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Pawadee Lohavanichbutr,
Eduardo Méndez,
Chris Holsinger,
Tessa C Rue,
Yuzheng Zhang,
John Houck,
Melissa Upton, Neal Futran,
Stephen M Schwartz,
Pei Wang,
Chu Chen
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ABSTRACT: PURPOSE: To identify a prognostic gene signature for HPV-negative OSCC patients. EXPERIMENTAL DESIGN: Two gene expression datasets were used; a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC) (n=97), and a validation dataset from the MD Anderson Cancer Center (MDACC) (n=71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131-gene signature previously identified to be prognostic in OSCC patients to identify a prognostic model specific for high-risk HPV-negative OSCC patients. The models were tested with the MDACC dataset using a receiver operating characteristic analysis. RESULTS: A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the median. The estimated 2-year mortality (± SE) of patients with high risk scores was 47.1 (±9.24)% compared with 6.35 (± 4.42)% for patients with low risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score (0.78, 95%CI: 0.74-0.86) and risk score plus tumor stage (0.79, 95%CI: 0.75-0.87) were substantially higher than for the model with tumor stage (0.54, 95%CI: 0.48-0.62). CONCLUSIONS: We identified and validated a 13-gene signature that is considerably better than tumor stage in predicting survival of HPV-negative OSCC patients. Further evaluation of this gene signature as a prognostic marker in other populations of patients with HPV-negative OSCC is warranted.
Clinical Cancer Research 01/2013; · 7.74 Impact Factor
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ABSTRACT: Oral and oropharyngeal squamous cell carcinomas (OSCC) are among the most common cancers worldwide, with approximately 60% 5-yr survival rate. To identify potential markers for disease progression, we used Affymetrix U133 plus 2.0 arrays to examine the gene expression profiles of 167 primary tumor samples from OSCC patients, 58 uninvolved oral mucosae from OSCC patients and 45 normal oral mucosae from patients without oral cancer, all enrolled at one of the three University of Washington-affiliated medical centers between 2003 to 2008. We found 2,596 probe sets differentially expressed between 167 tumor samples and 45 normal samples. Among 2,596 probe sets, 71 were significantly and consistently up- or down-regulated in the comparison between normal samples and uninvolved oral samples and between uninvolved oral samples and tumor samples. Cox regression analyses showed that 20 of the 71 probe sets were significantly associated with progression-free survival. The risk score for each patient was calculated from coefficients of a Cox model incorporating these 20 probe sets. The hazard ratio (HR) associated with each unit change in the risk score adjusting for age, gender, tumor stage, and high-risk HPV status was 2.7 (95% CI: 2.0-3.8, p = 8.8E-10). The risk scores in an independent dataset of 74 OSCC patients from the MD Anderson Cancer Center was also significantly associated with progression-free survival independent of age, gender, and tumor stage (HR 1.6, 95% CI: 1.1-2.2, p = 0.008). Gene Set Enrichment Analysis showed that the most prominent biological pathway represented by the 71 probe sets was the Integrin cell surface interactions pathway. In conclusion, we identified 71 probe sets in which dysregulation occurred in both uninvolved oral mucosal and cancer samples. Dysregulation of 20 of the 71 probe sets was associated with progression-free survival and was validated in an independent dataset.
PLoS ONE 01/2012; 7(9):e46575. · 4.09 Impact Factor
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ABSTRACT: The matrix metalloproteinases (MMP) cause degradation of the extracellular matrix and basement membranes, and thus may play a key role in cancer development.
In our search for biomarkers for oral squamous cell carcinomas (OSCC), we compared primary OSCC, oral dysplasia and control subjects with respect to: (i) expression of MMP1, MMP3, MMP10, and MMP12 in oral epithelial tissue using Affymetrix U133 2.0 Plus GeneChip arrays, followed by quantitative reverse transcription-PCR (qRT-PCR) for MMP1, and (ii) determination of MMP1 and MMP3 concentrations in saliva.
MMP1 expression in primary OSCC (n = 119) was >200-fold higher (P = 7.16 × 10(-40)) compared with expression levels in nonneoplastic oral epithelium from controls (n = 35). qRT-PCR results on 30 cases and 22 controls confirmed this substantial differential expression. The exceptional discriminatory power to separate OSCC from controls was validated in two independent testing sets (AUC% = 100; 95% CI: 100-100 and AUC% = 98.4; 95% CI: 95.6-100). Salivary concentrations of MMP1 and MMP3 in OSCC patients (33 stage I/II, 26 stage III/IV) were 6.2 times (95% CI: 3.32-11.73) and 14.8 times (95% CI: 6.75-32.56) higher, respectively, than in controls, and displayed an increasing trend with higher stage disease.
