Thomas V. McCaffrey

HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.

The hypoxic environment of tumors dictates the phenotype of local myeloid-derived suppressor cells (MDSCs) via HIF-1a expression; hypoxia converts splenic MDSCs from specific into nonspecific suppressors.

Mechanism Regulating Reactive Oxygen Species in Tumor-Induced Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47phox and gp91phox, compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.

Head and Neck Cancers

Recent evidence suggests that dysregulated translation and its control significantly contribute to the etiology and pathogenesis of the head and neck cancers, specifically to that of squamous cell carcinoma (HNSCC). eIF4E is one of the most studied components of the translation machinery implicated in the development and progression of HNSCC. It appears that dysregulation of eIF4E levels and activity, namely by the PI3K/AKT/mTOR pathway, plays an important role in the etiology and pathogenesis of HNSCC and correlates with clinical outcomes. In this chapter, we will discuss the role of eIF4E and some other translation factors as they relate to the biology and treatment of HNSCC.

Lipid accumulation and dendritic cell dysfunction in cancer

Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.

Head and neck cancers, version 1.2015 featured updates to the NCCN guidelines

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

Surgical Treatment of Extracranial Internal Carotid Artery Dissecting Aneurysms

Aneurysms of the extracranial internal carotid artery (ICA) are uncommon. A significant proportion of such aneurysms are now recognized to be caused by arterial dissection. In some patients, surgical treatment may become necessary. The surgical treatment of 22 patients with spontaneous or traumatic dissecting aneurysms arising from the extracranial ICAs is reviewed. The mean age of the 7 women and 15 men was 39 years. The aneurysm arose from the proximal third of the extracranial ICA in 1 patient, from the middle third in 1 patient, and from the distal third in 20 patients. Five patients underwent cervical carotid ligation; in 13 patients, the aneurysms were resected, and the ICAs were reconstructed, and 4 patients underwent cervical-to-intracranial ICA bypasses. There were 2 postoperative strokes (9%). Facial and lower cranial nerve palsies were commonly seen after high cervical exposure, but these cranial nerve palsies were transient. There were no long-term neurological sequelae during a mean follow-up of 6.2 years. In our relatively limited experience, extracranial ICA dissecting aneurysms can be treated with acceptable morbidity using a variety of techniques. However, the indications for surgical intervention in these aneurysms remain limited.

Combined neck dissection and postoperative radiation therapy in the management of the high-risk neck: A matched-pair analysis

PURPOSE The purpose of this study was to determine the efficacy of postoperative adjuvant radiation therapy with regard to reducing the rate of recurrence in the neck, cancer-related death, and death from any cause in patients with squamous cell carcinoma of the head and neck region metastatic to neck nodes. METHODS This was a retrospective review of patients with pathologically confirmed nodal metastases who underwent neck dissection and postoperative adjuvant radiation therapy for squamous cell carcinoma of the head and neck region. Time to recurrence in the dissected area of the neck, any recurrence in the neck, cancer-related death, and death from any cause were estimated with the Kaplan-Meier method. A matched-pair analysis was performed utilizing a cohort of patients who underwent neck dissection without postoperative radiation therapy. The patients from the two cohorts were matched according to previously reported high-risk features for cancer recurrence and death. Cox hazards models for the matched pairs were used to evaluate the relative risk of subsequent recurrence in the dissected side of the neck, any neck recurrence, cancer-related death, and overall survival. MATERIALS The medical records and pathologic slides of 95 consecutive patients with pathologically confirmed nodal metastases from squamous cell carcinoma of the head and neck region who underwent neck dissection and postoperative adjuvant radiation therapy between January 1974 and December 1990 were reviewed. Previously published data from 284 patients with squamous cell carcinoma of the head and neck region treated with neck dissection alone between January 1970 and December 1980 were used for a matched-pair analysis. RESULTS The relative risks for recurrence in the dissected side of the neck, any neck recurrence (dissected neck or delayed undissected neck metastasis), cancer-related death, and death from any cause for patients treated with operation alone relative to those treated with operation and postoperative radiation were 5.82, 4.72, 2.21, and 1.67, respectively. CONCLUSION This study provides evidence that postoperative adjuvant radiation therapy for the high-risk neck can reduce the rate of recurrence within a dissected neck, delayed metastasis within an undissected neck, cancer-related death, and death from any cause.

Sarcoidosis of the nose and paranasal sinuses.

Sarcoidosis is a chronic systemic disease of unknown etiology characterized by non‐caseating granulomatous inflammation of various organs. The records of 2319 patients with the diagnosis of sarcoidosis were reviewed to determine the incidence of nasal involvement. Seventeen patients or approximately 1% of the patients with sarcoidosis had histologically proven nasal mucosa involvement. These patients had symptoms of nasal crusting, congestion, epistaxis, pain, or anosmia. The clinical findings in these patients included friable nasal mucosa, nasal polyps, or a characteristic submucosal nodularity. Most patients also had abnormal sinus roentgenograms with either thickening of the sinus mucosa or opacification of the sinuses. Involvement of the nasal mucosa by non‐caseating granulomas in sarcoidosis is an infrequent manifestation of the disease. Biopsy of the nasal mucosa shows typical non‐caseating granulomas, but care must be exercised to exclude other causes of granulomatous inflammation of the nasal mucosa including tuberculosis, fungal infections, and other idiopathic granulomatous diseases such as Wegeners granulomatosis and Churg‐Strauss syndrome. The treatment of nasal sarcoidosis has consisted of systemic steroids and in some cases topical beclomethasone dipropionate.

Otologic Manifestations of Wegener's Granulomatosis

Review of 112 patients with Wegeners granulomatosis showed that 21 (19%) had ear involvement. Conductive deafness, which was present in all 21 patients, was due to serous middle ear fluid, suppurative otitis media with thickening of the tympanic membrane, perforation of the tympanic membrane, or granulation tissue in the middle ear space. Nine patients also had sensorineural hearing loss. Sensorineural hearing loss was improved in five of the nine patients after control of the disease with prednisone and cyclophosphamide.

Adjuvant Radiotherapy for Squamous Cell Carcinoma of the Tongue Base: Improved Local-Regional Disease Control Compared with Surgery Alone

PURPOSE The purpose of this retrospective study is to present the results of postoperative adjuvant radiotherapy after primary surgery for squamous cell carcinoma of the tongue base and to compare these results to those obtained with surgery alone. METHODS Between 1974 and 1993, continuous-course postoperative radiotherapy was delivered to 24 patients (Adjuvant Radiotherapy Group). Results were compared to those from a group of 55 patients treated with surgery alone (Surgery Group). RESULTS Characteristics of the two groups were similar, except that a larger proportion of patients in the Adjuvant Radiotherapy Group had higher pathologic TNM stages. Ipsilateral neck control (87% vs. 68%, p = 0.04), contralateral neck control (100% vs. 76%,p = 0.002), relapse-free survival (64% vs. 46%,p = 0.04), and control above the clavicles (80% vs. 48%, p = 0.007) were significantly higher in the Adjuvant Radiotherapy Group compared to those in the Surgery Group (5-year figures shown). CONCLUSION The use of adjuvant radiotherapy after surgical resection of tongue base squamous cell carcinoma significantly decreased the rate of local-regional recurrence and improved relapse-free survival compared with surgery alone but did not alter cause-specific or overall survival.