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author:("Shah, latin P")
1.  Surgical Technique Refinements in Head and Neck Oncologic Surgery 
Journal of surgical oncology  2010;101(8):661-668.
The head and neck region poses a challenging arena for oncologic surgery. Diseases and their treatment can affect a myriad of functions, including sight, hearing, taste, smell, breathing, speaking, swallowing, facial expression and appearance. This review discusses several areas where refinements in surgical techniques have led to improved patient outcomes. This includes surgical incisions, neck lymphadenectomy, transoral laser microsurgery, minimally invasive thyroid surgery, and the use of vascularized free flaps for oromandibular reconstruction.
doi:10.1002/jso.21454
PMCID: PMC2957802  PMID: 20512941
Neck Dissection; Minimally Invasive Thyroidectomy; Transoral Laser Microsurgery; Facial Incisions; Oromandibular Reconstruction
2.  Quality of Life after Skull Base Surgery: The Patient's Predicament 
Skull Base  2010;20(1):3-4.
doi:10.1055/s-0029-1242977
PMCID: PMC2853065  PMID: 20592850
3.  VIABLE TUMOR IN POSTCHEMORADIATION NECK DISSECTION SPECIMENS AS AN INDICATOR OF POOR OUTCOME 
Head & neck  2010;33(10):1387-1393.
Background
The objective of this study was to determine the prognostic significance of viable tumor in post-chemoradiation neck dissection specimens in patients with squamous cell carcinoma of the laryngopharynx.
Methods
Retrospective analysis identified 181 patients treated with primary concurrent chemoradiation for carcinoma of the laryngopharynx at Memorial Sloan-Kettering Cancer Center between the years 1995 and 2005. Of these, 56 patients had a comprehensive neck dissection either as a planned or salvage procedure. Neck dissection specimens were analyzed by a single pathologist for the presence of viable tumor. The presence of viable tumor was correlated to the timing of neck dissection after chemoradiation and to tumor response. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were determined by the Kaplan–Meier method, and correlation to tumor viability was determined with the log-rank test.
Results
Nineteen (33%) patients had viable tumor in their neck dissection specimens. Viable tumor was higher in patients who had a less-than-complete response to chemoradiation compared with those who had a complete response (42% vs 25%, p = .1). There was no correlation to timing of neck dissection. The 5-year OS, DSS, and RFS were significantly lower in patients who had viable tumor in their neck dissection specimens (OS 49% vs 93%, p = .0005; DSS 56% versus 93%, p = .003; RFS 40% vs 75%, p = .004).
Conclusions
Patients with viable tumor in postchemoradiation neck dissection specimens had a poorer outcome compared with patients with no viable tumor.
doi:10.1002/hed.21612
PMCID: PMC3772770  PMID: 21928410
viable tumor; chemoradiation; neck dissection; prognosis
4.  Prognostic Significance of Regulators of Cell Cycle and Apoptosis, p16INK4a, p53, and bcl-2 in Primary Mucosal Melanomas of the Head and Neck 
Head and Neck Pathology  2011;6(2):184-190.
Abnormalities in cell cycle regulation, tumor suppressor gene functions and apoptosis are frequent events in tumorigenesis. Their role in the pathogenesis and prognosis of primary mucosal melanomas (MM) of the upper aerodigestive tract remains unknown. Sixty-four patients (40 men, 24 women, median age 64 years) with MM were included in this study; 32 had tumors in the nasal/paranasal cavities, 28 in the oral cavity and 4 in the pharynx. Archival tissues from 47 initial mucosal tumors, 17 mucosal recurrences, and 13 nodal/distant metastases were subjected to immunohistochemistry using antibodies against p16, p53, and bcl-2. The results were correlated with histological features and survival data. Expressions of p16, p53, and bcl-2 proteins were seen in 25% (N = 19/76), 21% (N = 16/76), and 74% (N = 56/76) of all tumors, respectively. bcl-2 expression in the initial tumors was associated with significantly longer overall and disease specific survival (3.3 vs. 1.5 years, P ≤ 0.05). Expression of p16 was increasingly lost, from 32% in initial tumors to 12% in recurrent and 15% in metastatic tumors (P = 0.06). Tumors comprised of undifferentiated cells were significantly more p53 positive than epithelioid or spindle cells (80% vs. 33%, P = 0.02). Expression of these markers did not correlate with necrosis, or vascular and/or deep tissue invasion. Expression of bcl-2 is associated with better survival in MM. Loss of p16 was seen with tumor progression whereas aberrant p53 expression was frequent in undifferentiated tumor cells.
doi:10.1007/s12105-011-0319-2
PMCID: PMC3370030  PMID: 22160615
Mucosal melanoma; Head and neck; p16; p53; bcl-2
5.  The Impact of Distant Metastases at Presentation on Prognosis in Patients with Differentiated Carcinoma of the Thyroid Gland 
Thyroid  2012;22(9):884-889.
