and site were insignificant (P > 0.05). DISCUSSION: Ipsilateral neck levels II-IV should be included during elective nodal irradiation in patients with N0-stage oropharyngeal carcinoma, regardless of the primary tumor site, stage, and grade.

    Title Docetaxel Associated Pathways in Cisplatin Resistant Head and Neck Squamous Cell Carcinoma: a Pilot Study.
    Date January 2006
    Journal The Laryngoscope
    Excerpt

    PURPOSE: This is a pilot study to identify changes in gene and protein expressions after treatment with docetaxel in cisplatin-resistant head and neck squamous cell carcinoma (HNSCC). METHODS: Two cisplatin-resistant HNSCC cell lines, HN30 and HN12, were treated with either docetaxel or cisplatin. After 48 hours, differential gene expression between the two treatment groups (docetaxel-treated cells and cisplatin-treated cells) was analyzed using cDNA microarray. Differential protein expression between these two treatment groups was determined using PowerBlot and Western Blot analysis RESULTS: A total of 150 genes and proteins were found to have differential expression patterns in HNSCC after treatment with docetaxel versus cisplatin. Many of these differentially expressed genes and proteins were involved in the cell cycle (decreased E2F), apoptosis (increased bax), angiogenesis (increased thrombospondin), and signal transduction (decreased epidermoid growth factor receptor) regulatory pathways. CONCLUSIONS: Gene and protein expression are different and distinct between cells treated with docetaxel and cells treated with cisplatin. This finding provides evidence that different molecular pathways leading to cell death are targeted by docetaxel and cisplatin. Future studies focusing on these differentially expressed genes and proteins may improve our understanding, at the molecular level, of the mechanisms responsible for docetaxel-induced apoptosis in cisplatin-resistant HNSCC. Furthermore, these differentially expressed genes and proteins can be exploited as useful surrogate endpoint biomarkers in future clinical trials using docetaxel.

    Title Prognostic Significance of G1 Cell-cycle Inhibitors in Early Laryngeal Cancer.
    Date June 2005
    Journal American Journal of Otolaryngology
    Excerpt

    BACKGROUND: Radiation therapy yields a 2-year local control rate of 80% to 90% in early laryngeal squamous cell carcinoma. However, a subset of early laryngeal cancers has a significantly higher rate of local recurrence and lower rate of overall survival. OBJECTIVE: The objective of this study was determine the prognostic significance of p53, p27, and p21 expression in patients with early laryngeal cancer. METHODS: Expression of p53, p27, and p21 proteins in pretreatment biopsies from sixty-eight patients was analyzed by using immunohistochemistry. Low (</=10% cells) and high (>10% cells) levels of expression were measured. All patients were newly diagnosed and treated with external beam radiation. Other contributing factors were also studied, such as age, sex, race, tumor site, and stage. RESULTS: Forty (58.8%) and 28 (41.2%) lesions were staged as T1 and T2, respectively, whereas 16 (23.5%) and 52 (76.5%) were located in the supraglottis and glottis, respectively. Overexpression of p27, p53, and p21 was found in 36.7%, 60.6%, and 60% of cases, respectively. Overexpression of p27 was found to be a significant predictor of recurrence by multivariate analysis (RR 3.3, P = .017). Overexpression of p21 and/or p53 was not predictive of recurrence. No factor predicted disease specific or nonspecific overall survival. CONCLUSION: Our results indicate the significance of p27 overexpression as an indicator of recurrence in patients with early laryngeal squamous cell carcinoma.

    Title Proteome-wide Analysis of Head and Neck Squamous Cell Carcinomas Using Laser-capture Microdissection and Tandem Mass Spectrometry.
    Date June 2005
    Journal Oral Oncology
    Excerpt

    Remarkable progress has been made to identify genes expressed in squamous cell carcinomas of the head and neck (HNSCC). However, limited information is available on their corresponding protein products, whose expression, post-translational modifications, and activity are ultimately responsible for the malignant behavior of this tumor type. We have combined laser-capture microdissection (LCM) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify proteins expressed in histologically normal squamous epithelium and matching SCC. The protein fraction from approximately 10,000-15,000 normal and tumor cells was solubilized, digested with trypsin, and the resulting peptides were analyzed by LC-MS/MS. Database searching of the resulting sequence information identified 30-55 proteins per sample. Keratins were the most abundant proteins in both normal and tumor tissues. Among the proteins differentially expressed, keratin 13 was much lower in tumors, whereas heat-shock (Hsp) family members were highly expressed in neoplastic cells. Wnt-6 and Wnt-14 were identified in both normal and tumor tissues, respectively, and placental growth factor (PIGF) was detected only in tumors. Immunohistochemical analysis of HNSCC tissues revealed lack of keratin 13 in tumor tissues, and strong staining in normal epithelia, and high expression of Hsp90 in tumors. Our study, by combining LCM and proteomic technologies, underscores the advantages of this approach to investigate complex changes at the protein level in HNSCC, thus complementing existing and emerging genomic technologies. These efforts may likely result in the identification of new biomarkers for HNSCC that can be used to diagnose disease, predict susceptibility, and monitor progression in individual patients.

    Title An in Vivo Evaluation of Docetaxel Delivered Intratumorally in Head and Neck Squamous Cell Carcinoma.
    Date June 2005
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To identify activity and biological mechanisms of intratumoral (IT) docetaxel on head and neck squamous cell carcinoma (HNSCC). METHODS: Docetaxel IT therapy was tested in xenograft models of 2 HNSCC lines, HN30 and HN12. The overall and disease-free survival rates, tumor growth, and toxic effects were measured. The pharmacokinetic profiles of docetaxel in plasma and tumor were compared after IT and intravenous (IV) administration. Comparisons between common and supradoses of docetaxel with regard to expression of regulators in the cell cycle, apoptosis, and signal transduction pathways were determined using Western blot analysis. RESULTS: In the HN30 and HN12 xenograft models, IT docetaxel improved overall as well as disease-free survival and reversed tumor growth. The only toxic effects noted were local (alopecia and skin breakdown). Skin breakdown resolved in all cases. At equivalent dosing levels, IT docetaxel achieved a 26-fold higher peak tumor concentration and 24-fold longer tumor exposure than IV treatment. Furthermore, limited plasma exposure was noted with IT docetaxel. Supradose levels of docetaxel produced distinct protein expression patterns for regulators of the cell cycle (cyclins A and B, p21, and p27), apoptosis (cleaved caspase-3 and cleaved PARP), and signal transduction (EGFR, pEGFR, pc-Jun, and pERK) in HNSCC, which supports a distinctive mechanism of action for supradose docetaxel levels. Since levels of cleaved caspase-3 and PARP, markers of apoptosis, were only elevated with lower doses, the observed cell death at supradose levels was probably due to necrosis. CONCLUSIONS: Injections of IT docetaxel at usual and supradoses are associated with a pharmacokinetic profile and biological mechanism distinct from those observed with usual IV doses. It is calculated that IT therapy in men will increase peak concentrations of docetaxel in tumors by 1000-fold over the conventional IV dose used clinically. These preclinical results support further testing of IT docetaxel in HNSCC.

    Title Prognostic Significance of P53 and Fhit in Advanced Oropharyngeal Carcinoma.
    Date May 2005
    Journal American Journal of Otolaryngology
    Excerpt

    OBJECTIVE: To determine the prognostic significance of p53 and fragile histidine triad (FHIT) expression in advanced oropharyngeal squamous cell carcinoma. STUDY DESIGN: A retrospective collection of clinical data was correlated with the protein expression. METHOD: The expression of p53 and FHIT in specimens from patients with previously untreated advanced squamous cell carcinoma of the oropharynx was determined by immunohistochemistry. The expression of p53 and FHIT was statistically correlated with survival outcome. The primary endpoints were overall survival and disease-free survival. RESULTS: Thirty-four patients were analyzed in this study. Overexpression of p53 was observed in 41.2% (14/34) of tumors and was associated with a trend toward an improved overall survival using univariate (P =.1088, risk ratio [RR] = 0.503) and multivariate (P =.1533, RR = 0.470) analyses. Marked reduction or complete absence of FHIT expression was observed in 57.6% (19/33) of tumors. Patients with tumors showing no reduction in FHIT expression had a lower overall survival using univariate (P =.04, RR = 2.27) and multivariate (P =.013, RR = 4.41) analyses. CONCLUSION: Overexpression of p53 predicted a trend toward an improved prognosis, whereas no reduction in FHIT expression predicted a significantly poorer outcome in patients with advanced oropharyngeal cancer.

