Vicente A. Resto

Frequent gain of the p40/p51/p63 gene locus in primary head and neck squamous cell carcinoma

We have identified a new human p53 homologue, p40 (p51/p63). This gene was mapped to the distal arm of 3q and was found to be essential for normal epithelial development. We used microsatellite and FISH analyses to search for genetic alterations of p40 in primary HNSCC. A more precise localization of p40 was completed using 6 known markers on 3q and a newly isolated microsatellite marker within the p40 gene. We also determined the genomic organization of the p40 gene using human YAC and BAC clones. Microsatellite analysis revealed that 14 of 26 (54%) primary HNSCC had allelic imbalance in at least 1 of the 7 microsatellite loci. However, FISH analysis with a p40 probe showed that a majority of HNSCC had an increased copy number of the locus regardless of allelic status. Thus, overrepresentation of the p40 locus may play an important role in the development of HNSCC. Int. J. Cancer 86:684–689, 2000.

Esthesioneuroblastoma: the Johns Hopkins experience.

Esthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of the upper nasal cavity. Therapeutic management approaches for this neoplasm lack uniformity and there is no universally accepted staging system.

Nasal glioma and encephalocele: diagnosis and management.

Objective To review the biology of nasal glioma and encephalocele and to present an algorithm for preoperative evaluation and surgical management.

Extent of surgery in the management of locally advanced sinonasal malignancies.

The relative importance of surgery within multimodality regimens commonly used to treat advanced sinonasal malignancies remains unknown.

Oral Cavity Squamous Cell Carcinoma and the Clinically N0 Neck: The Past, Present, and Future of Sentinel Lymph Node Biopsy

Oral cavity squamous cell carcinoma (OCSCC) has a yearly incidence of 274,000 patients. Twenty percent to 30% of patients will harbor occult regional metastases, an important feature that correlates with worse outcomes. Supraomohyoid neck dissection (SND) is the gold standard treatment, but because of recent successes of sentinel lymph node (SLN) biopsy in the management of breast cancer and melanoma, many have begun evaluating its use in head and neck mucosal cancers. SLN biopsy offers patients decreased morbidity compared with SND, and has shown reproducibly low false-negative rates, high-negative predictive values, and high sensitivities. Limitations with floor-of-mouth primaries and delayed secondary SNDs have been described, but a new agent designed to address these shortcomings, Lymphoseek (Neoprobe Corp.; Dublin, OH), is currently under investigation. This article reviews the current literature on SLN biopsy and introduces a phase 3 study evaluating the efficacy of Lymphoseek in SLN biopsy of OCSCCs.

Case-matching analysis of head and neck squamous cell carcinoma in racial and ethnic minorities in the United States—Possible role for human papillomavirus in survival disparities

Several studies have documented disparities in head and neck cancer outcomes for black patients in the United States. Recent studies have found that differences in oropharyngeal tumor human papillomavirus (HPV) status may be a cause of this disparity.

L-selectin-mediated Lymphocyte-Cancer Cell Interactions under Low Fluid Shear Conditions

Cell migration in blood flow is mediated by engagement of specialized adhesion molecules that function under hemodynamic shear conditions, and many of the effectors of these adhesive interactions, such as the selectins and their ligands, are well defined. However, in contrast, our knowledge of the adhesion molecules operant under lymphatic flow conditions is incomplete. Among human malignancies, head and neck squamous cell cancer displays a marked predilection for locoregional lymph node metastasis. Based on this distinct tropism, we hypothesized that these cells express adhesion molecules that promote their binding to lymphoid tissue under lymphatic fluid shear stress. Accordingly, we investigated adhesive interactions between these and other cancer cells and the principal resident cells of lymphoid organs, lymphocytes. Parallel plate flow chamber studies under defined shear conditions, together with biochemical analyses, showed that human head and neck squamous cell cancer cells express heretofore unrecognized L-selectin ligand(s) that mediate binding to lymphocyte L-selectin at conspicuously low shear stress levels of 0.07–0.08 dynes/cm2, consistent with lymphatic flow. The binding of head and neck squamous cancer cells to L-selectin displays canonical biochemical features, such as requirements for sialylation, sulfation, and N-glycosylation, but displays a novel operational shear threshold differing from all other L-selectin ligands, including those expressed on colon cancer and leukemic cells (e.g. HCELL). These data define a novel class of L-selectin ligands and expand the scope of function for L-selectin within circulatory systems to now include a novel activity within shear stresses characteristic of lymphatic flow.

Carcinoma matrix controls resistance to cisplatin through talin regulation of NF-kB.

Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin β1 was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin β1, talin and FAK pathways that regulate NF-kB nuclear activity.

Immunohistochemical distinction of intestinal-type sinonasal adenocarcinoma from metastatic adenocarcinoma of intestinal origin

Objectives: Distinction of intestinal-type sinonasal adenocarcinoma (ITAC) from adenocarcinoma of intestinal origin metastatic to the sinonasal cavity may be extremely difficult on histologic grounds alone. We studied the role of cytokeratin (CK) and mucin (MUC) expression in differentiating ITAC, metastatic adenocarcinoma of intestinal origin, and non-intestinal-type sinonasal adenocarcinoma (non-ITAC). Methods: We stained specimens from 5 cases of ITAC and 4 cases of non-ITAC, along with 4 colonic and 3 duodenal adenocarcinoma controls, with CK7 and CK20, MUC2 and MUC5, neuron-specific enolase (NSE), chromogranin (CHR), and carcinoembryonic antigen (CEA) in order to examine the possible combinations of markers that best aid in the diagnosis of these lesions. We also performed a retrospective review of our clinical experience with these rare lesions. Results: CK7 staining was positive in all ITAC and non-ITAC cases, whereas all cases displaying gastrointestinal-type differentiation (ITAC and metastatic intestinal cases) stained positive for both CK20 and MUC2. Staining for MUC5, NSE, CHR, and CEA was variable. Conclusions: Tumors with the CK7+, CK20+, MUC2+ immunophenotype are likely primary sinonasal lesions, whereas tumors with the CK7−, CK20+, MUC2+ profile warrant further clinical evaluation to exclude metastatic disease from the gastrointestinal tract. Complete surgical resection of ITAC remains the mainstay of therapy.

In vivo layer-resolved characterization of oral dysplasia via nonlinear optical micro-spectroscopy

Optical spectroscopy has proven to be a powerful technique for studying neoplastic transformation in epithelial tissue. Since specific intra-layer precancerous changes originate in the stratified layers of the oral mucosa, layer-resolved analysis will likely improve both our understanding of the mechanism of premalignant transformation, and clinical diagnostic outcomes. However, the native fluorescence signal in linear spectroscopy typically originates from a multi-layered focal volume. In this study, nonlinear spectroscopy was exploited for in vivo layer-resolved discrimination between normal and dysplastic tissue for the first time. Our results revealed numerous intra-layer specific differences.