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Biomedical subjects

Theodoros N Teknos

Publications and source records attributed to Theodoros N Teknos.

At least 19 recordsLinked to original sources
PubMed2007

Acceleration of hyperfractionated chemoradiation regimen for advanced head and neck cancer.

BACKGROUND: Our aim was to evaluate the acceleration of a hyperfractionated, concurrent chemoradiation regimen (HxCRT) for advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with unresectable HNSCC were treated based on a previously published HxCRT regimen: 1.25 Gy twice daily to 70 Gy concurrent with cisplatin 12 mg/m(2)/day and 5-fluorouracil 600 mg/m(2)/day for 5 days, weeks 1, 5. This regimen was accelerated in this series by shortening the treatment from 7 to 6 weeks by omitting the planned mid-treatment 1-week break. RESULTS: Forty-six patients with T3-4/N3 disease were treated. The main acute toxicity was pharyngeal. Median weight change during therapy in patients with and without enteral feeding tubes was -3.8% and -7.9%, respectively (p = .08). Fifteen percent had late grade III pharyngeal toxicity. Local/regional and distant failure rates were 28% and 17%, respectively; 52% are alive without evidence of disease. CONCLUSIONS: In nonresectable HNSCC, acceleration of the HxCRT regimen is feasible, requiring enteral feeding tubes during therapy in most patients.

Adult↗
PubMed2006

Targeted disruption of protein kinase C epsilon reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma.

Over 70% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced stage III and IV disease. In spite of aggressive therapy, locoregional disease recurs in 60% and metastatic disease develops in 15% to 25% of patients causing a major decline in quality and length of life. Therefore, there is a need to identify and understand genes that are responsible for inducing an aggressive HNSCC phenotype. Evidence has shown that protein kinase C (PKC) epsilon is a transforming oncogene and may play a role in HNSCC progression. In this study, we determine the downstream signaling pathway mediated by PKC epsilon to promote an aggressive HNSCC phenotype. RNA interference knockdown of PKC epsilon in UMSCC11A and UMSCC36, two highly invasive and motile HNSCC cell lines with elevated endogenous PKC epsilon levels, resulted in cells that were significantly less invasive and motile than the small interfering RNA-scrambled control transfectants; 51 +/- 5% (P < 0.006) and 49 +/- 3% (P < 0.010) inhibition in invasion and 69 +/- 1% (P < 0.0005) and 66 +/- 3% (P < 0.0001) inhibition in motility, respectively. PKC epsilon-deficient UMSCC11A clones had reduced levels of active and serine-phosphorylated RhoA and RhoC. Moreover, constitutive active RhoA completely rescued the invasion and motility defect, whereas constitutive active RhoC completely rescued the invasion and partially rescued the motility defect of PKC epsilon-deficient UMSCC11A clones. These results indicate that RhoA and RhoC are downstream of PKC epsilon and critical for PKC epsilon-mediated cell invasion and motility. Our study shows, for the first time, that PKC epsilon is involved in a coordinated regulation of RhoA and RhoC activation, possibly through direct post-translational phosphorylation.

Carcinoma, Squamous Cell↗
PubMed2006

RhoC GTPase expression as a potential marker of lymph node metastasis in squamous cell carcinomas of the head and neck.

PURPOSE: Survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained unchanged for several decades due to local tumor recurrences as well as regional and distant metastases. Recent evidence has shown that RhoC GTPase is overexpressed in stages III and IV regionally metastatic SCCHN compared with stages I and II localized disease. This study evaluated the expression of RhoC in head and neck carcinoma and investigated the prognostic use of this marker on a large cohort of previously untreated patients with SCCHN. EXPERIMENTAL DESIGN: Standard Western blot techniques were used to evaluate RhoC protein expression in nine established head and neck cancer cell lines and in normal oral epithelium. In vivo expression of RhoC in metastatic and nonmetastatic SCCHN was investigated using immunohistochemical analysis on a tissue microarray composed of 113 independent tumor samples. RhoC expression was analyzed as it related to clinical and pathologic variables of interest. RESULTS: Levels of RhoC protein were increased in the SCCHN cell lines compared with normal oral epithelium. The in vivo expression of RhoC correlated with advanced clinical stage and lymph node metastases for the entire patient cohort as well as in small primary tumors (T(1) and T(2)). CONCLUSIONS: This study is the first to examine the expression of RhoC GTPase protein in SCCHN and normal squamous epithelium. It is clear from the results that RhoC is a specific marker of lymph node metastases in patients with this challenging form of carcinoma. RhoC levels seem to identify a subset of patients with early tumor stage primary tumors and high metastatic potential that might benefit from more aggressive therapy. Through continued investigation, blockade of RhoC activity may be a potential target in the development of novel strategies for treating metastases of head and neck cancer.