Tumor and salivary MMPs are robust diagnostic biomarkers of OSCC.
The capacity of MMP gene expression to identify OSCC provides support for further investigation into MMPs as potential markers for OSCC development. Detection of MMP proteins in saliva in particular may provide a promising means to detect and monitor OSCC noninvasively.
Cancer Epidemiology Biomarkers & Prevention 09/2011; 20(12):2628-36. · 4.12 Impact Factor
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Eduardo Méndez,
Pawadee Lohavanichbutr,
Wenhong Fan,
John R Houck,
Tessa C Rue,
David R Doody, Neal D Futran,
Melissa P Upton,
Bevan Yueh,
Lue Ping Zhao,
Stephen M Schwartz,
Chu Chen
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ABSTRACT: To determine the differential gene expression between oral squamous cell carcinoma (OSCC) with and without metastasis to cervical lymph nodes and to assess prediction of nodal metastasis by using molecular features.
We used Affymetrix U133 2.0 plus arrays to compare the tumor genome-wide gene expression of 73 node-positive OSCCs with 40 node-negative OSCCs (≥ 18 months). Multivariate linear regression was used to estimate the association between gene expression and nodal metastasis. Stepwise logistic regression and receiver operating characteristics (ROC) analysis were used to generate predictive models and to compare these with models by using tumor size alone.
We identified five genes differentially expressed between node-positive and node-negative OSCCs after adjusting for tumor size and human papillomavirus status: REEP1, RNF145, CTONG2002744, MYO5A, and FBXO32. Stepwise regression identified a four-gene model (MYO5A, RFN145, FBXO32, and CTONG2002744) as the most predictive of nodal metastasis. A leave-one-out ROC analysis revealed that our model had a higher area under the curve (AUC) for identifying occult nodal metastasis compared with that of a model by tumor size alone (respective AUC: 0.85 and 0.61; P = 0.011). A model combining tumor size and gene expression did not further improve the prediction of occult metastasis. Independent validation using 31 metastatic and 13 nonmetastatic cases revealed a significant underexpression of CTONG2002744 (P = 0.0004).
These results suggest that our gene expression markers of OSCC metastasis hold promise for improving current clinical practice. Confirmation by others and functional studies of CTONG2002744 is warranted.
Clinical Cancer Research 02/2011; 17(8):2466-73. · 7.74 Impact Factor
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Chang Xu,
Yan Liu,
Pei Wang,
Wenhong Fan,
Tessa Rue,
Melissa Upton,
John Houck,
Pawadee Lohavanichbutr,
David Doody, Neal Futran,
Lue Zhao,
Stephen Schwartz,
Chu Chen,
Eduardo Méndez
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ABSTRACT: Abstract
Background
Lymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival. In an effort to identify genes that may be responsible for the initiation of OSCC lymphotropism, we examined DNA copy number gains and losses and corresponding gene expression changes from tumor cells in metastatic lymph nodes of patients with OSCC.
Results
We performed integrative analysis of DNA copy number alterations (CNA) and corresponding mRNA expression from OSCC cells isolated from metastatic lymph nodes of 20 patients using Affymetrix 250 K Nsp I SNP and U133 Plus 2.0 arrays, respectively. Overall, genome CNA accounted for expression changes in 31% of the transcripts studied. Genome region 11q13.2-11q13.3 shows the highest correlation between DNA CNA and expression. With a false discovery rate < 1%, 530 transcripts (461 genes) demonstrated a correlation between CNA and expression. Among these, we found two subsets that were significantly associated with OSCC (n = 122) when compared to controls, and with survival (n = 27), as tested using an independent dataset with genome-wide expression profiles for 148 primary OSCC and 45 normal oral mucosa. We fit Cox models to calculate a principal component analysis-derived risk-score for these two gene sets ('122-' or '27-transcript PC'). The models combining the 122- or 27-transcript PC with stage outperformed the model using stage alone in terms of the Area Under the Curve (AUC = 0.82 or 0.86 vs. 0.72, with p = 0.044 or 0.011, respectively).
Conclusions
Genes exhibiting CNA-correlated expression may have biological impact on carcinogenesis and cancer progression in OSCC. Determination of copy number-associated transcripts associated with clinical outcomes in tumor cells with an aggressive phenotype (i.e., cells metastasized to the lymph nodes) can help prioritize candidate transcripts from high-throughput data for further studies.
