Joseph C. Dort

Simultaneous 3-T fMRI and high-density recording of human auditory evoked potentials.

We acquired simultaneous high-field (3 T) functional magnetic resonance imaging (fMRI) and high-density (64- and 128-channel) EEG using a sparse sampling technique to measure auditory cortical activity generated by right ear stimulus presentation. Using dipole source localization, we showed that the anatomical location of the grand mean equivalent dipole of auditory evoked potentials (AEPs) and the center of gravity of fMRI activity were in good agreement in the horizontal plane. However, the grand mean equivalent dipole was located significantly superior in the cortex compared to fMRI activity. Interhemispheric asymmetry was exhibited by fMRI, whereas neither the AEP dipole moments nor the mean global field power (MGFP) of the AEPs showed significant asymmetry. Increasing the number of recording electrodes from 64 to 128 improved the accuracy of the equivalent dipole source localization but decreased the signal-to-noise ratio (SNR) of MR images. This suggests that 64 electrodes may be optimal for use in simultaneous recording of EEG and fMRI.

Head and neck cancer: from anatomy to biology.

The 20th century saw great advances in anatomy‐based (surgery and radiotherapy) and chemotherapy approaches for treating head and neck squamous cell carcinoma (HNSCC) and improving quality of life (QoL). However, despite these advances, the survival rate in HNSCC remains at ∼50%. Front‐line treatments often cause severe toxicity and debilitating long‐term impacts on QoL. In recent decades, dramatic advances have been made in our knowledge of fundamental tumor biology and signaling pathways that contribute to oncogenesis and cancer progression. These insights are presenting unprecedented opportunities to develop more effective and less toxic treatments that are specific to particular molecular targets. This review discusses some of the major, potentially targetable, molecular pathways associated with head and neck carcinogenesis. We present the general mechanism underlying the functional components for each signaling pathway, discuss how these components are aberrantly regulated in HNSCC and describe their potential as therapeutic targets. We have restricted our discussion to “drug‐able targets” such as oncogenes including those associated with HPV, tumor hypoxia and microRNAs and present these changes in the context of HNSCC patient care. The specific targeting of these pathways to achieve cancer control/remission and reduce toxicity is now challenging conventional treatment paradigms in HNSCC. This new “biologic era” is transforming our ability to target causal pathways and improve survival outcomes in HNSCC.

Clinical utility of PET/CT in the evaluation of head and neck squamous cell carcinoma with an unknown primary: A prospective clinical trial

Metastatic head and neck squamous cell carcinoma with an unknown primary is an uncommon but important problem. PET/CT, as an adjunct to diagnosis, is potentially useful but has never been studied in a prospective, single‐blinded clinical trial.

A prospective quantitative study of sensory deficits after whole sural nerve biopsies in diabetic and nondiabetic patients Surgical approach and the role of collateral sprouting

Background Sural nerve biopsy (Sbx) has been employed for the diagnosis of peripheral neuropathies and for multicenter trials of therapy in diabetic neuropathy. There is only limited prospective information available about what factors influence the resolution of the sensory deficit (Sdef) after biopsy. Methods We prospectively studied the surface area of skin Sdef after whole human Sbx in diabetic and nondiabetic patients for up to 18 months after the procedure. Sdef was determined by mapping, in two dimensions, the area of loss to pinprick and light touch in the sural distribution using a transparent boot-like device with 1—square-cm grid markings. At the same time, patients were interviewed about biopsy-related symptoms. Results Overall, the Sdef in all patients declined by an average of 91 ± 3% at 18 months. The pattern of Sdef decline indicated that collateral sprouting was the mechanism of sensory reinnervation. The extent of Sdef at 6, 12, or 18 months did not differ between diabetics and nondiabetics. In diabetics, there was a correlation between sensory reinnervation with pre-biopsy sural nerve potential amplitude and HbA1C level, but not with age or diabetes duration. Diabetic patients who had nerve resections starting at or below the center of a plane through the lateral malleolus and traveling proximally for 7 cm or less had a Sdef that was less than patients with longer and more proximal nerve resections. The majority of patients had unpleasant but mild mechanically elicited sensory symptoms at 1 year that had improved in most, but not all patients, by 18 months. Conclusions Sbx is associated with prolonged sensory symptoms and sensory loss. Recovery occurs by collateral reinnervation.