Background
Distant metastases at presentation are rare in well-differentiated thyroid cancer (WDTC). The objective of this study was to report outcomes for patients presenting with distant metastases managed by thyroidectomy and radioactive iodine (RAI) therapy.
Methods
Fifty-two patients with distant metastases from thyroid cancer diagnosed before thyroid surgery (n=32) or on a postoperative RAI scan after thyroid surgery (n=20) were identified from a database of patients with WDTC treated between 1985 and 2005. The median age was 58 years (range 12–83 years), with a male-to-female ratio of 3:2. Forty-seven patients (90%) had total thyroidectomy and two (4%) had thyroid lobectomy, and three patients (6%) were found to be unresectable. Distant metastases were classified into pulmonary and extrapulmonary. Overall survival (OS), disease-specific survival (DSS), and locoregional recurrence-free survival were calculated by the Kaplan–Meier method. Factors predictive of the outcome were determined by univariate and multivariate analyses.
Results
Thirty-nine patients (75%) were diagnosed with pulmonary metastases alone and 13 (25%) with extrapulmonary metastases. The sites of extrapulmonary metastases were bone in nine, mediastinum in one, pyriform sinus in one and skin in one, and one patient had synchronous lung, bone, and intracerebral metastases. After thyroid surgery, 47 patients (90%) were treated with RAI alone, and 2 patients had external beam radiation in addition to RAI. With a median follow-up after surgery of 78.5 months, the 5-year OS and DSS were 65% and 68%, respectively. Twenty-nine patients (56%) died during follow-up, of whom 24 (46%) died of thyroid cancer. Six patients (12%) developed recurrent disease in the lateral neck, and three patients (6%) developed recurrence in the thyroid bed. Over 45 years, follicular pathology and extrapulmonary metastases were predictive of lower 5-year DSS (56% vs. 100%, p<0.001; 50% vs. 70%, p=0.004; and 46% vs. 75%, p=0.013, respectively).
Conclusion
Approximately half of patients with WDTC presenting with distant metastases die of disease within 5 years of initial diagnosis despite thyroid surgery and RAI. Age over 45 years, extrapulmonary metastases, and follicular pathology were significant predictors of the poor outcome.
doi:10.1089/thy.2011.0535
PMCID: PMC3714454  PMID: 22827579
6.  HIGH RATES OF REGIONAL FAILURE IN SQUAMOUS CELL CARCINOMA OF THE HARD PALATE AND MAXILLARY ALVEOLUS 
Head & neck  2010;33(6):824-830.
Background
The purpose of this study was to determine the incidence of neck metastasis in hard palate and maxillary alveolus squamous cell carcinoma (SCC) and to identify factors predictive of regional failure.
Methods
In 139 patients treated for SCC of the hard palate and maxillary alveolus (from 1985–2006), the incidence rates of regional metastasis at presentation and at recurrence were calculated. Factors predictive of regional recurrence-free survival were identified on Cox multivariable regression analysis.
Results
Regional failure occurred in 28.4% of patients and was significantly associated with pathologic T classification, ranging from 18.7% (pT1) to 37.3% (pT4). T classification was an independent predictor of regional recurrence-free survival (RRFS) on multivariable analysis. Most patients (65.6%) with regional recurrence were not able to be salvaged.
Conclusion
Patients with T2 to T4 primary tumors of the hard palate and maxillary alveolus exhibited high rates of regional failure. In most cases, successful salvage was not achieved. Elective treatment of the neck with surgery or radiation is therefore recommended.
doi:10.1002/hed.21547
PMCID: PMC3061243  PMID: 20949448
cervical; regional; neck; metastases; hard palate; alveolus; gingiva
7.  Secondary Skull Base Malignancies in Survivors of Retinoblastoma: The Memorial Sloan Kettering Cancer Center Experience 
Skull Base  2011;21(2):103-108.
