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1.  Functional and Oncologic Outcomes of Primary versus Salvage Transoral Laser Microsurgery for Supraglottic Carcinoma 
To evaluate the functional and oncologic outcomes of transoral laser microsurgery (TLM) in patients with previously untreated supraglottic carcinoma compared with salvage cases after radiation-based treatment.
We conducted a retrospective case-control study at a single academic tertiary care institution. Functional outcomes were stratified by prior radiation, and assessed at baseline, <1 week postoperatively, and last follow-up.
Five patients underwent TLM for previously untreated disease and five previously radiated patients underwent salvage TLM for local failure. No patient required tracheostomy. There was no local recurrence after TLM as primary therapy and none required radiotherapy. One salvage patient developed local recurrence. Length of feeding tube dependence (p=0.049) and rates of chronic aspiration (>1 month postoperatively, p=0.048) were significantly higher in salvage TLM cases compared with previously untreated cases. Median PSS-HN Understandability of Speech scores were 75 (“usually understandable”) in the salvage group compared with 100 (“always understandable”) in the previously untreated group.
Both local control and function were superior in previously untreated patients compared with salvage patients. Our findings provide support for the use of TLM as a primary treatment modality for selected supraglottic carcinomas, but also suggest a potential for functional recovery in both previously untreated and salvage cases.
PMCID: PMC4047706  PMID: 23130541
swallow; transoral laser microsurgery; supraglottis; cancer
2.  Final Results Following Platin-based Exclusive Chemotherapy for Selected Patients with Squamous Cell Carcinoma of the Larynx and Pharynx 
Cancer  2009;115(17):10.1002/cncr.24477.
To determine the long-term outcomes for patients with squamous cell carcinoma of the larynx and pharynx treated with platin-based exclusive chemotherapy (EC) after complete clinical response (CCR) to induction chemotherapy.
Materials and Methods
142 patients who achieved a CCR after platin-based induction chemotherapy were treated exclusively with additional chemotherapy. 98.6% were followed for a minimum of 3 years or until death; 35 patients had >10yrs of follow-up.
Survival at 1- and 5-year was 95.8% and 61.2%, respectively. The main causes of death were metachronous second primaries (27) and intercurrent disease (21). Death related to EC was not encountered and only two patients (1.4%) had grade 4 toxicity. In multivariate analysis, primary tumor arising outside the glottic larynx (p=.0001), and Charlson comorbidity index>1 (p=.0001) were associated with a statistically significant reduction in survival. The 1-and 5-year Kaplan-Meier local control estimates were 76.1% and 50.7%, respectively. Salvage treatment resulted in an observed final 93.0% local control rate and varied from 97.2% in patients with glottic cancer to 88.7% in patients with tumor originating from other sites (p = .097). PF chemotherapy allowed for successful modulation of local therapy in 54.9% of patients.
For selected patients, EC may provide long-term durable disease control. For patients with relapse after EC, this approach does not diminish survival and maintains function in a majority of patients. Future work should be directed to select markers of response to PF chemotherapy and thereby to identify which patients are optimally suited for this approach.
PMCID: PMC3851301  PMID: 19551883
larynx; pharynx; carcinoma; induction chemotherapy; complete response
3.  CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma 
Oncotarget  2014;5(16):6854-6866.
Tumor-initiating cells (TICs) in squamous cell carcinoma of the head and neck (SCCHN) are best characterized by their surface expression of CD44. Although there is great interest in identifying strategies to target this population, no marker of these cells has been found to be functionally active. Here, we examined the expression of the purported marker of normal human oral epithelial stem cells, CD271. We show that CD271 expression is restricted to a subset of the CD44+ cells. Using xenograft assays, we show that the CD44+CD271+ subpopulation contains the most tumorigenic cells. Loss of CD271 function results in a block in the G2-M phase of the cell cycle and a profound negative impact on the capacity of these cells to initiate tumor formation in vivo. Incubation with recombinant NGF results in enhanced phosphorylation of Erk, providing additional evidence that CD271 is functionally active. Finally, incubation of SCCHN cells with antibody to CD271 results in decreased Erk phosphorylation and decreased tumor formation in vivo. Thus, our data are the first to demonstrate that CD271 more specifically identifies the TIC subpopulation within the CD44+ compartment in SCCHN and that this receptor is a functionally active and targetable molecule.