    Title Bioactive Suture: a Novel Immunotherapy for Head and Neck Cancer.
    Date March 2005
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: We have proposed to characterize the mechanism through which bioactive surgical sutures generate a T(H)1 immune response and to define the immune-stimulating half-life of the sutures. EXPERIMENTAL DESIGN: Bioactive sutures of interferon gamma (IFNgamma), interleukin 2 (IL-2), anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNgamma sutures were used to stimulate lymphocytes from normal donors and from head and neck cancer patients in vitro over a 24-day period. Cell supernatants were analyzed by ELISA, and T cells were phenotyped to characterize the immune response generated. Intracellular cytokine staining was performed to measure the expansion of flu-specific T cells. Electromobility shift assay and supershift assay were used to measure the intranuclear DNA binding activity of nuclear factor kappaB and its p65 subunit in T cells activated by sutures in the presence and absence of a proteasome inhibitor, MG-132. RESULTS: Anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNgamma generated a prolonged T(H)1 immune response for 18 days in vitro. Anti-CD3/CD28 expanded flu-specific T cells. Activated T cells demonstrated enhanced CD40 ligand (CD40L) expression within 72 hours of stimulation, which stimulated other cells to secrete IL-12. Stimulated T cells demonstrated increased intranuclear expression of nuclear factor-kappaB, which was blocked by MG-132, and also reduced CD40L and IL-12 expression. CONCLUSIONS: This is the first report to demonstrate that bioactive surgical sutures can generate a prolonged T(H)1 immune response and expand flu-specific T cells. Bioactive sutures, which are primarily a T-cell stimulant, also stimulated other cells to secrete IL-12 and prolonged the immune response. Sutures may provide a novel in situ stimulating strategy for enhancing the immune system of cancer patients.

    Title Detection of Plasminogen Activators in Oral Cancer by Laser Capture Microdissection Combined with Zymography.
    Date February 2005
    Journal Oral Oncology
    Excerpt

    Plasminogen activation is believed to be critical to the progression of oral squamous cell carcinoma by facilitating matrix degradation during invasion and metastasis, and high levels of urokinase plasminogen activator (uPA) and plasminogen activator (PA) inhibitor-1 (PAI-1) in tumors predict poor disease outcome. We describe the development of a novel method for studying PA in oral cancer that combines the sensitivity and specificity of zymography with the spatial resolution of immunohistochemistry. Laser capture microdissection (LCM) was combined with plasminogen-casein zymography to analyze uPA, tissue PA (tPA), uPA-PAI-1 complexes, and tPA-PAI-1 complexes in 11 tumors and adjacent non-malignant epithelium from squamous cell carcinomas of the tongue, floor of mouth, larynx, and vocal cord. uPA was detectable in all tumor samples analyzed, uPA-PAI-1 complexes in three samples, and tPA in nine. PA was detectable in as little as 0.5 microg protein lysate from microdissected tumors. In all specimens, uPA expression was highly increased in tumor tissue compared to adjacent non-malignant tissue. In conclusion, LCM combined with zymography may be excellently suited for analyzing the prognostic significance and causal involvement of the plasminogen activation system in oral cancer.

    Title Enhancement of Ad-p53 Therapy with Docetaxel in Head and Neck Cancer.
    Date February 2005
    Journal The Laryngoscope
    Excerpt

    OBJECTIVE: The objective of this project was to determine the mechanisms in which docetaxel enhances Ad-p53 tumor suppressive effects in head and neck cancer. BACKGROUND: In advanced head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate is less than 40%. Because patients with advanced HNSCC have a high rate of local-regional failure (40-60%) with existing treatment modalities, aggressive local therapy approaches need to be developed. Previous data show that docetaxel or Ad-p53 alone have significant anti-tumor activity in HNSCC. Before testing whether a combination approach (Ad-p53 and docetaxel) could be developed in clinical trials, preclinical experiments were performed. METHODS: The p53 gene was overexpressed in 2 head and neck squamous carcinoma (HNSCC) cell lines, HN30 and HN12, and a murine Balb/c mucoepidermoid carcinoma (BMEC) cell line. Docetaxel's enhancement of adenoviral transduction (bGAL expression), coxsakie-adenovirus receptor (CAR) expression, and Ad-p53 induction of apoptosis (Annexin V expression) were measured. The modulation of regulators in the cell cycle, apoptosis and signal transduction pathways were measured using Western blot. RESULTS: Docetaxel increased adenoviral transduction, which was dependent on the dose of docetaxel and levels of Ad-bGAL. The enhanced viral transduction was due in part to the upregulation of the CAR protein. Pretreatment with docetaxel enhanced Ad-p53-induced apoptosis through increased expression of exogenous p53. Together, the combination of docetaxel and Ad-p53 altered expression of key regulators in the cell cycle, apoptosis and signal transduction pathways with an increase in the expression of p53, bax, cleaved PARP, cleaved caspase-3 and phosphorylation of c-Jun at position at Ser. Cyclin A and B1 expression were down regulated by docetaxel and Ad-p53. When comparing the docetaxel-resistant to sensitive cell lines, the altered expression of p27 and skp1 by docetaxel and Ad-p53 were dissimilar between these cell lines. CONCLUSIONS: Docetaxel enhanced Ad-p53 transduction and increased expression of exogenous p53 gene transfer, apoptosis, and antitumor mechanisms. These results support a clinical combination of docetaxel with p53 gene therapy in patients with head and neck cancer.

    Title Organ Preservation for Advanced Resectable Cancer of the Base of Tongue and Hypopharynx: a Southwest Oncology Group Trial.
    Date January 2005
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: The Southwest Oncology Group designed a phase II trial for patients with base of tongue or hypopharyngeal cancer to evaluate the complete histologic response rate at the primary site after induction chemotherapy followed by chemoradiotherapy for responders. Secondary end points were the rate of organ preservation and the need for salvage surgery. PATIENTS AND METHODS: Fifty-nine eligible patients were enrolled; 37 had base of tongue cancer, and 22 had hypopharynx cancer. Forty-two percent had stage III disease, and 58% had stage IV disease. Induction chemotherapy was two cycles of cisplatin 100 mg/m(2) and fluorouracil 1,000 mg/m(2)/d for 5 days. Patients who had a greater than 50% response at the primary site were treated with radiation 72Gy and concurrent cisplatin 100 mg/m(2) for three cycles. Patients with less than partial response at the primary had immediate salvage surgery. RESULTS: Forty-five patients (76%) had a greater than 50% response at the primary after induction chemotherapy; 43 went on to receive definitive chemoradiotherapy. Thirty-two patients (54%) achieved a histologic complete response at the primary site, and an additional nine patients had a complete clinical response, but biopsy was not done. Seventy-five percent of patients did not require surgery at the primary tumor site. The 3-year overall survival was 64%. The 3-year progression-free survival with organ preservation was 52%. CONCLUSION: Patients with base of tongue or hypopharyngeal cancer treated with this regimen of induction chemotherapy followed by definitive chemoradiotherapy have a good rate of organ preservation without compromise of survival.