We report the pathology and outcome of secondary skull base tumors in patients previously treated with external beam radiation for retinoblastoma (Rb). Rb patients are at increased risk of second head and neck primary malignancies due to early radiation exposure during treatment and loss of RB1 protein in genetic carriers. An institutional database was reviewed for patients with retinoblastoma who had previously received radiation therapy and subsequently developed skull base tumors. Seventeen patients met the selection criteria. The median age of Rb diagnosis was 12 months. Thirteen cases underwent enucleation in addition to radiation therapy as part of initial Rb treatment. A median of 19 years elapsed between the diagnosis of Rb and diagnosis of skull base malignancy. The most common tumors were osteogenic sarcoma (39%) and leiomyosarcoma (22%). Eleven (71%) patients received postoperative chemotherapy, and 7 (41%) received postoperative radiotherapy. Three (24%) patients underwent salvage surgery for recurrent disease. Five-year survival was 68%, and 10-year survival was 51% by Kaplan-Meier analysis. Secondary malignancy in Rb patients is a well-defined event. The use of surgery with appropriate adjuvant therapy was associated with a 51% 10-year survival in this study population.
doi:10.1055/s-0031-1275256
PMCID: PMC3312595  PMID: 22451810
Skull base neoplasms; retinoblastoma; neoplasms; second primary; radiotherapy
8.  Squamous Cell Carcinoma of the Oral Tongue in the Pediatric Age Group 
Objective
To compare outcomes of a pediatric cohort of patients compared with a matched cohort of adult patients, all diagnosed as having squamous cell carcinoma (SCC) of the oral tongue. Outcomes of oral cancer in pediatric patients have not been studied, to our knowledge.
Design
Retrospective matched-pair cohort study.
Setting
Memorial Sloan-Kettering Cancer Center, New York, New York.
Patients
A total of 10 pediatric and 40 adult patients diagnosed as having SCC of the oral tongue.
Main Outcome Measures
Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS).
Results
The 5-year OS was equivalent in the 2 groups: 70% in the pediatric group and 64% in the adult group (P=.97). The 5-year DSS was also equivalent: 80% in the pediatric group and 76% in the adult group (P=.90). The 5-year RFS was 70% in the pediatric group and 78% in the adult group (P=.54).
Conclusions
When pediatric and adult patients were matched for sex, tobacco use history, TNM status, surgical procedure, and adjuvant radiotherapy, outcomes for OS, DSS, and RFS were equivalent. Pediatric patients with SCC of the oral tongue should be treated similarly to adult patients.
doi:10.1001/archoto.2010.94
PMCID: PMC3005582  PMID: 20644066
9.  Paracrine Regulation of Pancreatic Cancer Cell Invasion by Peripheral Nerves 
Background
The ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown.
Methods
We used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function.
Results
Nerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean = 187.1 μm, 95% confidence interval [CI] = 148 to 226 μm vs 14.4 μm, 95% CI = 9.58 to 19.22 μm, difference = 143 μm; P < .001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras–mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/−, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P < .001; n = 60–66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFα1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice.
Conclusion
These data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer.
doi:10.1093/jnci/djp456
PMCID: PMC2911041  PMID: 20068194
10.  Results of Anterior Skull Base Surgery in Pediatric and Young Adult Patients 
Skull Base  2010;20(2):75-81.
ABSTRACT
We sought to better define the results of anterior skull base surgery in pediatric and young adult patients. We performed a single-institution, retrospective cohort study in a tertiary-care academic cancer center. Between 1973 and 2005, 234 patients underwent anterior skull base surgery at Memorial Sloan-Kettering Cancer Center. Of these, 19 patients were <21 years of age. Surgical indications, findings, and complications were reviewed. Survival outcomes were analyzed using the Kaplan-Meier method and compared with patients ≥21 years old. Nineteen patients <21 years old underwent a total of 20 procedures for lesions of the anterior skull base. Sarcoma was the most common indication for surgery including 6 (32%) patients treated for radiation-induced malignancies. Minor complications were noted with 6 (30%) procedures. There were no major complications and no perioperative deaths. The difference in 3-year recurrence-free (68% versus 59%; p = 0.623) and overall survival (83% versus 66%; p = 0.309) compared with patients ≥21 years old did not reach statistical significance. Anterior skull base surgery is well tolerated in pediatric and young adult patients <21 years of age. Survival is comparable to older patients treated similarly and appears strongly influenced by histology.
doi:10.1055/s-0029-1238215
PMCID: PMC2853072  PMID: 20808531
Craniofacial resection; skull base surgery; pediatric; complications; survival
11.  Average arterial input function for quantitative dynamic contrast enhanced magnetic resonance imaging of neck nodal metastases 
Background
The present study determines the feasibility of generating an average arterial input function (Avg-AIF) from a limited population of patients with neck nodal metastases to be used for pharmacokinetic modeling of dynamic contrast-enhanced MRI (DCE-MRI) data in clinical trials of larger populations.