PMCID: PMC4196168  PMID: 25149537
HNSCC; cancer stem cells; NGFR; p75NTR; cancer-initiating cell; CD44
4.  Long-term Functional and Survival Outcomes after Induction Chemotherapy and Risk-Based Definitive Therapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck 
Head & neck  2013;36(4):474-480.
To evaluate long-term outcomes after induction chemotherapy followed by “risk-based” local therapy for squamous cell carcinoma of the head and neck (SCCHN).
Forty-seven patients (stage IV, ≥N2b) were enrolled in a Phase II trial. Baseline and 24-months functional measures included modified barium swallow (MBS) studies, oropharyngeal swallow efficiency (OPSE), and the MD Anderson Dysphagia Inventory (MDADI). Functional status was assessed at 5 years.
Five-year overall survival was 89% (95% CI: 81%-99%). A non-significant 13% average reduction in swallowing efficiency (OPSE) was observed at 24-months relative to baseline (p=0.191). MDADI scores approximated baseline at 24-months. Among 42 long-term survivors (median=5.9 years), 3 (7.1%) had chronic dysphagia. The rate of final gastrostomy-dependence was 4.8% (2/42).
Sequential chemoradiotherapy achieved favorable outcomes among patients with locally-advanced SCCHN, mainly of oropharyngeal origin. MBS and MDADI scores found modest swallowing deterioration at 2 years, and chronic aspiration was uncommon in long-term survivors.
PMCID: PMC4034517  PMID: 23780650
5.  Late Dysphagia after Radiotherapy-Based Treatment of Head and Neck Cancer 
Cancer  2012;118(23):5793-5799.
Changing trends in head and neck cancer (HNC) merit an understanding of late effects of therapy, but few studies examine dysphagia beyond 2 years of treatment.
A case series was examined to describe the pathophysiology and outcomes in dysphagic HNC survivors referred for modified barium swallow (MBS) studies ≥5 years after definitive radiotherapy or chemoradiotherapy (01/2001–05/2011). Functional measures included the Penetration-Aspiration Scale (PAS), Performance Status Scale-Head and Neck (PSS-HN), Swallowing Safety Scale (NIH-SSS), and MBSImp.
Twenty-nine patients previously treated with radiotherapy (38%) or chemoradiotherapy (62%) were included (median years post-treatment: 9, range: 5–19). The majority (86%) had oropharyngeal cancer; 52% were never smokers. Seventy-five percent had T2-T3 disease; 52% were N+. Median age at diagnosis was 55 (range: 38–72). Abnormal late examination findings included: dysarthria/dysphonia (76%), cranial neuropathy (48%), trismus (38%), and radionecrosis (10%). MBS studies confirmed pharyngeal residue and aspiration in all dysphagic cases owing to physiologic impairment (median PAS: 8; median NIH-SSS: 10; median MBSImp: 18) whereas stricture was confirmed endoscopically in 7 (24%). Twenty-five (86%) developed pneumonia, half requiring hospitalization. Swallow postures/strategies helped 69% of cases, but no patient achieved durable improvement across functional measures at last follow-up. Ultimately 19 (66%) were gastrostomy dependent.
Although functional organ preservation is commonly achieved, severe dysphagia represents a challenging late effect that may develop or progress years after radiation-based therapy for HNC. These data suggest that novel approaches are needed to minimize and better address this complication that is commonly refractory to many standard dysphagia therapies.
PMCID: PMC4034519  PMID: 23640737
deglutition disorders; radiotherapy; head and neck cancer; toxicity; late effect
6.  Candidate Dosimetric Predictors of Long-Term Swallowing Dysfunction Following Oropharyngeal IMRT 
To investigate long-term swallowing function in oropharyngeal cancer patients treated with IMRT, and to identify novel dose-limiting criteria predictive for dysphagia.