Soft-tissue sarcomas of the head and neck: a retrospective analysis of the Alberta experience 1974 to 1999.

Background: Soft‐tissue sarcomas (STS) of the head and neck constitute a heterogeneous group of rare malignant tumors occurring in an uncommon site. The most common subtypes of STS in the head and neck are malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, and fibrosarcoma. Evidence based subtype‐specific treatment decisions are often not possible.

The effect of MR scanner noise on auditory cortex activity using fMRI

Auditory functional magnetic resonance imaging (fMRI) studies are limited by the presence of noise produced by echo planar imaging (EPI). The current study quantifies the effect of MR scanner noise on psychophysical measures of the perception of loudness and on measures of tonotopy, the representation of auditory frequencies within the auditory cortex. Seven normal hearing adults were examined using tones of 5 different auditory frequencies (250, 500, 1,000, 2,000, 4,000 Hz) of equal loudness. Using an imaging protocol with peak MR scanner noise at 1,460 Hz, the perception of loudness and detectable fMRI activity in response to a 1‐kHz tone was less compared to other frequencies. When the imaging protocol was changed such that peak MR scanner noise occurred at 2,080 Hz, the perception of loudness and detectable fMRI activity in response to a 2‐kHz tone was less compared to other frequencies. The reduction in the measured fMRI activity for tones near scanner frequencies may be due to an inflated scanner‐induced baseline at those frequencies. In addition, fMRI activity decreased with increasing frequency, possibly due to the upward spread of masking of low‐frequency, high‐intensity tonal stimuli or the proximity of low‐frequency core and belt areas of the auditory cortex. These results demonstrate the direct effect of scanner noise and high‐intensity tonal stimuli on measurements of auditory cortex tonotopy. Hum. Brain Mapping 22:341–349, 2004.

High stromal carbonic anhydrase IX expression is associated with nodal metastasis and decreased survival in patients with surgically-treated oral cavity squamous cell carcinoma

Every year, approximately 25,000 patients are diagnosed with oral cavity squamous cell carcinoma (OCSCC) in the USA. The 5-year survival rate for OCSCC is approximately 40%. Intratumoral hypoxia confers poor prognosis and treatment failure but direct tumor oxygen measurement is challenging. Carbonic anhydrase IX (CAIX) is a marker of tissue hypoxia and we have recently shown that stromal CAIX is associated with reduced survival in patients with HPV-negative head and neck cancer. We examined the importance of this observation in OCSCC patients. We identified patients diagnosed and treated with OCSCC in Calgary (Alberta, Canada) between 1998 and 2005. Clinical and pathologic data were obtained from the Alberta Cancer Registry and chart review. Tissue microarrays (TMAs) were assembled from triplicate cores of archived tumor tissue. Stromal CAIX expression was assessed by quantitative immunohistochemistry (AQUA-HistoRx). The primary endpoint was disease-specific survival. We identified 102 patients with OCSCC; 87 patients had surgery as their primary treatment and adequate tumor tissue for TMA construction was available for all patients. CAIX expression was evaluable for 61 patients. High (top quartile) stromal CAIX expression was associated with significantly reduced 5-year disease-specific survival compared to low stromal CAIX expression (p<0.006). This study confirms our previously reported association between high stromal CAIX expression and significantly reduced overall survival in an independent, predominantly p16-negative, cohort of surgically treated OCSCC. Assessment of stromal CAIX expression could identify patients with the least favorable prognosis and inform therapeutic strategies in OCSCC.