Methods
Twenty patients (mean age 50 years [range 27–77 years]) with neck nodal metastases underwent pretreatment DCE-MRI studies with a temporal resolution of 3.75 to 7.5 sec on a 1.5T clinical MRI scanner. Eleven individual AIFs (Ind-AIFs) met the criteria of expected enhancement pattern and were used to generate Avg-AIF. Tofts model was used to calculate pharmacokinetic DCE-MRI parameters. Bland-Altman plots and paired Student t-tests were used to describe significant differences between the pharmacokinetic parameters obtained from individual and average AIFs.
Results
Ind-AIFs obtained from eleven patients were used to calculate the Avg-AIF. No overall significant difference (bias) was observed for the transfer constant (Ktrans) measured with Ind-AIFs compared to Avg-AIF (p = 0.20 for region-of-interest (ROI) analysis and p = 0.18 for histogram median analysis). Similarly, no overall significant difference was observed for interstitial fluid space volume fraction (ve) measured with Ind-AIFs compared to Avg-AIF (p = 0.48 for ROI analysis and p = 0.93 for histogram median analysis). However, the Bland-Altman plot suggests that as Ktrans increases, the Ind-AIF estimates tend to become proportionally higher than the Avg-AIF estimates.
Conclusion
We found no statistically significant overall bias in Ktrans or ve estimates derived from Avg-AIF, generated from a limited population, as compared with Ind-AIFs.
However, further study is needed to determine whether calibration is needed across the range of Ktrans. The Avg-AIF obtained from a limited population may be used for pharmacokinetic modeling of DCE-MRI data in larger population studies with neck nodal metastases. Further validation of the Avg-AIF approach with a larger population and in multiple regions is desirable.
doi:10.1186/1756-6649-9-4
PMCID: PMC2679707  PMID: 19351382
12.  Utility of a Herpes Oncolytic Virus for the Detection of Neural Invasion By Cancer1 
Neoplasia (New York, N.Y.)  2008;10(4):347-353.
Prostate, pancreatic, and head and neck carcinomas have a high propensity to invade nerves. Surgical resection is a treatment modality for these patients, but it may incur significant deficits. The development of an imaging method able to detect neural invasion (NI) by cancer cells may guide surgical resection and facilitate preservation of normal nerves. We describe an imaging method for the detection of NI using a herpes simplex virus, NV1066, carrying tyrosine kinase and enhanced green fluorescent protein (eGFP). Infection of pancreatic (MiaPaCa2), prostate (PC3 and DU145), and adenoid cystic carcinoma (ACC3) cell lines with NV1066 induced a high expression of eGFP in vitro. An in vivo murine model of NI was established by implanting tumors into the sciatic nerves of nude mice. Nerves were then injected with NV1066, and infection was confirmed by polymerase chain reaction. Positron emission tomography with [18F]-2′-fluoro-2′-deoxyarabinofuranosyl-5-ethyluracil performed showed significantly higher uptake in NI than in control animals. Intraoperative fluorescent stereoscopic imaging revealed eGFP signal in NI treated with NV1066. These findings show that NV1066 may be an imaging method to enhance the detection of nerves infiltrated by cancer cells. This method may improve the diagnosis and treatment of patients with neurotrophic cancers by reducing injury to normal nerves and facilitating identification of infiltrated nerves requiring resection.
PMCID: PMC2288543  PMID: 18392138
13.  MUC1 plays a role in tumor maintenance in aggressive thyroid carcinomas 
Surgery  2005;138(6):994-1002.
Background
We recently identified MUC1 as a target driving selection for 1q21 amplification and validated it as an independent marker of aggressive behavior in thyroid cancer (TC). The aims of this study were to determine if TC cell lines retain MUC1 expression patterns seen in primary tumors, assess the role of MUC1 in tumor maintenance and develop a virally delivered anti-MUC1 RNAi that is effective in decreasing MUC1 expression in vitro.
Methods
Fifteen TC cell lines were screened for MUC1 protein expression. Cell lines with varying MUC1 protein levels were treated with anti-MUC1 monoclonal antibody to assess cell viability. A recombinant retroviral short hairpin RNAi (shRNA) delivery system against MUC1 was developed. Efficacy and optimal dosing of shRNA against MUC1 was determined.
Results
MUC1 expression patterns in TC cell lines were found to be similar to that seen in primary tumors. Treatment with anti-MUC1 antibody resulted in a significant decrease in cell viability in MUC1 over-expressing cell lines. MUC1-779 RNAi construct showed excellent infection efficiency and reproducible silencing.