    Title Correlation of Histopathological Variants, Cellular Dna Content, and Clinical Outcome in Adenoid Cystic Carcinoma of the Salivary Glands.
    Date January 2005
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    OBJECTIVE: To study the correlation between flow cytometrically measured DNA ploidy with prognostically important histopathologic groups and clinical outcome in patients with adenoid cystic carcinoma of the salivary glands. STUDY DESIGN: 46 tumor specimens were analyzed flow cytometrically for DNA content and assessed for histological grade. Correlations were made between tumor DNA ploidy and histopathological grade, and disease-free and overall survival of these patients. RESULTS: Of the 46 patients, 31 had a cribiform/tubular histologic pattern, and 15 had a solid pattern. 84% of the tumors with cribriform/tubular pattern were DNA diploid, compared with 33% of tumors that were graded solid. This difference proved to be statistically significant (chi(2)11.75, P = 0.0006). Overall and disease-free survival periods were longer for patients with DNA diploid tumors in both groups, 63% vs. 36% and 62% vs 38%, respectively. CONCLUSIONS: Tumor DNA ploidy correlates with prognostically important tumor histopathology as well as overall and disease-free survival in patients with adenoid cystic carcinoma of the salivary gland. EBM rating: B-3.

    Title Microsatellite Alterations in African Americans with Head and Neck Cancer.
    Date October 2004
    Journal The Laryngoscope
    Excerpt

    OBJECTIVE: To determine the genetic differences between African Americans (AA) and Non-African Americans (NAA) with head and neck squamous cell carcinoma (HNSCC). METHODS: DNA was obtained from tumor tissues and peripheral blood from 18 AA and 19 NAA patients with HNSCC. Microsatellite analysis using a fluorescent technique was performed on chromosomal arms 1p, 3p, 4q, 9p, 13q, and 17p. Statistical analyses were performed on the molecular and clinical outcome data. RESULTS: Based on the Surveillance, Epidemiologic, and End Result (SEER) data from southeast Michigan, the incidence rate of HNSCC in AA has been higher than for NAA, and the overall 5-year relative survival rate is lower for AA than NAA (36.2% vs. 47.6%). In this study, we found that the rate of loss of heterozygosity of chromosomal arms 1p, 3p, 4q, 9p, 13q, and 17p ranged from 68.8% to 83.3% for HNSCC in AA and from 66.7% to 90.0% in NAA. The difference in the rates of microsatellite alterations in chromosomal arms 3p, 4q, and 9p between AA and NAA were between 12.5% and 20% and were not statistically significant. CONCLUSION: The incidence and clinical outcomes for AA with HNSCC are different from that of NAA in southeast Michigan. In our group of patients with HNSCC, differences in rates of microsatellite alterations and survival were found between AA and NAA; however, these differences were not statistically significant. We conclude that genetic difference, as determined by the rates of microsatellite alterations, is not predictive of outcome difference between AA and NAA HNSCC patients.

    Title Microsatellite Analysis of Serum Dna in Patients with Head and Neck Cancer.
    Date July 2004
    Journal International Journal of Cancer. Journal International Du Cancer
    Excerpt

    We have shown previously that microsatellite alterations in serum DNA was predictive of distant metastasis in a study with 21 primary head and neck squamous cell carcinoma patients. To further investigate serum microsatellite alterations as a prognostic tool, we carried out microsatellite analysis of serum DNA with 10 markers on 152 patients with head and neck cancer. Forty-five percent (68/152) of patients had microsatellite alterations of serum DNA identical to corresponding tumor DNA. In 16 patients that had distant metastasis, 11 patients had a positive serum test (microsatellite alterations detectable in their serum DNA with one or more markers). The difference in distant metastasis rates between the negative and positive serum tests (6.0% [5/84] vs. 16.2% [11/68], RR = 2.7) was clinically significant and almost reached statistical significance (p = 0.06). When the analysis was restricted to patients with recurrent disease, a positive serum test correlated with those who developed distant metastasis (p = 0.04). Other parameters, such as development of recurrence, stage of the cancer, disease-free survival and overall survival, were not associated with a positive serum test. Detecting tumor DNA in serum by microsatellite analysis may help identify patients at risk for distant metastasis. Therefore, circulating tumor cells may contribute to the presence of tumor DNA in the serum. In the future if a serum test is positive, therapeutic approaches may by intensified, such as platinum-based chemoradiation, to reduce distant failures.

    Title Sclerosing Mucoepidermoid Carcinoma with Eosinophilia of the Thyroid: a Case Report and Review of the Literature.
    Date April 2004
    Journal American Journal of Otolaryngology
    Excerpt

    We present the clinical and histopathologic findings of a 38-year-old woman recently diagnosed with sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid (SMECE). This case is of particular interest because of its extremely aggressive clinical course. After total thyroidectomy, there was extensive bilateral thyroid lobe involvement with extension into perithyroidal soft tissues and the modified radical neck dissection contained 35 of 35 positive lymph nodes. This patient underwent 2 further surgeries; the first was a second right neck and supraclavicular surgery for lymph node metastases in which 8 of 11 were positive, followed a few months later by posterior neck surgery in which multiple lymph nodes were positive. Tumor was also documented by histological review from a right axillary lymph node. Imaging evidence of tumor in the lungs and liver was also present. Establishing the correct diagnosis of SMECE involves an awareness of the cyto- and histomorphologic features of this rare malignancy. As evidence that the biologic behavior of this neoplasm may well be more aggressive than previously considered, we briefly present the clinical and biologic course of this patient's neoplasm and a review of the literature.

    Title Docetaxel Induced Gene Expression Patterns in Head and Neck Squamous Cell Carcinoma Using Cdna Microarray and Powerblot.
    Date January 2003
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: The purpose is to identify gene expression patterns induced by docetaxelin head and neck squamous carcinoma (HNSCC) cells using high throughput techniques. EXPERIMENTAL DESIGN: HNSCC cells were treated with docetaxel or solvent. After mRNA extraction, cDNA fluorescent (Cy3 or Cy5)-labeled probes were synthesized. Then, Cy3 and Cy5-labeled samples were hybridized onto a microarray slide. The fluorescent images were scanned and analyzed for quantification. PowerBlot immunoblotting technique was used to measure protein expression level. Using this dual approach, we focused on genes in established pathways (cell cycle, apoptosis, angiogenesis, and signal transduction) of tumorigenesis and confirmed these results with conventional techniques. RESULTS: Using cDNA microarray, we found that docetaxel altered the expression of >100 genes in HNSCC cells. A total of 153 of 1191 genes was found to have altered expression in either HN12 (n = 102), HN30 (n = 72), or both (n = 21) by docetaxel. For the PowerBlot analysis, a subset of genes (n = 46) in the cDNA microarray analysis and an additional 98 genes in the cell cycle, apoptosis, angiogenesis, and signal transduction pathways were chosen. We found that PowerBlot data agreed with cDNA microarray in 65% of genes examined. The expression of a cell cycle inhibitor (p19) and promoters (cyclin A, cyclin B1, and cyclin E2F) were increased and decreased, respectively. Apoptosis induced by docetaxel was independent of p53 and, in part, related to increased Fas expression. Both vascular endothelial growth factor secretion and basic fibroblast growth factor expression were inhibited by docetaxel, whereas thrombospondin-1 expression was increased by docetaxel. Epidermal growth factor receptor, activated epidermal growth factor receptor, and activated c-Jun NH(2)-terminal kinase expression was lowered by docetaxel. Activated extracellular signal-regulated kinase was elevated by docetaxel, but not total extracellular signal-regulated kinase levels. CONCLUSIONS: The identification of altered gene expression induced by docetaxel demonstrates additional biological activity in HNSCC cells, and the altered expression of these genes may serve as potential biomarkers to both predict clinical activity and provide information regarding potential efficacy of adding novel agents.