Molecular Cancer. 01/2010;
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Pawadee Lohavanichbutr,
John Houck,
Wenhong Fan,
Bevan Yueh,
Eduardo Mendez, Neal Futran,
David R Doody,
Melissa P Upton,
D Gregory Farwell,
Stephen M Schwartz,
Lue Ping Zhao,
Chu Chen
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ABSTRACT: To study the difference in gene expression between human papillomavirus (HPV)-positive and HPV-negative oral cavity and oropharyngeal squamous cell carcinoma (OSCC).
We used Affymetrix U133 plus 2.0 arrays to examine gene expression profiles of OSCC and normal oral tissue. The HPV DNA was detected using polymerase chain reaction followed by the Roche LINEAR ARRAY HPV Genotyping Test, and the differentially expressed genes were analyzed to examine their potential biological roles using the Ingenuity Pathway Analysis Software, version 5.0.
Three medical centers affiliated with the University of Washington.
A total of 119 patients with primary OSCC and 35 patients without cancer, all of whom were treated at the setting institutions, provided tissues samples for the study.
Human papillomavirus DNA was found in 41 of 119 tumors (34.5%) and 2 of 35 normal tissue samples (5.7%); 39 of the 43 HPV specimens were HPV-16. A higher prevalence of HPV DNA was found in oropharyngeal cancer (23 of 31) than in oral cavity cancer (18 of 88). We found no significant difference in gene expression between HPV-positive and HPV-negative oral cavity cancer but found 446 probe sets (347 known genes) differentially expressed in HPV-positive oropharyngeal cancer than in HPV-negative oropharyngeal cancer. The most prominent functions of these genes are DNA replication, DNA repair, and cell cycling. Some genes differentially expressed between HPV-positive and HPV-negative oropharyngeal cancer (eg, TYMS, STMN1, CCND1, and RBBP4) are involved in chemotherapy or radiation sensitivity.
These results suggest that differences in the biology of HPV-positive and HPV-negative oropharyngeal cancer may have implications for the management of patients with these different tumors.
Archives of otolaryngology--head & neck surgery 03/2009; 135(2):180-8. · 1.92 Impact Factor
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ABSTRACT: To validate the DNA microarray results on a subset of genes that could potentially serve as biomarkers of oral squamous cell carcinoma (OSCC) by examining their expression with an alternate quantitative method and by assessing their protein levels.
Based on DNA microarray data from our laboratory and data reported in the literature, we identified 6 potential biomarkers of OSCC to investigate further. We used quantitative real-time polymerase chain reaction to examine expression changes of CDH11, MMP3, SPARC, POSTN, TNC, and TGM3 in OSCC and histologically normal control tissues. We further examined validated markers at the protein level by immunohistochemical analysis of OSCC tissue microarray sections.
Quantitative real-time polymerase chain reaction analysis revealed upregulation of CDH11, SPARC, POSTN, and TNC gene expression and decreased TGM3 expression in OSCC tissue compared with control tissue; MMP3 was not found to be differentially expressed. In tissue microarray immunohistochemical analyses, SPARC (secreted protein, acidic, rich in cysteine), periostin, and tenascin C exhibited increased protein expression in tumor tissue compared with control tissue, and their expression was primarily localized within tumor-associated stroma rather than tumor epithelium. Conversely, transglutaminase 3 protein expression was found only within keratinocytes in control tissue and was significantly downregulated in cancer cells.
Of 6 potential gene markers of OSCC, initially identified by DNA microarray analyses, differential expression of CDH11, SPARC, POSTN, TNC, and TGM3 were validated by quantitative real-time polymerase chain reaction. Differential expression and localization of proteins encoded by SPARC, POSTN, TNC, and TGM3 were clearly shown by tissue microarray immunohistochemical analysis.
Archives of otolaryngology--head & neck surgery 06/2008; 134(5):539-46. · 1.92 Impact Factor
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ABSTRACT: To compare lip-split and visor flap approaches to the oral cavity in terms of morbidity, margins, and locoregional recurrence.
Retrospective case series at the University of Washington, Seattle.
Seventy patients undergoing resection of advanced (T4) anterior oral cavity squamous cell carcinoma requiring fibula reconstruction were grouped according to surgical access procedure performed (lip-split [LS] or visor flap [VF]). Data on surgical morbidity, margin status, and outcomes were compared.