Conclusions
These data offer functional evidence implicating MUC1 over-expression as a key molecular event in the pathogenesis of aggressive TC. Retrovirally delivered anti-MUC1 RNAi is effective in silencing MUC1 and merits further investigation to establish therapeutic efficacy and safety in anticipation of potential clinical application.
doi:10.1016/j.surg.2005.09.030
PMCID: PMC1858643  PMID: 16360383
14.  Microvascular Reconstruction of the Skull Base: A Clinical Approach to Surgical Defect Classification and Flap Selection 
Skull Base  2007;17(1):5-15.
ABSTRACT
Skull-base tumor resection and reconstruction produce a major physiologic and anatomic impact on the patient. At our institution, the use of vascularized, free-tissue transfer has replaced pedicled flaps as the preferred modality for reconstructing complex cranial base defects involving resection of dura, brain, or multiple major structures adjacent to skull base, including the orbit, palate, mandible, skin, and other structures. The goals of reconstruction are to: (1) support the brain and orbit; (2) separate the CNS from the aerodigestive tract; (3) provide lining for the nasal cavity; (4) re-establish the nasal and oropharyngeal cavities; (5) provide volume to decrease dead space; and (6) restore the three-dimensional appearance of the face and head with bone and soft tissues. Surgical management requires a multidisciplinary effort with collaborating neurosurgical, head and neck, and plastic surgical teams. Successful reconstruction of skull base defects is predicated upon a careful appreciation of the specific region. Defects may be classified based on their anatomic location and loss of volume, support, and skin cover. Free flaps provide reliable, well-vascularized soft tissue to seal the dura, obliterate dead space, cover exposed cranial bone, and provide cutaneous coverage for skin or mucosa.
doi:10.1055/s-2006-959331
PMCID: PMC1852578  PMID: 17603640
Skull base; reconstruction; microvascular free flaps; classification
15.  Chromosomal aberrations in patients with head and neck squamous cell carcinoma do not vary based on severity of tobacco/alcohol exposure 
BMC Genetics  2002;3:22.
Background
Head and neck squamous cell carcinomas (HNSCC) have been causally associated with tobacco and alcohol exposure. However, 10–15% of HNSCC develop in absence of significant carcinogen exposure. Several lines of evidence suggest that the genetic composition of HNSCC varies based on the extent of tobacco/alcohol exposure, however, no genome wide measures have been applied to address this issue. We used comparative genomic hybridization (CGH) to screen for the genetic aberrations in 71 patients with head and neck squamous cell carcinoma and stratified the findings by the status of tobacco/alcohol exposure.
Results
Although the median number of abnormalities (9), gains (6) and losses (2) per case and the overall pattern of abnormalities did not vary significantly by the extent of tobacco/alcohol exposure, individual abnormalities segregating these patients were identified. Gain of 1p (p = 0.03) and 3q amplification (p = 0.05) was significantly more common in patients with a history of tobacco/alcohol exposure.
Conclusions
This data suggests that the overall accumulated chromosomal aberrations in head and neck squamous cell carcinoma are not significantly influenced by the severity of tobacco/alcohol exposure with limited exceptions.
doi:10.1186/1471-2156-3-22
PMCID: PMC138806  PMID: 12431278
head and neck neoplasms; squamous cell carcinoma; tobacco; alcohol; comparative genomic hybridization
16.  Management of Unresectable Malignant Tumors at the Skull Base Using Concomitant Chemotherapy and Radiotherapy with Accelerated Fractionation 
Skull base surgery  1994;4(3):127-131.
Between January 1988 and June 1992, 20 patients with unresectable malignant tumors at the skull base were treated. Eleven had T4 lesions of the paranasal sinus/cavity complex, and 9 had T4 nasopharynx cancer. All patients had stage IV disease by the American Joint Committee on Staging Criteria. The histology was squamous cell cancer in 15 patients and other minor salivary gland histologies in 5. There was brain and/or dural invasion in 11 patients and orbital invasion in 9. All patients received radiation therapy with accelerated fractionation to a total of 70 Gy in 6 weeks. Concomitant cisplatin (100 mg/m2) was given on days 1 and 22 of radiation. Seven patients received mitomycin C (7.5 mg/m2) on days 1 and 22, plus adjuvant chemotherapy with cisplatin and vinblastine. Median follow-up was 11 (range: 1 to 43) months. At 2 years, local progression-free survival was 94%, distant metastases-free survival was 57%, and overall survival was 80%. Complications occurred in 20% and caused the death of 1 patient. Treatment of this group of patients with aggressive chemotherapy and radiation therapy produced excellent local control in our early experience, but longer follow-up is needed. There is a high rate of distant failure. Future strategies are outlined.