    Title In Vivo Characteristics of Hpv-immortalized and Carcinogen Transformed Oral Keratinocytes.
    Date November 2002
    Journal The Laryngoscope
    Excerpt

    PURPOSE: To characterize in vivo features of HPV-immortalized and carcinogen transformed oral keratinocytes. METHODS: The growth and squamous differentiation of IHGK (immortalized human gingival keratinocyte with HPV), IHGKN [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)]-carcinogen transformed keratinocytes, and two head and neck squamous cell carcinoma (HNSCC) cell lines, HN30 and HN12, were tested by injecting these cells into SCID mice. The growth, histological features, and expression of PCNA, Involucrin, and high molecular weight keratin of the tumors formed were compared among these cell lines. RESULTS: All cell lines formed a palpable lesion at 2 weeks; however, only HN30 continued to grow. IHGK and IHGKN cells formed palpable nodules within 2 weeks with no further growth after 4 to 5 weeks, and no regression of the nodule was noted at 12 weeks. HN12 cells did not form tumor nodules unless these cells were co-injected with immortalized fibroblasts. Both IHGK and IHGKN cells formed a well-circumscribed epithelial lesion with islands of differentiated squamous cells bound by a myxoid matrix. Nests of basal-horny squamous cells centrally differentiated into anucleate squamous cells. IHGK and IHGKN nodules had more squamous differentiation than HN12 and HN30 and further differentiated over time. IHGK and IHGKN cells expressed differentiation (involucrin and high molecular weight keratin) and proliferation (PCNA) markers that suggest that IHGK and IHGKN behave as well-differentiated squamous lesions when compared with malignant HN12 and HN30 nodules. IHGK and IHGKN cells showed an initial growth phase followed by terminal differentiation, and then a phase characterized by regression and host inflammatory stage. CONCLUSIONS: The growth, histology, and expression of differentiation and proliferation markers of IHGK and IHGKN lesions into SCID mice demonstrate that these cells are endowed with a limited malignant potential. Our in vivo model with these intermediate cell lines can provide a short-term analysis for studying the biology of HNSCC progression and the activity of chemoprevention agents.

    Title Predictors of Nodal Metastasis in Salivary Gland Cancer.
    Date September 2002
    Journal Journal of Surgical Oncology
    Excerpt

    OBJECTIVES: This study was conducted to determine clinical and histologic factors that would predict nodal metastasis in patients with major salivary gland cancer. METHODS: A retrospective study of 40 patients who underwent surgery, including neck dissection, for major salivary gland cancer between 1975 and 1997 was performed. Patient charts were reviewed, and clinical and pathologic data were extracted along with outcome. Predictive factors were identified and survival curves were obtained. RESULTS: Neck dissections were performed in 40 patients, which revealed histologic evidence of tumor in lymph nodes in 15 cases. Histologically proven metastasis was found in 16% of specimens from elective and 73% of specimens from therapeutic neck dissection. Five-year overall and locoregional disease-free survival rates for histologically positive and negative groups were 40% versus 63% (P < 0.05) and 67% versus 69% (P = 0.59), respectively. Univariate analysis of the factors revealed that clinical evidence of nodal metastasis (P < 0.001) and high-grade cancer (P < 0.033) predicted histologic nodal involvement. Multivariate analysis revealed that only a positive neck examination was a significant predictive factor (OR = 31, 95%CI = 2.99-312). CONCLUSIONS: Our results suggest that clinical neck examination is a reliable predictor of regional metastasis in patients with major salivary gland cancer. In view of the low frequency of occult metastases, routine elective treatment of the neck is not recommended.

    Title A Multicenter Phase Ii Study of Tgdcc-e1a for the Intratumoral Treatment of Patients with Recurrent Head and Neck Squamous Cell Carcinoma.
    Date September 2002
    Journal Head & Neck
    Excerpt

    BACKGROUND: The anti-cancer gene, E1A, can be complexed to a lipid carrier, DC-Cholesterol:DOPE, to form tgDCC-E1A, which can be injected directly into tumors. METHODS: Twenty-four patients with recurrent, unresectable, head and neck cancer were treated with intratumoral injections of tgDCC-E1A over 8 weeks. Tumor response was assessed using CT scans. Time to progression and overall survival were calculated. RESULTS: Intratumoral tgDCC-E1A was well tolerated in all patients. No significant toxicities related to tgDCC-E1A were reported. One patient (4.2%) had a complete response, two patients (8.3%) had minor response, and seven patients (29.2%) had stable disease by two-dimensional cross-products on blinded CT scans. The median time to progression was 8.6 weeks (range, 3.3-43.7 weeks), and median survival was 4.6 months (range, 1.3-15.6 months). CONCLUSIONS: Intratumoral injections of tgDCC-E1A were safe and well tolerated. Modest tumor response was observed. Further development of tgDCC-E1A is warranted in combination with other treatment modalities.

    Title Clinical Significance of Poor Cd3 Response in Head and Neck Cancer.
    Date July 2002
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: The objective of our investigation was to prospectively study what the implications of an unresponsive CD3 receptor are on clinical outcome in advanced-stage head and neck cancer patients. EXPERIMENTAL DESIGN: Lymph node mononuclear cells were purified from cancer patients and stimulated with immobilized anti-CD3 in vitro for 8 days. Two populations were identified, nonresponders (NRs) with [(3)H]thymidine-counts per min (cpm) <3500 and responders (Rs) with cpm >or=3500. NRs and Rs were prospectively followed for a minimum of 24 months, and clinical outcomes were compared. Postoperative complications, length of hospitalization, toxicities associated with chemotherapy or radiation therapy, survival, and disease-free status were measured. RESULTS: Twenty-six patients were followed, of which 19 Rs [[(3)H](X) = 37,819 +/- 24,979 cpm (mean proliferative count +/- SD)] and 7 NRs ([(3)H](X) = 1,375 +/- 1,102 cpm) were identified. There were no phenotypic differences in lymph node T-cell subpopulations (CD3, CD4, CD8, CD28, CD45RO) between groups. There was a 71% (5/7) incidence of recurrent cancer in NRs compared with 16% (3/19) in Rs; the median disease-free interval was significantly less in NRs (P = 0.03). The risk ratio of Rs to develop a recurrent cancer was 0.237 (95% confidence interval, 0.057-0.994), much less than for NRs. CONCLUSIONS: Patients with an unresponsive CD3 receptor as measured by in vitro response to anti-CD3 monoclonal antibodies had a significantly higher incidence of recurrent cancer. Analyses using Cox proportion hazards models demonstrated that CD3 response was the single greatest predictor of reduced disease-free interval. This is the first prospective study to confirm the importance of regional lymph node mononuclear cell CD3 receptor function in head and neck squamous cell carcinoma patients for tumor control.

    Title Anticancer Activity of Docetaxel in Murine Salivary Gland Carcinoma.
    Date July 2002
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: The purpose of this study was to evaluate the biological mechanisms of docetaxel (TXT) on salivary gland carcinoma. EXPERIMENTAL DESIGN: The effects of TXT on a spontaneous murine salivary carcinoma were determined. Proliferation, cell cycle regulation, connexin43 expression, gap-junctional intercellular communication, apoptosis, and Fas receptor (FasR) expression were measured. RESULTS: We characterized a spontaneous mouse salivary gland carcinoma (SGC1). SGC1 is a poorly differentiated carcinoma that originated from the parotid gland of a BALB/c mouse. SGC1 cells were cultured and found to be immortal past 30 passages. Initially, cells formed tumor nodules in severe combined immunodeficient (SCID) mice. Afterward, SGC1 cells that were subcultured from SCID tumors readily formed colonies in soft agar and were highly tumorigenic in SCID mice and immune-competent BALB/c hosts. Dose response for TXT with respect to growth suppression, G(2)-M cell cycle arrest, and apoptosis was found. Induction of apoptosis by TXT coincided with an increase in cell surface FasR expression. Up-regulation of FasR with lower doses of TXT rendered cells susceptible to FasR agonist antibody-mediated apoptosis. In the absence of TXT, anti-FasR antibodies were completely without effect, suggesting that TXT is critical for priming apoptosis mediated through the Fas pathway. In addition, gap-junctional intercellular communication was augmented by TXT in SGC1 cells concomitant with increased connexin43 expression and membrane localization. CONCLUSIONS: We have identified several novel targets of TXT that contribute to its antitumor activity in poorly differentiated salivary gland carcinoma. These results suggest that TXT may be appropriate for additional in vivo studies and clinical trials in patients with salivary cancers.