Biomarkers, Tumor↗
PubMed2006

Combination tetrathiomolybdate and radiation therapy in a mouse model of head and neck squamous cell carcinoma.

OBJECTIVE: To assess the effect of combining tetrathiomolybdate therapy and radiation treatment (RT) on tumor growth in the mouse head and neck squamous cell carcinoma (HNSCC) model. DESIGN: One million HNSCC cells were injected subcutaneously into the flanks of C3H/HeJ mice and the tumors grown to an average of 301 mm3 (day 0). Mice were randomized into 4 groups: (a) no therapy, (b) tetrathiomolybdate alone, (c) RT alone, or (d) tetrathiomolybdate + RT. Data from 3 experiments with these 4 groups were analyzed. A gaussian mixed model was fit to the initialized logarithm of the tumor size counts between days 7 and 16 (linear component), and growth rates were compared. Assays using 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyltetrazolium bromide (MTT) were conducted on HNSCC cells in culture with varying doses of tetrathiomolybdate. INTERVENTIONS: Treated mice were given tetrathiomolybdate in their water and observed for clinical evidence of toxic effects associated with copper depletion as measured by ceruloplasmin assay. When tumor sizes reached an average of 535 mm(3), mice receiving RT were given a single fraction of 750 rad (7.5 Gy), a dose determined in previous experiments to slow but not cure tumor growth, permitting an examination of interaction of radiation with tetrathiomolybdate. RESULTS: Data from 3 separate experiments were analyzed. There were a total of 37 mice in the untreated group, 32 mice in the tetrathiomolybdate alone group, 38 mice in the RT alone group, and 46 mice in the tetrathiomolybdate + RT group. Ceruloplasmin assays showed that we had obtained adequate copper reduction throughout the experiments to inhibit angiogenesis with minimal toxic effects. The tetrathiomolybdate + RT combined therapy group of mice showed a statistically significant decrease in tumor growth compared with both the tetrathiomolybdate alone (P = .001) and RT alone groups (P<.001). CONCLUSION: The combination of the anti-angiogenic copper chelating agent tetrathiomolybdate with RT improved local control of HNSCC in an isogenic mouse model compared with either therapy alone.

Angiogenesis Inhibitors↗
PubMed2006

Variables associated with feeding tube placement in head and neck cancer.

OBJECTIVE: To identify clinical factors associated with enteral feeding tube placement in a head and neck cancer population. DESIGN: A self-administered survey was given to patients being treated for head and neck cancer while they were waiting to be seen in 1 of 4 otolaryngology clinics. The post hoc analysis presented here combines survey and chart review data to determine clinical and demographic variables associated with feeding tube placement. SETTING: Four otolaryngology clinics. PATIENTS: Otolaryngology clinic patients being treated for head and neck cancer. MAIN OUTCOME MEASURE: Enteral feeding tube placement. RESULTS: Of the 724 patients eligible for this study, 14% (n = 98) required enteral feeding tube placement. Multivariate analysis found the following variables to be independently associated with feeding tube placement: oropharynx/hypopharynx tumor site (odds ratio [OR], 2.4; P = .01), tumor stage III/IV (OR, 2.1; P = .03), flap reconstruction (OR, 2.2; P = .004), current tracheotomy (OR, 8.0; P<.001), chemotherapy (OR, 2.6; P<.001), and increased age (OR, 1.3; P = .02). In addition, there was a curvilinear relationship between time since treatment and feeding tube placement, with about 30% having a feeding tube at 1 month posttreatment, tapering down during the first 3 years to about 8% and leveling off thereafter. CONCLUSIONS: Identification of factors associated with an increased risk of feeding tube placement may allow physicians to better counsel patients regarding the possibility of feeding tube placement during treatment. Since feeding tube placement has been linked to decreased quality of life in head and neck cancer, such counseling is an integral part of the clinical management of these patients.