Recurrence rates and positive margins were similar for both groups. Rates of postoperative fistulae were 6.8% (LS) vs 0% (VF) and for oral incompetence 14.6% (LS) vs 6.9% (VF). Most of the fistulas (37.5%) were in irradiated patients. Neither group had any malunions.
There is no significant difference in pathological margins or rates of local recurrence when using either the lip-split or the visor approach. The lip-split approach has a higher rate of postoperative fistula formation than the visor flap approach; fistula formation may be associated with previous irradiation.
Otolaryngology Head and Neck Surgery 10/2007; 137(3):428-32. · 1.72 Impact Factor
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Robert C Rostomily,
Maria Elias,
Mei Deng,
Paul Elias,
Donald E Born,
David Muballe,
Daniel L Silbergeld, Neal Futran,
Ernest A Weymuller,
David A Mankoff,
Janet Eary
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ABSTRACT: For tumors that express somatostatin receptors (SSTR), radiolabeled somatostatin analogs, such as 111In-pentetreotide, can demonstrate the presence of tumor by radioligand uptake using somatostatin receptor scintigraphy (SRS). The use of 111In-pentetreotide for SRS depends on the specific high affinity of octreotide for SSTR subtypes 2, 3, and 5. Of these, SSTR2 has the greatest affinity for octreotide and the greatest relevance for tumor detection with Octreoscan imaging. Discriminating between postoperative changes and residual or recurrent tumor after extensive skull base surgery is often difficult, but in a case of recurrent esthesioneuroblastoma (ENB) we found the use of Octreoscan imaging clinically useful. To better define the general relevance of this imaging technique in this setting, we analyzed SSTR subtype expression in a panel of ENB tumors.
The case history and correlations between MRI and 111In-pentetreotide SRS of a patient with recurrent ENB were reviewed. The expression pattern of the SSTR subtypes in a panel of ENB tumors was then analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) to better define the potential of more general use of Octreoscan for imaging ENB. To correlate SSTR2 protein expression with 111In-pentetreotide uptake, immunohistochemistry to detect SSTR2 was performed on tumor samples from regions of increased uptake on Octreoscan.
The SSTR2 message was expressed at high levels in all five ENB tumor samples, and either SSTR2 protein or histologic findings typical for ENB were found in all tumor tissue obtained from regions of increased 111In-pentetreotide uptake. Furthermore, Octreoscan imaging in this case proved useful in clinical decision making.
The expression pattern of SSTR2 and the specificity of the Octreoscan for regions of active tumor growth support further investigation of the utility of Octreoscan imaging in the diagnosis and surveillance of ENB. Recent advances in novel therapies based on SSTR ligand binding also provide the rationale to consider such novel therapeutic approaches in patients with ENB.
Head & Neck 04/2006; 28(4):305-12. · 2.40 Impact Factor
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The Annals of otology, rhinology, and laryngology 06/2005; 114(5):416-8. · 1.05 Impact Factor
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ABSTRACT: To determine whether external beam radiation therapy (XRT), administered either before or after surgery, increases the rate and/or severity of local postoperative complications in patients with head and neck cancer who undergo microvascular free flap reconstruction.
Retrospective cohort study.
University of Washington Medical Center, Seattle, a tertiary care hospital.
A total of 100 consecutive patients underwent fibular free flap reconstruction of the mandible. The study cohort was divided according to radiation treatment status: (1) no XRT (28 patients), (2) preoperative XRT (37 patients), and (3) postoperative XRT (35 patients). The median follow-up after surgery was 11 months (range, 1-89 months).
Rate and severity of local postoperative complications.
Fifty-four patients (54%) had at least 1 postoperative complication. There were no differences among the 3 XRT subgroups in the overall proportion of patients with complications of any severity (15 [54%] of 28 patients in the no XRT group, 24 [65%] of 37 patients in the preoperative XRT group, and 16 [46%] of 35 patients in the postoperative XRT group; P = .26, chi(2) analysis). There were also no differences seen when mild and severe complication rates were specifically examined (P = .58 and P = .10, respectively). No case of complete flap loss was observed. We noted no significant correlations between the rate of postoperative complications and the following covariates: total radiation dose, size of radiation field, disease stage, exposure to chemotherapy, presence of serious medical comorbidities, patient age, or history of tobacco use.
Our experience suggests that XRT can be safely administered before or after surgery to patients undergoing head and neck free flap reconstruction at an experienced surgical referral center. Postoperative complication rates were not significantly affected by administration, timing, dose, or extent of XRT.