    Title The Effects of Exogenous P53 Overexpression on Hpv-immortalized and Carcinogen Transformed Oral Keratinocytes.
    Date February 2002
    Journal Cancer
    Excerpt

    BACKGROUND: Overexpression of p53 in head and neck carcinoma cells has demonstrated tumor growth suppression using in vitro and in vivo models. The effects of exogenous overexpression of wild-type p53 on human papilloma virus (HPV)-immortalized and carcinogen transformed oral keratinocytes were determined. METHODS: The p53 gene was overexpressed in IHGK (immortalized human gingival keratinocyte), IHGKN [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)]-carcinogen transformed keratinocytes, and two head and neck squamous carcinoma (HNSCC) cell lines, HN30 and HN12. The transfection efficiency, growth suppression, and inhibition of the cell cycle along with the induction of apoptosis were measured. RESULTS: Transfections with adenoviruses were more efficient for IHGK cells than for IHGKN, HN12, and HN30 cells. Inhibition of proliferation in all cell lines was proportional to the viral particle to cell (VPC) ratios. IHGK cells were more sensitive to p53 than IHGKN cells. HN12 cells were more suppressed than HN30 cells. HN12 were the most suppressed at 72 hours whereas HN30 cells were most suppressed at 24 hours. Expression of exogenous p53-induced G1 cell cycle arrest and p21 expression as VPC ratios increased in IHGK and IHGKN cell lines. Apoptosis also was induced in these cells by p53 as VPC increased. IHGK cells were more sensitive to p53-induced growth inhibition, cell cycle regulation, p21 expression and apoptosis than IHGKN cells. HN12 (mutated p53) cells were more sensitive to p53 overexpression than HN30 (wild-type p53) cells. Gene transfer and expression of exogenous p53 by using Ad-p53 demonstrates suppressive effects on HPV immortalized and carcinogen transformed oral keratinocytes. CONCLUSIONS: Cell cycle regulation by gene transfer is feasible in immortalized oral keratinocytes. Carcinogen transformed cells are less susceptible to the effects of p53 overexpression. Expression of exogenous p53 through p53 gene transfer can suppress HPV immortalization and carcinogen transformation in oral keratinocytes. The sensitivity of HNSCC cell lines to p53-induced cell cycle regulation and apoptosis is variable and dependent on the cell line and duration of exposure. In vitro results using p53 gene transfer must be validated in clinical studies with patients at risk for HNSCC.

    Title Craniocervical Necrotizing Fasciitis: an 11-year Experience.
    Date October 2001
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    OBJECTIVE: We review our experience and present our approach to treating craniocervical necrotizing fasciitis (CCNF). STUDY DESIGN: All cases of CCNF treated at Wayne State University/Detroit Receiving Hospital from January 1989 to April 2000 were reviewed. Patients were analyzed for source and extent of infection, microbiology, co-morbidities, antimicrobial therapy, hospital days, surgical interventions, complications, and outcomes. RESULTS: A review of 250 charts identified 10 cases that met the study criteria. Five cases (50%) had spread of infection into the thorax, with only 1 (10%) fatality. An average of 24 hospital days (7 to 45), 14 ICU days (6 to 21), and 3 surgical procedures (1 to 6) per patient was required. CONCLUSION: Aggressive wound care, broad-spectrum antibiotics, and multiple surgical interventions resulted in a 90% (9/10) overall survival and 80% (4/5) survival for those with thoracic extension. SIGNIFICANCE: This is the largest single institution report of CCNF with thoracic extension identified to date.

    Title Prognostic Factors in Major Salivary Gland Cancer.
    Date October 2001
    Journal The Laryngoscope
    Excerpt

    OBJECTIVE: To identify features of major salivary gland cancers that are prognostic for disease-free survival. STUDY DESIGN: A retrospective study of 78 patients with major salivary gland cancer (64 parotid and 14 submandibular gland) who underwent surgery for definitive treatment from 1976 to 1996. A select group of patients also received adjuvant radiation (56%) and/or chemotherapy (13%). METHOD: Clinical and pathological risk factors were obtained from patients' charts and pathology reports. Age, gender, tumor site, T-stage, facial paralysis, histologic neck involvement, perineural invasion, and cancer grade were analyzed with respect to disease-free survival. The role of adjuvant treatment in terms of clinical outcome was also investigated. RESULTS: In our series, the 5-year disease-free survival was 65%. Examining clinical and histologic features one at a time, we found poorer prognosis was associated with submandibular tumors compared with parotid (P =.02), higher T-stage (P =.001), positive cervical nodes (P <.001), perineural invasion (P =.002), and high-grade or adenoid cystic tumors (P =.002). A multivariable analysis indicated that positive lymph nodes (P =.07) and perineural invasion (P =.03) were important histologic predictors of shorter disease-free survival. Receipt of both adjuvant radiation and cisplatin-based chemotherapy (P =.05) was an independent predictor of longer disease-free survival. CONCLUSION: Our study indicated that the presence of positive lymph nodes and perineural invasion is important independent predictors of disease-free survival. Our limited data also suggest that adjuvant chemotherapy and radiation therapy may improve disease-free survival.

    Title Phase I Trial of Intratumoral Liposome E1a Gene Therapy in Patients with Recurrent Breast and Head and Neck Cancer.
    Date July 2001
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: We conducted a Phase 1 study to determine the maximal tolerated dose and maximum biologically active dose of the E1A gene delivered by intratumoral injection as a lipid complex with 3 beta[N-(n',n'-dimethylaminoethane)-carbamoyl] cholesterol/dioleoylphosphatidyl-ethanolamine (tgDCC-E1A). The E1A adenovirus gene functions as a tumor inhibitor gene by repressing oncogene transcription; modulating gene expression, resulting in cellular differentiation; and inducing apoptosis of cancer cells. E1A also sensitizes cancer cells to chemotherapeutic drugs such as etoposide, cisplatin, and taxol. EXPERIMENTAL DESIGN: Nine patients with recurrent and unresectable breast cancer and nine patients with head and neck cancer were enrolled. One tumor nodule in each patient was injected with tgDCC-E1A. Safety, tumor response, E1A gene transfer, and down-regulation of HER-2/neu were evaluated. RESULTS: No dose-limiting toxicity was observed in the four dose groups (15, 30, 60, and 120 microg DNA/cm of tumor). All patients tolerated the injections, although several experienced pain and bleeding at the injection site. A maximally tolerated dose was not reached in this study. E1A gene transfer was demonstrated in 14 of 15 tumor samples tested, and down-regulation of HER-2/neu was demonstrated in two of the five patients who overexpressed HER-2/neu at baseline. HER-2/neu could not be assessed in other posttreatment tumor samples because of extensive necrosis. In one breast cancer patient, no pathological evidence of tumor was found on biopsy of the treated tumor site at week 12. In 16 patients evaluable for tumor response, 2 had minor responses, 8 had stable disease, and 6 had progressive disease. CONCLUSIONS: Gene therapy with an E1A gene:lipid complex appears to be safe and warrants further testing.

    Title Titanium Mesh Repair of the Severely Comminuted Frontal Sinus Fracture.
    Date June 2001
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    BACKGROUND: Severely comminuted frontal sinus fractures are difficult to contour and immobilize. Frequently, plates or wires are inadequate in fixating all fragments together, resulting in less than optimal outcomes. Advancements in the development of biomaterials have now made titanium mesh a new option for the repair of severely comminuted fractures. METHODS: Fourteen patients with severely comminuted frontal sinus fractures were treated with titanium mesh from 1994 to 1999. The fractures were reduced and immobilized using a simple algorithm: (1) Isolated anterior table fractures were repaired with reduced bony fragments attached to titanium mesh. (2) Anterior table fractures with nasofrontal duct involvement were repaired by sinus obliteration and anterior wall reconstruction with reduced bony fragments attached to titanium mesh. (3) Anterior and posterior table fractures with cerebrospinal fluid leak or displacement were treated with the cranialization of the sinus and anterior wall reconstruction with reduced bony fragments attached to titanium mesh. RESULTS: Of the 14 patients treated, 12 were available for postoperative evaluation. Parameters such as nasal function, cranial nerve V and VII function, cosmesis, and complications (hardware extrusions, sinusitis, meningitis, osteomyelitis, mucopyocele, brain abscess, pneumocephalus, and cerebrospinal fluid leak) were evaluated. All patients had good function of the superior division of cranial nerves V and VII. Two patients (16%) had minor wound infections, which resolved under treatment with antibiotics. All had excellent cosmetic results as measured by postreduction radiographs and personal and family perceptions of forehead contour. CONCLUSION: Titanium mesh reconstruction of severely comminuted frontal sinus fractures has few complications while providing excellent forehead contour and cosmesis.