Adult↗
PubMed2006

Evaluation of the thyroid nodule.

BACKGROUND: Thyroid nodules are common, yet treatment modalities range from observation to surgical resection. Because thyroid nodules are frequently found incidentally during routine physical examination or imaging performed for another reason, physicians from a diverse range of specialties encounter thyroid nodules. Clinical decision making depends on proper evaluation of the thyroid nodule. METHODS: The current literature was reviewed and synthesized. RESULTS: Current evidence allows the formulation of recommendations and a general algorithm for evaluating the incidental thyroid nodule. CONCLUSIONS: Only a small percentage of thyroid nodules require surgical management. Diagnosis and treatment selection require a risk stratification by history, physical examination, and ancillary tests. Nodules causing airway compression or those at high risk for carcinoma should prompt evaluation for surgical treatment. In nodules larger than 1 cm, fine-needle aspiration biopsy is central to the evaluation as it is accurate, low risk, and cost effective. Subcentimeter nodules, often found incidentally on imaging obtained for another purpose, can usually be evaluated by ultrasonography. Other laboratory and imaging evaluations have specific and more limited roles. An algorithm for the evaluation of the thyroid nodule is presented.

Biopsy, Fine-Needle↗
PubMed2005

Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy.

Tumor metastasis is the major cause of morbidity and mortality in patients with breast cancer. It is critical to identify metastasis enabling genes and understand how they are responsible for inducing specific aspects of the metastatic phenotype to allow for improved clinical detection and management. Protein kinase C epsilon (PKC epsilon), a member of a family of serine/threonine protein kinases, is a transforming oncogene that has been reported to be involved in cell invasion and motility. In this study, we investigated the role of PKC epsilon in breast cancer development and progression. High-density tissue microarray analysis showed that PKC epsilon protein was detected in 73.6% (106 of 144) of primary tumors from invasive ductal breast cancer patients. Increasing PKC epsilon staining intensity was associated with high histologic grade (P = 0.0206), positive Her2/neu receptor status (P = 0.0419), and negative estrogen (P = 0.0026) and progesterone receptor status (P = 0.0008). Kaplan-Meier analyses showed that PKC epsilon was significantly associated with poorer disease-free and overall survival (log-rank, P = 0.0478 and P = 0.0414, respectively). RNA interference of PKC epsilon in MDA-MB231 cells, an aggressive breast cancer cell line with elevated PKC epsilon levels, resulted in a cell phenotype that was significantly less proliferative, invasive, and motile than the parental or the control RNA interference transfectants. Moreover, in vivo tumor growth of small interfering RNA-PKC epsilon MDA-MB231 clones was retarded by a striking 87% (P < 0.05) and incidence of lung metastases was inhibited by 83% (P < 0.02). PKC epsilon-deficient clones were found to have lower RhoC GTPase protein levels and activation. Taken together, these results revealed that PKC epsilon plays a critical and causative role in promoting an aggressive metastatic breast cancer phenotype and as a target for anticancer therapy.

Animals↗
PubMed2005

Predictive factors of local-regional recurrences following parotid sparing intensity modulated or 3D conformal radiotherapy for head and neck cancer.

BACKGROUND AND PURPOSE: Predictive factors for local-regional (LR) failures after parotid-sparing, Intensity modulated (IMRT) or 3D conformal radiotherapy for head and neck (HN) cancers were assessed. PATIENTS AND METHODS: One hundred and fifty-eight patients with mostly stages III-IV HN squamous cell carcinoma underwent curative bilateral neck irradiation aimed at sparing the parotid glands. Patient, tumor, and treatment factors were analyzed as predictive factors for LR failure. RESULTS: Twenty-three patients had LR recurrence (19 in-field and four marginal). No differences were found in the doses delivered to the PTVs of patients with or without in-field recurrences. In univariate analysis, tumor site was highly predictive for LR failure in both postoperative and definitive RT patients. In postoperative RT patients, pathologic tumor size, margin status, extracapsular extension (ECE) and number of lymph node metastases, were also significantly predictive. Multivariate analysis showed tumor site (oropharynx vs. other sites) to be a significant predictor in all patients, and involved margins and number of involved lymph nodes in postoperative patients. CONCLUSIONS: Clinical rather than dosimetric factors predicted for LR failures in this series, and were similar to those reported following standard RT. These factors may aid in the selection of patients for studies of treatment intensification using IMRT.