PMCID: PMC1661798  PMID: 17171161
17.  Comparing primary tumors and metastatic nodes in head and neck cancer using intravoxel incoherent motion imaging: a preliminary experience 
Journal of computer assisted tomography  2013;37(3):10.1097/RCT.0b013e318282d935.
Objective
To use intravoxel incoherent motion (IVIM) imaging for investigating differences between primary head and neck tumors and nodal metastases and evaluating IVIM efficacy in predicting outcome.
Methods
Sixteen patients with HN cancer underwent IVIM DWI on a 1.5T MRI scanner. The significance of parametric difference between primary tumors and metastatic nodes were tested. Probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.
Results
In comparison to metastatic nodes, the primary tumors had significantly higher vascular volume fraction (f) (p<0.0009), and lower diffusion coefficient (D) (p<0.0002). Patients with lower standard deviation for D had prolonged PFS and OS (p<0.05).
Conclusion
Pretreatment IVIM measures were feasible in investigating the physiological differences between the two tumor tissues. After appropriate validation, these findings might be useful in optimizing treatment planning and improving patient care.
doi:10.1097/RCT.0b013e318282d935
PMCID: PMC3655331  PMID: 23674004
Intravoxel incoherent motion imaging (IVIM); head and neck (HN) cancer; primary tumor; metastatic neck node
18.  The Mutational Landscape of Adenoid Cystic Carcinoma 
Nature genetics  2013;45(7):10.1038/ng.2643.
Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here, we determined the ACC mutational landscape and report the exome or whole genome sequences of 60 ACC tumor/normal pairs. These analyses revealed a low exonic somatic mutation rate (0.31 non-silent events/megabase) and wide mutational diversity. Interestingly, mutations selectively involved chromatin state regulators, such as SMARCA2, CREBBP, and KDM6A, suggesting aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to DNA damage and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying these aberrations as critical events. Lastly, we identified recurrent mutations in the FGF/IGF/PI3K pathway that may potentially offer new avenues for therapy (30%). Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.
doi:10.1038/ng.2643
PMCID: PMC3708595  PMID: 23685749
19.  Correlation of a priori DCE-MRI and 1H-MRS data with molecular markers in neck nodal metastases: Initial analysis 
Oral oncology  2012;48(8):717-722.
Objectives
The aim of the present study is to correlate non-invasive, pretreatment biological imaging (dynamic contrast enhanced-MRI [DCE-MRI] and proton magnetic resonance spectroscopy [1H-MRS]) findings with specific molecular marker data in neck nodal metastases of head and neck squamous cell carcinoma (HNSCC) patients.
Materials and Methods
Pretreatment DCE-MRI and 1H-MRS were performed on neck nodal metastases of 12 patients who underwent surgery. Surgical specimens were analyzed with immunohistochemistry (IHC) assays for: Ki-67 (reflecting cellular proliferation), vascular endothelial growth factor (VEGF) (the “endogenous marker” of tumor vessel growth), carbonic anhydrase (CAIX), hypoxia inducible transcription factor (HIF-1α), and human papillomavirus (HPV). Additionally, necrosis was estimated based on H&E staining. The Spearman correlation was used to compare DCE-MRI, 1H-MRS, and molecular marker data.
Results
A significant correlation was observed between DCE-MRI parameter std(kep) and VEGF IHC expression level (rho = 0.81, p = 0.0001). Furthermore, IHC expression levels of Ki-67 inversely correlated with std(Ktrans) and std(ve) (rho = −0.71; p = 0.004, and rho = −0.73; p = 0.003, respectively). Other DCE-MRI, 1H-MRS and IHC values did not show significant correlation.
Conclusion
The results of this preliminary study indicate that the level of heterogeneity of perfusion in metastatic HNSCC seems positively correlated with angiogenesis, and inversely correlated with proliferation. These results are preliminary in nature and are indicative, and not definitive, trends portrayed in HNSCC patients with nodal disease. Future studies with larger patient populations need to be carried out to validate and clarify our preliminary findings.
doi:10.1016/j.oraloncology.2012.02.001
PMCID: PMC3368067  PMID: 22366441
Head and neck squamous cell carcinoma; 1H-MRS; DCE-MRI; molecular markers
20.  Craniofacial Surgery for Esthesioneuroblastoma: Report of an International Collaborative Study 
Introduction Impact of treatment and prognostic indicators of outcome are relatively ill-defined in esthesioneuroblastomas (ENB) because of the rarity of these tumors. This study was undertaken to assess the impact of craniofacial resection (CFR) on outcome of ENB.