    Title Neutron Radiation Enhances Cisplatin Cytotoxicity Independently of Apoptosis in Human Head and Neck Carcinoma Cells.
    Date March 2001
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    Recent advances in combined modality treatment of locally advanced head and neck cancer have improved local and regional disease control and survival with better functional outcome. However, the local and regional failure rate after radiation therapy is still high for tumors that respond poorly to cisplatin-based neoadjuvant chemotherapy. This clinical observation suggests a common biological mechanism for resistance to cisplatin and photon irradiation. In this report, we investigated the molecular basis underlying cisplatin resistance in head and neck squamous carcinoma (HNSCC) cells and asked if fast neutron radiation enhances cisplatin cytotoxicity in cisplatin-resistant cells. We found that cisplatin sensitivity correlates with caspase induction, a cysteine proteinase family known to initiate the apoptotic cell death pathway, suggesting that apoptosis may be a critical determinant for cisplatin cytotoxicity. Neutron radiation effectively enhanced cisplatin cytotoxicity in HNSCCs including cisplatin-resistant cells, whereas photon radiation had little effect on cisplatin cytotoxicity. Interestingly, neutron-enhanced cisplatin cytotoxicity was associated neither with apoptosis nor with cell cycle regulation, as determined by caspase activity assay, annexin V staining, and flow cytometric analysis. Taken together, the present study provides a molecular insight into cisplatin resistance and may also provide a basis for more effective multimodality protocols involving neutron radiation for patients with locally advanced head and neck cancer.

    Title Progression of Head and Neck Cancer in an in Vitro Model.
    Date November 2000
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To identify alterations in angiogenesis and cell cycle regulation as preneoplastic cells progress to cancer in an in vitro model of head and neck tumor progression. METHODS: Immortal human gingival keratinocyte (IHGK) cells (preneoplastic) were derived from normal oral keratinocytes and were immortalized with human papillomavirus 16. Transformation of IHGK cells with a carcinogen (NNK, 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone) gave rise to IHGKN cells. We determined the growth rates, cell cycle phase, expression of cell cycle regulators, and expression of vascular endothelial growth factor along with the organotypic features of these cells and compared them with characteristics of head and neck cancer cells. RESULTS: IHGK and IHGKN cells grown in raft culture were morphologically similar to severe dysplasia and carcinoma, respectively. The proportion of cells in G(0)/G(1) was similar between IHGK and IHGKN. However, the proportion of IHGK cells was 35% greater in S phase as compared with the IHGKN cells, while a greater percentage (40%) of IHGKN cells were in G(2)/M. The expression of the other cell cycle regulators tested was unchanged. IHGK cells secreted less vascular endothelial growth factor on day 1 when compared with IHGKN (50.6 vs 245.6 pg/mL), along with a lower overall production rate (79% vs 133%). CONCLUSIONS: Transformation of IHGK cells resulted in the activation of vascular endothelial growth factor associated with angiogenesis. Inactivation of the G(1) cell cycle regulation occurred during immortalization and before transformation, and was sustained after carcinogen exposure. These alterations correspond to changes observed in patients with head and neck squamous cell carcinoma. This model can be useful in testing novel therapeutic and preventive strategies.

    Title Imaging Quiz Case 4. Dentigerous Cyst.
    Date October 2000
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Anti-cd3/anti-cd28 Bead Stimulation Overcomes Cd3 Unresponsiveness in Patients with Head and Neck Squamous Cell Carcinoma.
    Date May 2000
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVES: To test whether T-cell CD3 responses are altered in patients with advanced-stage head and neck squamous cell carcinoma (HNSCC) and whether anti-CD3/anti-CD28 (alphaCD3/alphaCD28) bead stimulation could reverse CD3 unresponsiveness. DESIGN: Anti-CD3 (alphaCD3) monoclonal antibody immobilized on tissue culture plastic was used to stimulate lymph node mononuclear cells (LNMCs) and peripheral blood mononuclear cells (PBMCs) from patients with advanced-stage HNSCC. Proliferation, T-cell phenotype, and cytokines were measured during 8-day in vitro stimulation. Immune-enhancing properties of alphaCD3/ alphaCD28 beads were also tested on LNMCs and PBMCs. Cytotoxicity of bead-activated T cells (ATCs) was measured against autologous and allogeneic HNSCC. RESULTS: Six patients were nonresponders to alphaCD3 stimulation defined by tritium (3H) incorporation of less than 3500 cpm, whereas 11 patients were responders with 3H incorporation of 3500 cpm or more. Responders produced higher levels of interleukin (IL)-12 and interferon gamma (IFN-gamma) after alphaCD3 stimulation than nonresponders. No phenotypic or clinical differences were identified between groups. Stimulation with alphaCD3/alphaCD28 beads enhanced IFN-gamma and IL-2 produced by both groups. Bead ATCs were generated from PBMCs of patient 11 in the responder group and lysed (+/- SD) 100% +/-1% of autologous tumor and 49% +/-1% of allogeneic tumor. Bead ATCs from LNMCs of this patient lysed 58%+/-1% of autologous tumor and 63%+/-1% of allogeneic tumor. CONCLUSIONS: A subpopulation of patients with HNSCC who are nonresponders to alphaCD3 stimulation has been identified, showing reduced proliferation and IL-12 and IFN-gamma secretion. Nonresponders stimulated with alphaCD3/alphaCD28 beads reversed immune unresponsiveness and induced a type 1 cytokine response. Bead-generated ATCs from patient 11 in the responder group lysed autologous and allogeneic HNSCC in vitro, suggesting a possible effective immunotherapeutic modality in the treatment of HNSCC.

    Title Assessment of Carotid Artery Invasion in Patients with Head and Neck Cancer.
    Date March 2000
    Journal The Laryngoscope
    Excerpt

    PURPOSE: Define radiological and histological features in which patients with head and neck cancer would benefit from a carotid artery resection. Resection of the carotid artery has been advocated for local control of advanced squamous cell carcinoma of the head and neck. To provide appropriate preoperative counseling and optimize the utilization of resources, the criteria for patient selection has to be defined. METHODS: Thirty-four patients underwent carotid artery resection based on the clinical impression of tumor fixation. Eighteen and 28 patients were evaluated using computed tomography (CT) and histological analysis, respectively. The distance between the tumor cells and external elastic lamina was measured. CT scans were examined to determine the circumference of tumor attachment around the carotid artery. RESULTS: Clinical assessment predicted tumor within 1.8 mm of the carotid artery in 68% of cases. The overall survival for patients with tumor greater than 1.8 mm (N = 9) was better than that of patients with less (N = 19) than 1.8 mm (33.3% vs. 5.3%; median 24 versus 9 mo, P = .0899). Three of six patients (50%) with less than 180 degrees circumference tumor attachment had tumor within 1.8 mm from the external elastic lamina. Eight of twelve patients (67%) with tumors encompassing more than 180 degrees of the artery wall had tumor within 1.8 mm from the external elastic lamina. The overall survival rates for patients with tumor attachment greater and less than 180 degrees were 8.3% and 33%, respectively. DISCUSSION: Tumor invasion into the carotid artery was the strongest predictor of outcome. Clinical assessment was as predictive as CT for tumor invasion. If tumor involvement of the carotid artery is less than 180 degrees, peeling the tumor is an alternative to carotid artery resection.