Adult↗
PubMed2005

Metabolic abnormalities associated with weight loss during chemoirradiation of head-and-neck cancer.

PURPOSE: Weight loss caused by acute mucositis and dysphagia is common during concurrent chemoirradiation (chemo-RT) of head-and-neck (HN) cancer. The metabolic consequences of weight loss during chemo-RT were investigated. PATIENTS AND METHODS: Ninety-six patients with locally advanced HN cancer were treated from 1995 to 2001 on protocols that consisted of 1 to 2 cycles of induction cisplatin/5-fluorouracil followed by irradiation (70 Gy over 7 weeks) concurrent with cisplatin (100 mg/m2 every 3 weeks). Body weights and metabolic evaluations were obtained before and during induction chemotherapy and chemo-RT. Greatest percent changes in weight and in the laboratory values were calculated for each phase of therapy. RESULTS: During induction chemotherapy, significant changes were found in BUN, BUN:creatinine ratio, HCO3, Mg, and albumin, but not in creatinine, Na, K, or weight. During chemo-RT, significant additional changes were observed in all parameters measured, including increases in BUN, creatinine, BUN: creatinine ratio, and HCO3 and decreases in Mg, albumin, Na, K, and weight. The magnitude of most of these changes was significantly greater during chemo-RT than during induction chemotherapy. During chemo-RT, 35% of the patients had more than 10% body weight loss and 6 patients had an increase in creatinine of more than 100%, including 5 patients with Grade 2 nephrotoxicity, all of whom had weight loss 10% or more. Significant correlations were found between weight loss and creatinine (p < 0.0001) or BUN (p = 0.0002) rises, but not with BUN:creatinine ratio or other metabolic changes. Age, gender, tobacco history, hypertension, and diabetes mellitus were not significant predictors of nephrotoxicity. CONCLUSIONS: Weight loss during cisplatin-containing chemo-RT was found to be associated with reduced kidney function. These findings do not establish cause-effect relationships; however, they highlight the importance of intensive supportive measures of nutrition and hydration beyond standard hydration during cisplatin administration. These intensive measures should be enacted before a 10% weight loss is reached.

Analysis of Variance↗
PubMed2005

Voice and swallowing outcomes of an organ-preservation trial for advanced laryngeal cancer.

INTRODUCTION: Organ-preservation treatment approaches for advanced laryngeal cancer patients that use combination chemoradiotherapy result in cure rates similar to primary laryngectomy with postoperative radiotherapy. In the national VA Larynx Cancer Trial, successful organ preservation was associated with an overall improvement in quality of life but not in subjective speech compared with long-term laryngectomy survivors. As part of a Phase II clinical trial, a prospective study of speech and swallowing results was conducted to determine if larynx preservation is associated with improved voice and swallowing compared with results in patients who require salvage laryngectomy. SUBJECTS: A total of 97 patients with advanced laryngeal cancer (46 Stage III, 51 Stage IV) were given a single course of induction chemotherapy (cisplatin 100 mg/m2 on Day 1 and 5-FU 1,000 mg/m2/day x 5 days), followed by assessment of response. Patients with less than 50% response underwent early salvage laryngectomy, and patients with 50% or better response underwent concurrent chemoradiation (72 Gy and cisplatin 100 mg/m2 on Days 1, 22, and 43), followed by two cycles of adjuvant chemotherapy (DDP/5-FU). Direct laryngoscopy and biopsy were performed 8 weeks after radiation therapy to determine final tumor response. Late salvage surgery was performed on patients with persistent or recurrent disease. METHODS: Completed survey data on voice and swallowing utilizing the Voice-Related Quality of Life Measure (V-RQOL) and the List Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) were obtained from 56 patients who were alive and free of disease at the time of survey, with a minimum follow-up of 8 months. Comparisons were made between patients with an intact larynx (n = 37) vs. laryngectomy (n = 19), as well as early (n = 12) vs. late salvage laryngectomy (n = 7). Multivariate analysis was performed to determine factors predictive of voice and swallowing outcomes. Overall 3-year determinant survival was 87%, with median follow-up of 40 months. RESULTS: Patients with an intact larynx demonstrated significantly higher (p = 0.02) mean V-RQOL scores (80.3) than did laryngectomy patients (65.4). This finding was consistent in the social-emotional (p = 0.007) and physical functioning domains (p = 0.03). No differences in V-RQOL scores were found in comparisons between early and late salvage laryngectomy. Multiple linear regression revealed that predictors of higher total V-RQOL scores include lower T stage (p = 0.03), organ preservation (p = 0.0007), and longer duration since treatment (p = 0.01). Understandability of speech was better in patients with an intact larynx (p = 0.001). Overall swallowing function was comparable between groups. Multiple logistic regression revealed that longer duration since treatment (p = 0.03, odds ratio = 1.1) and lower maximal mucositis grade (p = 0.03, odds ratio = 0.3) were predictive of higher likelihood of eating in public. Nutritional mode consisting of oral intake alone without nutritional supplements was achieved in 88.9% of patients with an intact larynx compared with 64.3% of laryngectomees (p = 0.09). CONCLUSIONS: Voice-related quality of life is better in patients after chemoradiation therapy compared with salvage laryngectomy. Earlier salvage, although known to be associated with fewer surgical complications, did not result in improved voice; however, the number of patients analyzed is small. Overall swallowing function is good in all patients; however, patients with an intact larynx are more likely to obtain nutrition with oral intake alone without supplements. Such measures of function and quality of life are important endpoints to help judge overall effectiveness as newer, more aggressive treatment protocols with added toxicities are developed and evaluated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

The effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth in squamous cell carcinoma of the head and neck.

OBJECTIVE: To assess the effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth rate in human squamous cell carcinoma (SCC). DESIGN: Three human SCC cell lines were used in this study for both in vitro and in vivo investigations. Conditioned media from untreated and tetrathiomolybdate-treated cell lines were compared with regard to cytokine levels, endothelial cell chemotaxis, endothelial cell tubule formation, and migration and the ability to induce angiogenesis in a rat aortic ring array. In vivo UM-SCC-38 was seeded onto tissue-engineered scaffolds and surgically implanted into the flanks of immunodeficient mice. Tumor growth rates and the level of angiogenesis were compared after 2 weeks of therapy. SETTING: A tertiary care facility. RESULTS: In this study, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by head and neck SCC (HNSCC) cell lines in vitro. Furthermore, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by HNSCC cell lines in vitro. Furthermore, tetrathiomolybdate treatment of HNSCC cell lines results in significantly decreased endothelial cell chemotaxis, tubule formation, and neovascularization in a rat aortic ring assay. This in vitro evidence of decreased angiogenesis by tetrathiomolybdate is confirmed in vivo by using a severe combined immunodeficiency disorder mouse model in which tetrathiomolybdate therapy is shown to prevent human blood vessel formation. Finally, human HNSCC implanted into immunodeficient mice grow to a much larger size in untreated mice compared with those treated with 0.7 mL/kg per day of oral tetrathiomolybdate. CONCLUSIONS: These findings illustrate the ability of tetrathiomolybdate to down-regulate proinflammatory and proangiogenic cytokines in HNSCC. These observations are potentially exciting from a clinical perspective because a global decrease in these cytokines may decrease tumor aggressiveness and reverse the resistance to chemotherapy and radiation therapy seen in this tumor type.

Angiogenesis Inhibitors↗
PubMed2005

Osseocutaneous radial forearm free tissue transfer for repair of complex midfacial defects.