Methods and Materials
Thirty-one patients with stage IV oropharyngeal squamous carcinoma enrolled on a phase II trial were prospectively evaluated by modified barium swallow studies at baseline, and 6, 12, and 24 months post-radiation. Candidate dysphagia-associated organs-at-risk (OARs) were retrospectively contoured into original treatment plans. Twenty-one (68%) cases were base of tongue, and 10 (32%) were tonsil. Stage distribution was T1 (12), T2 (10), T3 (4), T4 (2), and TX (3), and N2 (24), N3 (5), and NX (2). Median age was 52.8 years (Range: 42–78). Thirteen (42%) received concurrent chemotherapy during IMRT. Thirteen (42%) were former smokers. Mean dose to glottic larynx for the cohort was limited to 18 Gy (range: 6–39 Gy) by matching IMRT to conventional low neck fields.
Dose-volume constraints (V30 < 65% and V35 < 35% for anterior oral cavity and V55 < 80% and V65 < 30% for high superior pharyngeal constrictors) predictive for objective swallowing dysfunction were identified by univariate and multivariate analyses. Aspiration and feeding tube dependence were observed in only one patient at 24 months.
In the context of glottic laryngeal shielding, we describe candidate oral cavity and superior pharyngeal constrictor OARs and dose-volume constraints associated with preserved long-term swallowing function; these constraints are currently undergoing prospective validation. Strict protection of the glottic larynx via beam-split IMRT techniques promises to make chronic aspiration an uncommon outcome.
PMCID: PMC4034521  PMID: 20646872
Dysphagia; IMRT; radiation; head and neck cancer; dose-volume constraints; toxicity; swallowing
Head & neck  2008;30(5):559-566.
PMCID: PMC4012760  PMID: 18098304
supracricoid laryngectomy; swallowing; aspiration; function; swallowing outcomes
8.  A 13-gene signature prognostic of HPV-negative OSCC: discovery and external validation 
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.
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).
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.
PMCID: PMC3593802  PMID: 23319825
gene signature; prognosis; HPV-negative; OSCC
9.  Gene Expression in Uninvolved Oral Mucosa of OSCC Patients Facilitates Identification of Markers Predictive of OSCC Outcomes 
PLoS ONE  2012;7(9):e46575.
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.
PMCID: PMC3460916  PMID: 23029552
To investigate the dosimetry and feasibility of carotid-sparing intensity-modulated radiotherapy (IMRT) for early glottic cancer and to report preliminary clinical experience.
Methods and Materials
Digital Imaging and Communications in Medicine radiotherapy (DICOM-RT) datasets from 6 T1–2 conventionally treated glottic cancer patients were used to create both conventional IMRT plans. We developed a simplified IMRT planning algorithm with three fields and limited segments. Conventional and IMRT plans were compared using generalized equivalent uniform dose and dose–volume parameters for in-field carotid arteries, target volumes, and organs at risk. We have treated 11 patients with this simplified IMRT technique.
Intensity-modulated radiotherapy consistently reduced radiation dose to the carotid arteries (p < 0.05) while maintaining the clinical target volume coverage. With conventional planning, median carotid V35, V50, and V63 were 100%, 100%, and 69.0%, respectively. With IMRT planning these decreased to 2%, 0%, and 0%, respectively (p < 0.01). Radiation planning and treatment times were similar for conventional radiotherapy and IMRT. Treatment results have been excellent thus far.
Intensity-modulated radiotherapy significantly reduced unnecessary radiation dose to the carotid arteries compared with conventional lateral fields while maintaining clinical target volume coverage. Further experience and longer follow-up will be required to demonstrate outcomes for cancer control and carotid artery effects.
PMCID: PMC3307784  PMID: 19679406
Glottic cancer; Radiotherapy; IMRT; Larynx
11.  Transoral robotic-assisted thyroidectomy with central neck dissection: preclinical cadaver feasibility study and proposed surgical technique 
Journal of Robotic Surgery  2011;5(4):279-282.
Recently, a transoral robotic-assisted technique to access the thyroid gland has been introduced. Despite the advantages this approach may have over other minimally invasive and robotic-assisted techniques, we found that the placement of the camera through the floor of mouth led to restricted freedom of movement. We describe our modification to this technique to overcome this problem. In a study using two fresh human cadavers, the camera port of the da Vinci robot was placed in the midline oral vestibule instead of the floor of the mouth. A transoral thyroidectomy and central neck dissection was successfully performed. Our modification led to an unfettered view of the central neck and allowed for a total thyroidectomy and central neck dissection. Our modification of transoral robotic-assisted thyroidectomy provides superior access to the central compartment of the neck over other robotic-assisted thyroidectomy techniques.