    Title Gene Promoter Hypermethylation in Tumors and Serum of Head and Neck Cancer Patients.
    Date March 2000
    Journal Cancer Research
    Excerpt

    Promoter hypermethylation is an important pathway for repression of gene transcription in cancer cells. We analyzed aberrant DNA methylation at four genes in primary tumors from 95 head and neck cancer patients and then used the presence of this methylation as a marker for cancer cell detection in serum DNA. These four genes were tested by methylation-specific PCR and included: p16 (CDKN2A), O6-methylguanine-DNA-methyltransferase, glutathione S-transferase P1, and death-associated protein kinase (DAP-kinase). Fifty-five % (52 of 95) of the primary tumors displayed promoter hypermethylation in at least one of the genes studied: 27% (26/95) at p16, 33% (31 of 95) at O6-methylguanine-DNA-methyltransferase; and 18% (17 of 92) at DAP-kinase. No promoter hypermethylation was observed at the glutathione S-transferase P1 gene promoter. We detected a statistically significant correlation between the presence of DAP-kinase gene promoter hypermethylation and lymph node involvement (P = 0.014) and advanced disease stage (P = 0.016). In 50 patients with paired serum available for epigenetic analysis, the same methylation pattern was detected in the corresponding serum DNA of 21 (42%) cases. Among the patients with methylated serum DNA, 5 developed distant metastasis compared with the occurrence of metastasis in only 1 patient negative for serum promoter hypermethylation (P = 0.056). Promoter hypermethylation of key genes in critical pathways is common in head and neck cancer and represents a promising serum marker for monitoring affected patients.

    Title Nasal Alar Reconstruction: a Critical Analysis Using Melolabial Island and Paramedian Forehead Flaps.
    Date April 1999
    Journal The Laryngoscope
    Excerpt

    OBJECTIVES: To qualitatively and quantitatively describe aesthetic and functional outcomes following Mohs ablative surgery involving the alar subunit, using a paramedian or subcutaneous melolabial island flap. STUDY DESIGN: Retrospective review. METHODS: A single surgeon's results in 38 consecutive patients were analyzed. Objective measures (alar rim thickness, donor scar width and length), subjective assessment (seven aesthetic parameters) by three academic otolaryngologists, and patient satisfaction questionnaires were evaluated. Student t test was used to ascertain statistically significant differences between reconstructive groups. RESULTS: Questionnaire results demonstrate a significant (P = .026) difference in donor site rating favoring melolabial group responses. Objective scar measurements and subjective ratings of textural quality and alar notching also favored melolabial reconstructions. CONCLUSIONS: More favorable aesthetic and functional outcomes are seen with single subunit cutaneous alar defects reconstructed with the melolabial island flap than with deep composite or extensive unilateral nasal defects reconstructed with the paramedian forehead flap.

    Title Prognostic Significance of P53 Gene Mutations in Laryngeal Cancer.
    Date April 1999
    Journal The Laryngoscope
    Excerpt

    OBJECTIVE/HYPOTHESIS: We examined whether p53 gene mutations were predictive of clinical behavior in laryngeal cancer. STUDY DESIGN: Retrospective study of 45 patients with laryngeal cancer from 1985 to 1997. METHODS: DNA was extracted from tumor tissue and subject to polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP) as well as DNA sequencing. The clinical outcome was correlated to the presence or absence of a p53 mutation. RESULTS: The p53 gene was analyzed by direct DNA sequencing and was found to be mutated in 33% (15/45) of patients. The presence of a p53 mutation was associated with a significant improvement in overall survival (80% vs. 43%, P < .03) and a trend toward improved disease-free survival (87% vs. 60%, P = .08). When other prognostic factors were adjusted, multivariate analysis revealed a trend toward improvement in overall survival as well as disease-free survival. CONCLUSION: Depending on the location of a p53 mutation, the suppressive functions or clinical outcome may or may not be affected. Fifty-three percent of mutations were detected in nonconserved regions as opposed to 17% as reported in colon cancer. In colon cancer, mutations in conserved regions of the p53 gene predicted a poorer survival, whereas nonconserved gene mutations were not predictive. In our group of patients. p53 mutations predicted a better prognosis, which may be due to a large proportion of mutations that lie within nonconserved areas. The predictive power of p53 gene mutations may depend on functional loss and inactivation of highly conserved areas and must be tested in a prospective trial.

    Title Fast and Slow Gating Types of Sr Ryanodine Receptor/channel Purified from Canine Latissimus Dorsi Muscle.
    Date December 1996
    Journal Yonsei Medical Journal
    Excerpt

    The ryanodine receptor/channel (RyR) mediates the release of calcium from the sarcoplasmic reticulum (SR) in both skeletal and cardiac muscle cells. There are three isoforms of the RyR: RyR1, RyR2, and RyR3. RyR1 is specifically expressed in skeletal muscles and RyR2 in cardiac muscles. RyR3 is yet another isoform found in non-muscle cells such as neuronal cells. Single channel recordings of RyR1 and RyR2 reconstituted in artificial lipid bilayer show that the characteristics of two isoforms are very distinct. RyR1 has a shorter mean open time and is activated at a higher concentration of Ca2+ than RyR2. In this study, we isolated the heavy SR membranes from canine latissimus dorsi muscles and investigated the single channel activities from the heavy SR membrane fraction using Cs+ as a charge carrier. Two different types of activities were observed. The fast-gating type (FG) with the mean open time of 0.9 ms was more frequently recorded (n = 12) than the slow-gating type (SG) with the mean open time of 269.2 ms. From the I-V relation, the slope conductance of the FG was calculated to be 514.7 pS and the SG, to 625.6 pS. The activity of the fast gating type increased by raising the concentration of Ca2+ in the cis-solution up to 100 microM. The appearance of the SG in the canine heavy SR membrane fraction suggests a possibility that two types of RyR isoform are co-expressed in mammalian skeletal muscle as well as in avian, amphibian and piscine fast twitch muscles.

    Title P53 Mutation and Locoregional Treatment Failure in Head and Neck Squamous Cell Carcinoma.
    Date December 1996
    Journal Journal of the National Cancer Institute
    Excerpt

    BACKGROUND: The p53 gene (also known as TP53) may be the most common genetic target involved in the malignant transformation of human cells. Direct sequence analysis has demonstrated that alteration of this gene occurs in approximately 45% of head and neck squamous cell carcinomas. The consequences of p53 mutations in these cancers with respect to tumor behavior and patient survival have not been rigorously determined. PURPOSE: We evaluated the implications of p53 mutations in relation to the control of locoregional disease and overall survival following radiation therapy. METHODS: Data from 110 consecutive patients with invasive disease who were treated with primary radiation therapy (given with curative intent) or with adjuvant radiation therapy (following complete surgical extirpation of gross disease) were included in the analysis. A 1.8-kilobase fragment of the p53 gene encompassing exons 5-9 was amplified from the DNA of stored (frozen) tumor specimens; the amplified DNA was cloned and sequenced by use of standard techniques. Overall survival and locoregional disease-free survival after the completion of radiation therapy were estimated by the Kaplan-Meier method; survival comparisons were made by use of the logrank test or proportional hazards regression models. Reported P values are two-sided. RESULTS: Fortyeight (44%) of the 110 tumors had cells bearing p53 mutations. The risk of locoregional recurrence following either primary or adjuvant radiation therapy was significantly greater (i.e., the time to recurrence was shorter) for patients whose tumors contained mutant p53 genes (univariate model hazard ratio [HR] for p53 mutation versus wild-type = 2.2; 95% confidence interval [CI] = 1.2-4.1; P = .02). The presence of regional lymph node metastases (presence versus absence, HR = 2.0; 95% CI = 1.0-4.2; P = .05) and treatment type (primary radiation therapy versus surgery plus adjuvant radiation therapy, HR = 2.3; 95% CI = 1.2-4.3; P = .01) were also associated with greater risks of locoregional failure. The presence of p53 mutations and lymph node metastases and treatment with primary, as opposed to adjuvant, radiation therapy remained significant risk factors in multivariate regression analysis. No relationship was demonstrated between p53 status and overall survival (mutant versus wild-type, HR = 1.1; 95% CI = 0.6-2.1; P = .66); however, a relationship was shown for tumor stage and overall survival (stages III and IV [more advanced] versus stages I and II [less advanced], HR = 3.3; 95% CI = 1.0-10.8; P = .05). Mutation of the p53 gene was not associated with patient age, sex, tumor stage, primary tumor site, regional lymph node status, degree of tumor cell differentiation, or treatment method. CONCLUSIONS: Mutation of the p53 gene is associated with an increased risk of locoregional failure in patients with invasive head and neck squamous cell carcinoma who are treated with radiation therapy.