OBJECTIVE: To evaluate the resulting aesthetics, function, and donor site morbidity of the osseocutaneous radial forearm free flap (OCRFFF) used for midface reconstruction. DESIGN: Prospective case series and a retrospective review of results. PATIENTS: Ten patients from an academic practice who underwent reconstruction at the University of Michigan Hospitals between 1995 and 2001. INTERVENTIONS: All patients had maxillectomy defects in which the entire infraorbital rim was reconstructed with an OCRFFF. Of the 10 patients included in the study, 3 underwent a total maxillectomy with orbital exenteration, 4 had a total maxillectomy without orbital exenteration, and 3 had a limited maxillectomy that did not involve the palate. Patients with palatal defects underwent reconstruction with a prosthetic palatal obturator. MAIN OUTCOME MEASURES: Facial contour and aesthetic results, speech understandability, ability to eat solid foods, oronasal separation, socializing outside the home, and return-to-work status. Flap success, donor site morbidity, and orbital complications were also studied. RESULTS: Mean +/- SEM follow-up was 23.2 +/- 5.0 months. A modified Funk facial deformity scale was used, and 7 of the 10 patients had either no deformity or minimal deformity. The mean aesthetic score for these reconstructions was 2.1 +/- 0.3 on a scale of 1 to 4, with 1 representing no deformity and 4 representing a severe deformity. All patients returned to a solid diet and had understandable speech, although patients who had an orbital exenteration trended to poorer scores. All patients socialized either frequently or occasionally outside the home, and all patients not retired or disabled prior to surgery returned to work. CONCLUSION: The OCRFFF reconstruction of the infraorbital rim in patients with total maxillectomy defects and obturator of the palatal defect controls orbital complications and optimizes aesthetic outcome while achieving nearly normal palatal function.

Adult↗
PubMed2005

Reliability of sentinel lymph node biopsy for regional staging of head and neck Merkel cell carcinoma.

OBJECTIVE: To determine (1) the reliability of sentinel lymph node (SLN) biopsy and (2) the need for cytokeratin 20 (CK-20) immunostaining in the staging of head and neck Merkel cell carcinoma (MCC). DESIGN: Retrospective cohort study (median follow-up of 34.5 months). SETTING: Tertiary care center. PATIENTS: Ten patients with head and neck MCC who underwent regional staging with SLN biopsy (SLNB) and CK-20 immunostaining. INTERVENTIONS: Sentinel lymph nodes were identified using preoperative lymphoscintigraphy, intraoperative gamma probe, and isosulfan blue dye. The SLNs were evaluated with hematoxylin-eosin and CK-20 immunostaining. Patients with negative SLNB results were followed up clinically. MAIN OUTCOME MEASURES: Percentage of positive SLNs, regional recurrence in the setting of a negative finding from SLNB, and percentage of positive SLNs requiring CK-20 immunostaining for diagnosis of micrometastatic MCC. RESULTS: At least 1 SLN was identified in every patient. Of 24 nodes, 19 (79%) were from the neck region and 5 (21%) were from the parotid basin. Two of the 24 SLNs, in 2 (20%) of 10 patients, were positive for metastatic disease. Both positive SLNs appeared negative on hematoxylin-eosin-stained sections, but small foci of micrometastatic MCC were identified with CK-20 immunostaining. No cranial nerve complications occurred. Regional failure in the setting of a negative finding on SLNB was observed in 1 (12%) of 8 patients. CONCLUSIONS: Biopsy of SLNs represents a safe and reliable technique for regional staging of MCC of the head and neck. It provides pathologists with a limited number of SLNs for focused analysis, which is imperative because hematoxylin-eosin immunostaining is often insufficient for identifying micrometastatic MCC. The use of anti-CK-20 antibody allows accurate identification of micrometastatic MCC.

Aged↗
PubMed2004

Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma.

BACKGROUND: The survival of patients with head and neck squamous cell carcinoma (HNSCC) remains unaffected despite recent therapeutic advances. To reverse this trend, reliable and clinically applicable markers of tumor aggressiveness must be identified. One such marker may be the tumor-associated macrophage content. The authors hypothesized that tumor-associated macrophages contribute to HNSCC aggressiveness, and the objective of the current study was to prove this hypothesis using mRNA expression analysis and a large cohort of clinical specimens. METHODS: Oligonucleotide microarray analysis was performed on a prospective cohort of 20 patients with previously untreated oral cavity or oropharynx squamous cell carcinoma (OC/OP SCCA) and on normal oropharyngeal mucosa from 4 patients. After determining whether macrophage chemoattractants were produced by tumors, conditioned media from three HNSCC cell lines were used to quantify macrophage migration in an in vitro assay. A high-density tissue microarray of 102 patients with previously untreated OC/OP SCCA was stained immunohistochemically for CD68 to identify tissue macrophages, and the results were correlated with clinicopathologic data and survival. RESULTS: Monocyte chemoattractant protein 1 was up-regulated significantly in tumors compared with normal mucosa (P=0.0025; fold change=1.89). All University of Michigan SCC tumor cell line conditioned media caused a significant increase in macrophage migration (P <0.05). Tissue microarray data revealed that macrophage content of the primary tumor was associated strongly with lymph node metastasis (P <0.0001), extracapsular lymph node spread (P=0.0001), and advanced clinical disease stage (P=0.0002). When it was evaluated along with other clinicopathologic data, the macrophage content was found to be an independent predictor of lymph node metastasis (P <0.0001). CONCLUSIONS: Primary tumor macrophage content is a strong predictor of tumor aggressiveness in HNSCC.