Electronic supplementary material
The online version of this article (doi:10.1007/s11701-011-0287-2) contains supplementary material, which is available to authorized users.
PMCID: PMC3214254  PMID: 22162981
Transoral thyroidectomy; Thyroid; Robotic-assisted surgery; Robot; Minimally invasive; Central neck
12.  Serum signature of hypoxia-regulated factors is associated with progression after induction therapy in head and neck squamous cell cancer 
Molecular cancer therapeutics  2010;9(6):1755-1763.
Tumor hypoxia regulates many cytokines and angiogenic factors (CAFs) and is associated with worse prognosis in head and neck squamous cell cancer (HNSCC). Serum CAF profiling may provide information regarding the biology of the host and tumor, prognosis, and response to therapy. We investigated 38 CAFs in HNSCC patients receiving induction therapy on a Phase II trial of carboplatin, paclitaxel, and cetuximab. CAFs were measured by multiplex bead assay and enzyme-linked immunosorbent assay in 32 patients. Baseline and post-induction CAF levels were correlated with disease progression (PD) and human papilloma virus (HPV) status by Wilcoxon rank sum test. Baseline levels of 8 hypoxia-regulated CAFs (the “high-risk signature” including vascular endothelial growth factor, interleukins-4 and -8, osteopontin, growth-related oncogene-α (Gro-α), eotaxin, granulocyte-colony stimulating factor, and stromal cell derived factor-1α) were associated with subsequent PD. Elevation in ≥6/8 factors was strongly associated with shorter time to progression (p=0.001) and was 73% specific and 100% sensitive for PD. Rising Gro-α from baseline to week six was also associated with PD. Progression free and overall survival were shorter in patients with HPV-negative tumors (p=0.012 and 0.046, respectively), but no individual CAF was associated with HPV-status. However, among 14 HPV-negative patients, the high-risk CAF signature was seen in all 6 patients with PD, but only 2/14 without PD. In conclusion, serum CAF profiling, particularly in HPV-negative patients, may be useful for identifying those at highest risk for recurrence.
PMCID: PMC2913168  PMID: 20530716
head and neck squamous cell cancer; serum markers; hypoxia
13.  Durable Long-Term Remission With Chemotherapy Alone for Stage II to IV Laryngeal Cancer 
Journal of Clinical Oncology  2009;27(12):1976-1982.
For patients with stage II to IV laryngeal cancer, radiation therapy (RT) either alone or with concurrent chemotherapy provides the highest rate of organ preservation but can be associated with functional impairment. Thus, we studied the use of induction chemotherapy with or without conservation laryngeal surgery (CLS). Our objectives were to study the sensitivity of laryngeal cancer to platinum-based chemotherapy alone and to highlight the efficacy of CLS in this setting.
Patients and Methods
Thirty-one previously untreated patients with laryngeal cancer (T2-4, N0-1, M0), who were resectable with CLS, were enrolled. Patients received three to four cycles of paclitaxel, ifosfamide, and cisplatin (TIP) chemotherapy, and response was assessed histologically. Patients with partial response (PR) proceeded to CLS. Patients achieving pathologic complete response (pCR) received an additional three cycles of TIP and no other treatment.
Thirty patients were assessable for response. With TIP chemotherapy alone, 11 patients (37%) achieved pCR, 10 of whom (33%) remain alive with durable disease remission and no evidence of recurrence over a median follow-up time of 5 years. Nineteen patients (63%) treated with TIP alone achieved PR. The overall laryngeal preservation (LP) rate was 83%, and only five patients (16%) required postoperative RT. No patient required a gastrostomy tube or tracheotomy.
Chemotherapy alone in selected patients with T2-4, N0-1 laryngeal cancer can provide durable disease remission at 5 years. For patients with PR, CLS provides a high rate of LP. This prospective study suggests that chemotherapy alone may cure selected patients with laryngeal cancer, warranting further prospective investigation.
PMCID: PMC2738635  PMID: 19289628

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