    Title Infrequent Inactivation of the Retinoblastoma Gene Despite Frequent Loss of Chromosome 13q in Head and Neck Squamous Cell Carcinoma.
    Date September 1994
    Journal Cancer Research
    Excerpt

    Our recent allelic analysis of head and neck squamous cell carcinomas identified a high incidence of chromosomal loss on 13q. To further define an area of minimal loss, we tested 60 primary head and neck squamous cell carcinomas in 59 patients for loss of heterozygosity (LOH) by using 10 polymorphic microsatellite markers spanning the long arm of chromosome 13. We examined the same primary tumors for inactivation of the retinoblastoma (Rb) gene by immunohistochemical analysis of paraffin-embedded specimens. Thirty-one of 60 (52%) tumors demonstrated LOH in at least one 13q marker. Twenty-nine of 31 (94%) lost a portion of 13q that included D13s133, which lies just telomeric to the Rb gene at 13q14.3. However, immunohistochemical staining revealed absence of Rb protein in only 6 of these 31 tumors (19.4%) with LOH. All but one tumor without LOH on 13q displayed normal Rb protein staining. Although Rb may be inactivated by an unusual mechanism in some head and neck squamous cell carcinomas, our data suggest that another tumor suppressor gene locus at 13q14 is likely to be involved in head and neck tumor progression.

    Title Warthin's Tumor: a 40-year Experience at The Johns Hopkins Hospital.
    Date August 1994
    Journal The Laryngoscope
    Excerpt

    Warthin's tumor previously has been thought to occur much more commonly in men than in women and rarely in African Americans. One hundred thirty-two cases of Warthin's tumor treated at The Johns Hopkins Hospital from 1952 to 1992 were retrospectively reviewed. There were 90 (68%) men and 42 (32%) women, with an overall man-to-woman ratio of 2.2:1. The number and percentage of women with Warthin's tumor increased over each consecutive decade: 1952 to 1962, 5 (21%); 1963 to 1972, 6 (29%); 1973 to 1982, 11 (31%); and 1983 to 1992, 20 (39%). A positive smoking history was found in 88% of the men and in 89% of the women with a Warthin's tumor. Eleven (8%) African Americans and 1 (0.75%) Asian American were diagnosed to have a Warthin's tumor. Also, the incidence of African Americans with a Warthin's tumor increased over each decade: 0 (0%), 1 (4.8%), 2 (5.5%), and 8 (16%). This study's results indicate a progressive increase in the occurrence of this tumor in women and in African Americans and a higher overall incidence in African Americans than previously reported.

    Title Advantages of Mandibular Reconstruction with the Titanium Hollow Screw Osseointegrating Reconstruction Plate (thorp).
    Date June 1994
    Journal The Laryngoscope
    Excerpt

    Alloplastic reconstruction following segmental mandibulectomy is a simple way to maintain mandibular segmental relationships, partially preserving form and function for many patients. This study is a retrospective review of 40 patients who had mandibular reconstruction with metal plates over a 6-year period (April 1986 through August 1992). The results of reconstruction with titanium hollow-screw osseointegrating reconstruction plates (THORP [n = 12]) and solid screw (SS) steel and titanium plates (n = 28) are compared. One THORP has been removed as compared to 14 SS plates. While the improved results with THORP may be attributable in part to its advanced design, the success of soft-tissue reconstruction and tumor extirpation are important factors in the early outcome seen in this series. Longer follow-up is needed to determine if THORP can serve as a permanent implant. THORP is the authors' method of choice for alloplastic mandibular reconstruction.

    Title Imaging Quiz Case. Noninvasive Aspergillus Sinusitis.
    Date February 1993
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title High-lying Resonances Observed in Heavy-ion Transfer Reactions.
    Date
    Journal Physical Review C: Nuclear Physics
    Title Structure of the Neutron-halo Nucleus 6he.
    Date
    Journal Physical Review C: Nuclear Physics
    Title Functional Outcomes of the Retromaxillary-infratemporal Fossa Dissection for Advanced Head and Neck/skull Base Lesions.
    Date
    Journal Skull Base Surgery
    Excerpt

    The retromaxillary-infratemporal fossa (RM-ITF) dissection, using a preauricular incision, was initially popularized for the treatment of temporomandibular joint disorders, facial fractures, and orbital tumors. This approach has been expanded for the treatment of advanced head and neck and skull base tumors extending into the infratemporal fossa. We studied prospectively eight consecutive patients requiring a RM-ITF dissection. Pre- and postoperative functional outcomes measured were mastication, speech, swallowing, cranial nerve function, pain, and cosmesis. A significant reduction in pain was noted postoperatively in all patients studied. Limited changes were identified in mastication, speech, swallowing, vision, hearing, or cosmesis postoperatively. The RM-ITF dissection should be considered when resecting advanced head and neck/skull base lesions that extend into this region. We have found minimal morbidity associated with this dissection. This procedure may have a useful place in palliation of patients with incurable pain caused by tumor invasion into the infratemporal fossa.

    Title Craniocervical Necrotizing Fasciitis with and Without Thoracic Extension: Management Strategies and Outcome.
    Date
    Journal American Journal of Otolaryngology
    Excerpt

    OBJECTIVE: First objective was to review cases of craniocervical necrotizing fasciitis (CCNF) at Wayne State University/Detroit Medical Center (Detroit, MI) for the last 18 years. Second was to analyze patients with and without thoracic extension for contributing factors. METHODS: Retrospective review of 660 patients with necrotizing fasciitis treated at WSU/DMC from January 1989 to January 2007 was conducted. Data regarding source/extent of infection, presenting signs/symptoms, computed tomography, microbiology, antibiotics, comorbidities, number/type of operations, hyperbaric oxygen (HBO) therapy, hospital duration, complications, and overall outcome were compared/analyzed between patients with and without thoracic extension. RESULTS: Twenty patients with CCNF for the past 18 years met the inclusion criteria. Ten patients had thoracic extension, and 10 patients did not have. Individuals in the thoracic extension group were likely to be older, had increased comorbidity, required more surgical debridement, experienced increased postoperative complications, and had lower overall survival. Three patients with thoracic extension underwent HBO therapy and 66% survived. CONCLUSION: This is the largest single institutional review of CCNF comparing patients with and without thoracic extension. Patients with thoracic extension have a poorer outcome as follows: 60% (6/10) survival vs 100% (10/10) for those without thoracic extension (P < .05). The CCNF patients without thoracic extension treated at our institution all survived after prompt medical and surgical intervention. Overall survival of CCNF patients without thoracic extension may be attributed to rigorous wound care, broad spectrum intravenous antibiotics, aggressive surgical debridement, and vigilant care in surgical intensive care unit. The HBO therapy should be included if the patient can tolerate it.

    Title Clinical Outcome of Acute Myocarditis in Children According to Treatment Modalities.
    Date
    Journal Korean Journal of Pediatrics
    Excerpt

    There is currently little evidence to support intravenous immune globulin (IVIG) therapy for pediatric myocarditis. The purpose of our retrospective study was to assess the effects of IVIG therapy in patients with presumed myocarditis on survival and recovery of ventricular function and to determine the factors associated with its poor outcome.


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