Adult↗
PubMed2004

Recurrences near base of skull after IMRT for head-and-neck cancer: implications for target delineation in high neck and for parotid gland sparing.

PURPOSE: Locoregional (LR) failures near the base of the skull, and their relationships to the targets in the high neck, were examined in a series of patients who underwent intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. METHODS AND MATERIALS: Between 1994 and 2002, 133 patients with non-nasopharyngeal head-and-neck squamous cell carcinoma completed a course of curative, parotid-sparing RT. Treatment was delivered until 1996 with conformal three-dimensional techniques and thereafter with multisegmental static IMRT. Of the 133 patients, 80 had oropharyngeal, 27 oral cavity, 12 hypopharyngeal, 11 laryngeal, and 3 unknown primary cancer. The AJCC stage was I in 1, II in 6, III in 26, IVA in 83, and IVB in 12; cancer was recurrent in 5. Sixty patients received primary and 73 postoperative IMRT. 86% of patients (n = 115) had ipsilateral neck metastasis. In all patients, the contralateral neck was clinically node negative but was judged to be at high risk of subclinical disease. Delineation of the superior-most extent of the nodal targets was consistent and corresponded with Rouviere's observations. In the contralateral clinically node-negative neck, the uppermost Level II nodal target was the subdigastric (SD) nodes. To ensure coverage, the uppermost clinical target volume was delineated at the axial CT image in which the posterior belly of the digastric muscle crossed the jugular vein. In the ipsilateral neck, which was node positive in most patients, the uppermost Level II clinical target volume was delineated through the base of the skull. The uppermost retropharyngeal (RP) nodal target was delineated at the level of the top of the C1 vertebral body, accommodating Rouviere's description of the location of the lateral RP nodes. The dose prescription was 70 Gy for the primary planning target volumes (PTVs); 64 Gy and 60 Gy for PTV of the postoperative beds with and without extracapsular extension, respectively; and 50-54 Gy for PTVs of nonoperated subclinical disease, at 1.8-2.0 Gy fractions. In-field or marginal recurrences were defined as those occurring when >95% or 20-95% of the recurrence volume, respectively, had received >95% of the prescribed dose. RESULTS: At a median follow-up of 32 months (range, 6-107 months), 21 patients (16%) had locoregional recurrence. Seventeen recurrences were in-field and four were marginal. The most prevalent nodal recurrence was in Level II bilaterally, where all failures were in-field. In-field failures were observed in the ipsilateral high neck cranial to the SD nodes (all in initially node-positive neck). No recurrences occurred in the contralateral high neck, cranial to the SD nodes, which was not included in the targets. The 95% confidence interval for the risk of recurrence in that region was 0-2.7%. Three RP nodal failures were observed; two were marginal, occurring ipsilateral and contralateral to the primary tumors, and centered cranial to the top of C1. After these recurrences, the RP nodal clinical target volumes were delineated bilaterally through the base of skull, without subsequent RP recurrence. These target delineation guidelines allowed the achievement of a mean contralateral parotid dose of < or =26 Gy (found previously to preserve salivary output significantly) in 82% of the patients. The 3-year actuarial LR recurrence-free survival rate of primary and postoperative IMRT patients was similar (81% and 84%, respectively). Oropharyngeal cancer patients had the greatest LR recurrence-free survival rate (94%, p <0.001). No statistically significant differences were found in the dose delivered to the PTVs or the in-field recurrence volume between patients who had or did not have LR failure. CONCLUSION: These results suggest that when the contralateral node-negative side of the neck has a high risk of subclinical metastasis, it is adequate to include the SD nodes as the cranial-most Level II nodal target in non-nasopharyngeal head-and-neck cancer. In the node-positive side of the neck, this nodal level should be delineated more cranially. The RP nodal targets should be delineated more cranially. The RP nodal targets should be delineated bilaterally and should extend to the base of the skull, rather than to the top of C1. These guidelines allowed substantial sparing of the contralateral parotid gland. The results of this series validate a consensus for target delineation adopted recently by cooperative radiotherapy groups.