Patients and Methods Data on 151 patients who underwent CFR for ENB were collected from 17 institutions that participated in an international collaborative study. Patient, tumor, treatment, and outcome data were collected by questionnaires and variables were analyzed for prognostic impact on overall, disease-specific and recurrence-free survival. The majority of tumors were staged Kadish stage C (116 or 77%). Overall, 90 patients (60%) had received treatment before CFR, radiation therapy in 51 (34%), and chemotherapy in 23 (15%). The margins of surgical resection were reported positive in 23 (15%) patients. Adjuvant postoperative radiation therapy was used in 51 (34%) and chemotherapy in 9 (6%) patients.
Results Treatment-related complications were reported in 49 (32%) patients. With a median follow-up of 56 months, the 5-year overall, disease-specific, and recurrence-free survival rates were 78, 83, and 64%, respectively. Intracranial extension of the disease and positive surgical margins were independent predictors of worse overall, disease-specific, and recurrence-free survival on multivariate analysis.
Conclusion This collaborative study of patients treated at various institutions across the world demonstrates the efficacy of CFR for ENB. Intracranial extension of disease and complete surgical excision were independent prognostic predictors of outcome.
doi:10.1055/s-0032-1311754
PMCID: PMC3424016  PMID: 23730550
nose neoplasms/mortality/pathology/surgery/*therapy; esthesioneuroblastoma; olfactory/*therapy; combined modality therapy; radiotherapy; adjuvant; survival analysis
21.  Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Predictor of Outcome in Head and Neck Squamous Cell Carcinoma Patients with Nodal Metastases 
Purpose
Dynamic contrast-enhanced-MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of the present study was to assess the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery.
Methods and Materials
Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE-MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using Tofts model. DCE-MRI parameters were related to treatment outcome (progression free survival [PFS] and overall survival [OS]). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD) or dead of other causes (DOC). Prognostic significance was assessed using the log rank test for single variables and Cox proportional hazards regression for combinations of variables.
Results
At last clinical follow-up, for stage III, all 12 pts were NED, for stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. Ktrans is volume transfer constant. In a stepwise Cox regression skewness of Ktrans was the strongest predictor for stage IV patients (PFS and OS: p<0.001).
Conclusion
Our study shows that skewness of Ktrans was the strongest predictor of PFS and OS in stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter Ktrans as a predictor of outcome in these patients.
doi:10.1016/j.ijrobp.2011.03.006
PMCID: PMC3177034  PMID: 21601373
Dynamic Contrast Enhanced-MRI (DCE-MRI); head and neck squamous cell carcinoma (HNSCC); volume transfer constant (Ktrans)
22.  Tumor Metabolism and Perfusion in Head and Neck Squamous Cell Carcinoma: Pretreatment Multimodality Imaging with 1H-Magnetic Resonance Spectroscopy, Dynamic Contrast-Enhanced MRI and 18F-FDG PET 
Purpose
To correlate proton magnetic resonance spectroscopy (1H-MRS), dynamic contrast-enhanced MRI (DCE-MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in nodal metastases of patients with head and neck squamous cell carcinoma (HNSCC) for assessment of tumor biology. Additionally, pretreatment multimodality imaging (MMI) was evaluated for its efficacy in predicting short-term response to treatment.
Methods and Materials
Metastatic neck nodes were imaged with 1H-MRS, DCE-MRI and 18F-FDG PET in 16 patients with newly diagnosed HNSCC before treatment. Short-term radiological response was evaluated at 3–4 months. The correlations between 1H-MRS (choline concentration, Cho/W), DCE-MRI (volume transfer constant, Ktrans; volume fraction of the extravascular extracellular space, ve; and redistribution rate constant, kep) and 18F-FDG PET (standard uptake value, SUV; and total lesion glycolysis, TLG) were calculated using non-parametric Spearman rank correlation. To predict the short-term response, logistic regression analysis was performed.
Results
A significant positive correlation was found between Cho/W and TLG (ρ = 0.599, p = 0.031). Cho/W correlated negatively with heterogeneity measures std(ve) (ρ = −0.691, p = 0.004) and std(kep) (ρ = −0.704, p = 0.003). SUVmax values correlated strongly with MRI tumor volume (ρ = 0.643, p = 0.007). Logistic regression indicated that std(Ktrans) and SUVmean were significant predictors of short-term response (p < 0.07).