Optimal Perioperative Care in Major Head and Neck Cancer Surgery With Free Flap Reconstruction: A Consensus Review and Recommendations From the Enhanced Recovery After Surgery Society

Importance Head and neck cancers often require complex, labor-intensive surgeries, especially when free flap reconstruction is required. Enhanced recovery is important in this patient population but evidence-based protocols on perioperative care for this population are lacking. Objective To provide a consensus-based protocol for optimal perioperative care of patients undergoing head and neck cancer surgery with free flap reconstruction. Evidence Review Following endorsement by the Enhanced Recovery After Surgery (ERAS) Society to develop this protocol, a systematic review was conducted for each topic. The PubMed and Cochrane databases were initially searched to identify relevant publications on head and neck cancer surgery from 1965 through April 2015. Consistent key words for each topic included “head and neck surgery,” “pharyngectomy,” “laryngectomy,” “laryngopharyngectomy,” “neck dissection,” “parotid lymphadenectomy,” “thyroidectomy,” “oral cavity resection,” “glossectomy,” and “head and neck.” The final selection of literature included meta-analyses and systematic reviews as well as randomized controlled trials where available. In the absence of high-level data, case series and nonrandomized studies in head and neck cancer surgery patients or randomized controlled trials and systematic reviews in non–head and neck cancer surgery patients, were considered. An international panel of experts in major head and neck cancer surgery and enhanced recovery after surgery reviewed and assessed the literature for quality and developed recommendations for each topic based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. All recommendations were graded following a consensus discussion among the expert panel. Findings The literature search, including a hand search of reference lists, identified 215 relevant publications that were considered to be the best evidence for the topic areas. A total of 17 topic areas were identified for inclusion in the protocol for the perioperative care of patients undergoing major head and neck cancer surgery with free flap reconstruction. Best practice includes several elements of perioperative care. Among these elements are the provision of preoperative carbohydrate treatment, pharmacologic thromboprophylaxis, perioperative antibiotics in clean-contaminated procedures, corticosteroid and antiemetic medications, short acting anxiolytics, goal-directed fluid management, opioid-sparing multimodal analgesia, frequent flap monitoring, early mobilization, and the avoidance of preoperative fasting. Conclusions and Relevance The evidence base for specific perioperative care elements in head and neck cancer surgery is variable and in many cases information from different surgerical procedures form the basis for these recommendations. Clinical evaluation of these recommendations is a logical next step and further research in this patient population is warranted.

Intraoperative magnetic resonance imaging for skull base surgery.

Objectives/Hypothesis Skull base surgery has evolved over the past several decades. Major improvements in the imaging of skull base pathology led to better target localization and better surgical planning. The objectives of this study were to assess the use of intraoperative magnetic resonance (MR) imaging in the management of a series of patients with skull base pathology. We hypothesized that high‐quality intraoperative MR imaging would have an impact on surgery in this patient group.

High stromal carbonic anhydrase IX expression is associated with decreased survival in P16-negative head-and-neck tumors.

PURPOSE Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide. Alcohol use and tobacco use are the most established risk factors; however, human papilloma virus (HPV) infection is a major risk factor for a subset of HNSCCs. Although HPV-positive tumors typically present at a more advanced stage at diagnosis, they are associated with a better prognosis. Tumor hypoxia confers poor prognosis and treatment failure, but direct tumor oxygen measurement is challenging. Endogenous markers of hypoxia (EMHs) have been proposed but have not replicated the prognostic utility of direct oxygen measurement. The expression of endogenous markers of hypoxia may be influenced by oxygen-independent factors, such as the HPV status of the tumor. METHODS AND MATERIALS Consecutive cases of locally advanced HNSCC, treated with a uniform regimen of combined radiotherapy and chemotherapy, were identified. Tissue microarrays were assembled from triplicate 0.6-mm cores of archived tumor tissue. HPV status was inferred from semiquantitative p16 immunostaining and directly measured by use of HPV-specific chromogenic in situ hybridization and polymerase chain reaction. Automated quantitative fluorescent immunohistochemistry was conducted to measure epithelial and stromal expression of carbonic anhydrase IX (CAIX) and glucose transporter 1 (GLUT1). RESULTS High stromal CAIX expression was associated with significantly reduced overall survival (p = 0.03) in patients with p16-negative tumors. CONCLUSIONS This is the first study to use quantitative immunohistochemistry to examine endogenous markers of hypoxia stratified by tumor p16/HPV status. Assessment of CAIX expression in p16-negative HNSCC could identify patients with the least favorable prognosis and inform therapeutic strategies.