Adult↗
PubMed2004

Pectoralis major myocutaneous flap vs revascularized free tissue transfer: complications, gastrostomy tube dependence, and hospitalization.

OBJECTIVE: To evaluate the factors related to surgical complications, rate of gastrostomy tube (G-tube) dependence, and hospitalization in patients undergoing reconstruction with a pectoralis myocutaneous flap vs a soft-tissue revascularized flap. DESIGN: Quasi-experimental case series with a historic control group. POPULATION: A total of 179 patients (138 men and 41 women) with a mean (SD) age of 58 (14) years treated between January 1, 1986, and December 31, 1995, with a pectoralis flap (108 patients) or a revascularized free flap (71 patients). METHODS: Inclusion criteria were first or second extirpation, reconstruction with soft-tissue flap, or defect including the upper aerodigestive tract. Exclusion criteria were secondary reconstruction, or reconstruction for salvage of a complication. RESULTS: Although the major complication rate was not significantly different according to reconstructive approach, hypopharyngeal defects had a significantly higher major complication rate of 30% (6/20) compared with 8% (13/159) for other defect sites (P<.003). The minor complication rate was higher in the pectoralis group, at 57% (62/108), than in the revascularized flap group, at 21% (15/71) (P<.001). G-tube dependence was higher in the pectoralis group at 42% (40/96), in contrast to the revascularized flap group at 16% (10/63) (P<.001). G-tube dependence was 25% higher in patients who underwent salvage surgery after radiation (42% [30/72]) than in patients treated with postoperative radiation (17% [12/69]) (P<.004). Revascularized flaps helped ameliorate the effects of radiation before surgery; 56% (23/41) of the patients who received pectoralis flaps were G-tube dependent, while the rate of G-tube dependence in the revascularized flap group was 23% (7/31) (P<.004). Hospitalization was longer in the pectoralis group (14 days) than the revascularized flap group (12 days) (P<.006). CONCLUSION: Patients who undergo reconstruction with a pectoralis flap have significantly higher minor complication rates, a higher rate of G-tube dependence, and longer hospitalization than patients who undergo reconstruction with a soft-tissue revascularized flap.

Female↗
PubMed2004

Molecular profiling and the identification of genes associated with metastatic oral cavity/pharynx squamous cell carcinoma.

OBJECTIVE: To investigate differences in gene expression profiles between oral cavity/oropharynx squamous cell carcinoma (OC/OP SCC) primary tumors that have metastasized to cervical lymph nodes and nonmetastatic OC/OP SCC tumors. DESIGN: Oligonucleotide microarray analysis of primary tumors was used to produce gene expression profiles. Profile comparisons between metastatic and nonmetastatic tumors were performed using principal component analysis, t test, and fold change differences. A similar comparison between metastatic tumors and noncancer oral mucosa samples was performed to ensure tumor origin. SUBJECTS: A prospective cohort of 20 patients with previously untreated OC/OP SCC who underwent pathologic staging following surgical resection and lymphadenectomy. RESULTS: Of the approximately 9600 genes profiled, 101 demonstrated significant expression differences between the metastatic and nonmetastatic tumors (fold change > or =1.5; P<.01). Among this subset, 57 genes also exhibited significant differences between metastatic tumors and normal mucosa samples (fold change > or =1.5; P<.05). This profile included genes related to the extracellular matrix, adhesion, motility, inflammation, and protease inhibition. Collagen type 11 alpha-1 (COL11A1) demonstrated the greatest differential expression between metastatic and nonmetastatic OC/OP SCC tumors (fold change=7.61; P=.002). Tissue inhibitor of metalloproteinase 1 (TIMP-1) also demonstrated increased expression in metastatic tumors (fold change=3.3; P=.003). CONCLUSIONS: Metastatic OC/OP SCC has a distinct gene expression profile compared with nonmetastatic OC/OP SCC and normal oral mucosa. This metastatic profile includes genes related to the extracellular matrix, adhesion, motility, and protease inhibition. Knowledge gained through tumor gene expression profiling may facilitate early detection of aggressive tumors and targeted therapeutic interventions.

Carcinoma, Squamous Cell↗