Archives of Otolaryngology - Head and Neck Surgery 12/2004; 130(11):1308-12. · 1.63 Impact Factor
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ABSTRACT: Reconstruction of hypopharyngeal and cervical esophageal defects remains one of the greatest challenges to head and neck and reconstructive surgeons. Although the jejunal free flap is a well-known reconstructive choice, many authors prefer alternative methods because of the complication rates and donor site morbidity associated with traditional jejunal flap harvest. Laparoscopic resection of the small intestine is a well-documented surgical technique. However, laparoscopic harvest of a jejunal segment for use in free tissue transfer reconstruction of defects of the hypopharynx and cervical esophagus has primarily been described in animal models, with only a few clinical studies existent in the recent literature.
To evaluate the use of a laparoscopic technique for harvesting jejunal segments for use in free tissue transfer reconstruction of pharyngoesophageal defects.
The records of 12 patients who underwent laparoscopic jejunal flap harvest for reconstruction of large hypopharyngeal or cervical esophageal defects at the University of Washington, Seattle, from January 1998 through April 2001 were retrospectively reviewed. Time of harvest, need to convert to "open" technique, failure rate, complications, and length of hospital stay were evaluated.
All harvests were completed laparoscopically. The average operative time for the abdominal portion of the procedure was 2.4 hours. Warm ischemia time required for flap removal from the peritoneal cavity was less than 4 minutes. Each patient received a completely endoscopic jejunum harvest, bowel reanastomosis, and placement of a feeding jejunostomy tube. Enteral feedings began on the first postoperative day. No major complications were seen resulting from this technique, and no donor site morbidity was identified. All flaps were viable, with no revisions required. Activity in hospital and time to discharge were independent of the abdominal procedure.
Given the low complication rate and relative ease of harvest, we conclude that this new technique is currently the best way to harvest jejunal flaps for reconstructing these challenging defects and should renew enthusiasm for this versatile flap.
Archives of Otolaryngology - Head and Neck Surgery 01/2003; 128(12):1384-7. · 1.63 Impact Factor
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ABSTRACT: Although cosmetic defects produced by posterior fossa surgery may not seem obvious, a poor cosmetic result can overshadow an otherwise successful operation. It is important to approach the operation with knowledge that each phase of a surgical procedure either directly or indirectly influences the eventual cosmetic result. The careful use of anatomic dissection and repair and attempts to reconstitute bony defects to their native contour as well as avoidance of complications all contribute to excellent cosmetic outcomes.
Neurosurgery Clinics of North America 11/2002; 13(4):475-89. · 1.76 Impact Factor
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Doug Villaret,
Bonnie Glisson,
Daniel Kenady,
Ehab Hanna,
Mary Carey,
Lyon Gleich,
George H Yoo, Neal Futran,
Mien-Chie Hung,
Pervin Anklesaria,
Alison E Heald
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ABSTRACT: 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.
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.
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).
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.
Head & Neck 08/2002; 24(7):661-9. · 2.40 Impact Factor
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ABSTRACT: Atelectasis is one of the most common postoperative complications encountered in head and neck surgery. Risk factors include preexisting pulmonary disease, the procedure performed, and the length of anesthetic. Regional flaps used to reconstruct defects in the head and neck predispose to radiographic atelectasis. The rectus abdominis myocutaneous flap is usually transferred as a free tissue transfer. Harvesting the flap results in abdominal wall pain and postoperative splinting that may contribute to an increased development of atelectasis. To our knowledge, this issue has not been previously examined.
Retrospective review.
Fifty-three patients underwent rectus abdominis myocutaneous free flap reconstruction following major ablative procedures for head and neck cancer. The flap size ranged from 5 x 7 to 25 x 27 cm. Most flaps were 8 x 15 cm. The cutaneous area transferred ranged from 35 to 600 cm(2) (mean, 120 cm(2)). These patients were compared with a group of 53 patients who were matched for age, sex, length of the procedure, and stage of disease. Postoperative atelectasis was radiographically detected in 37 (70%) of the patients who underwent rectus abdominis myocutaneous free flap reconstruction vs 41 (77%) of the controls. Major atelectasis was not encountered in any patient in either group. Patients with a larger cutaneous paddle (>120 cm(2)) had a higher atelectasis score than patients with smaller cutaneous paddles (< or =120 cm(2)) (P =.02).
The incidence of radiographic postoperative atelectasis in patients undergoing rectus abdominis myocutaneous free tissue transfer is high. The degree of atelectasis is small, and the clinical correlation and relevance are minimal.
Archives of Otolaryngology - Head and Neck Surgery 03/2002; 128(3):249-52. · 1.63 Impact Factor