Conclusion
Pretreatment multi-modality imaging using 1H-MRS, DCE-MRI and 18F-FDG PET is feasible in HNSCC patients with nodal metastases. Additionally, combined DCE-MRI and 18F-FDG PET parameters were predictive of short-term response to treatment.
doi:10.1016/j.ijrobp.2010.11.022
PMCID: PMC3137671  PMID: 21236594
Head and neck squamous cell carcinoma; 1H-MRS; DCE-MRI; 18F-FDG PET; short-term treatment response
23.  Imaging of Lymph Node Micrometastases Using an Oncolytic Herpes Virus and [18F]FEAU PET 
PLoS ONE  2009;4(3):e4789.
Background
In patients with melanoma, knowledge of regional lymph node status provides important information on outlook. Since lymph node status can influence treatment, surgery for sentinel lymph node (SLN) biopsy became a standard staging procedure for these patients. Current imaging modalities have a limited sensitivity for detection of micrometastases in lymph nodes and, therefore, there is a need for a better technique that can accurately identify occult SLN metastases.
Methodology/Principal Findings
B16-F10 murine melanoma cells were infected with replication-competent herpes simplex virus (HSV) NV1023. The presence of tumor-targeting and reporter-expressing virus was assessed by [18F]-2′-fluoro-2′-deoxy-1-β-D-β-arabinofuranosyl-5-ethyluracil ([18F]FEAU) positron emission tomography (PET) and confirmed by histochemical assays. An animal foot pad model of melanoma lymph node metastasis was established. Mice received intratumoral injections of NV1023, and 48 hours later were imaged after i.v. injection of [18F]FEAU. NV1023 successfully infected and provided high levels of lacZ transgene expression in melanoma cells. Intratumoral injection of NV1023 resulted in viral trafficking to melanoma cells that had metastasized to popliteal and inguinal lymph nodes. Presence of virus-infected tumor cells was successfully imaged with [18F]FEAU-PET, that identified 8 out of 8 tumor-positive nodes. There was no overlap between radioactivity levels (lymph node to surrounding tissue ratio) of tumor-positive and tumor-negative lymph nodes.
Conclusion/Significance
A new approach for imaging SLN metastases using NV1023 and [18F]FEAU-PET was successful in a murine model. Similar studies could be translated to the clinic and improve the staging and management of patients with melanoma.
doi:10.1371/journal.pone.0004789
PMCID: PMC2651472  PMID: 19274083
24.  Oral tongue cancer gene expression profiling: Identification of novel potential prognosticators by oligonucleotide microarray analysis 
BMC Cancer  2009;9:11.
Background
The present study is aimed at identifying potential candidate genes as prognostic markers in human oral tongue squamous cell carcinoma (SCC) by large scale gene expression profiling.
Methods
The gene expression profile of patients (n=37) with oral tongue SCC were analyzed using Affymetrix HG_U95Av2 high-density oligonucleotide arrays. Patients (n=20) from which there were available tumor and matched normal mucosa were grouped into stage (early vs. late) and nodal disease (node positive vs. node negative) subgroups and genes differentially expressed in tumor vs. normal and between the subgroups were identified. Three genes, GLUT3, HSAL2, and PACE4, were selected for their potential biological significance in a larger cohort of 49 patients via quantitative real-time RT-PCR.
Results
Hierarchical clustering analyses failed to show significant segregation of patients. In patients (n=20) with available tumor and matched normal mucosa, 77 genes were found to be differentially expressed (P< 0.05) in the tongue tumor samples compared to their matched normal controls. Among the 45 over-expressed genes, MMP-1 encoding interstitial collagenase showed the highest level of increase (average: 34.18 folds). Using the criterion of two-fold or greater as overexpression, 30.6%, 24.5% and 26.5% of patients showed high levels of GLUT3, HSAL2 and PACE4, respectively. Univariate analyses demonstrated that GLUT3 over-expression correlated with depth of invasion (P<0.0001), tumor size (P=0.024), pathological stage (P=0.009) and recurrence (P=0.038). HSAL2 was positively associated with depth of invasion (P=0.015) and advanced T stage (P=0.047). In survival studies, only GLUT3 showed a prognostic value with disease-free (P=0.049), relapse-free (P=0.002) and overall survival (P=0.003). PACE4 mRNA expression failed to show correlation with any of the relevant parameters.
Conclusion
The characterization of genes identified to be significant predictors of prognosis by oligonucleotide microarray and further validation by real-time RT-PCR offers a powerful strategy for identification of novel targets for prognostication and treatment of oral tongue carcinoma.
doi:10.1186/1471-2407-9-11
PMCID: PMC2649155  PMID: 19138406

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