James Y. Suen

In vivo, Noninvasive, Label-Free Detection and Eradication of Circulating Metastatic Melanoma Cells Using Two-Color Photoacoustic Flow Cytometry with a Diode Laser

The circulating tumor cell (CTC) count has been shown as a prognostic marker for metastasis development. However, its clinical utility for metastasis prevention remains unclear, because metastases may already be present at the time of initial diagnosis with existing assays. Their sensitivity ex vivo is limited by a small blood sample volume, whereas in vivo examination of larger blood volumes may be clinically restricted by the toxicity of labels used for targeting of CTCs. We introduce a method for in vivo photoacoustic blood cancer testing with a high-pulse-repetition-rate diode laser that, when applied to melanoma, is free of this limitation. It uses the overexpression of melanin clusters as intrinsic, spectrally-specific cancer markers and signal amplifiers, thus providing higher photoacoustic contrast of melanoma cells compared with a blood background. In tumor-bearing mouse models and melanoma-spiked human blood samples, we showed a sensitivity level of 1 CTC/mL with the potential to improve this sensitivity 10(3)-fold in humans in vivo, which is impossible with existing assays. Additional advances of this platform include decreased background signals from blood through changes in its oxygenation, osmolarity, and hematocrit within physiologic norms, assessment of CTCs in deep vessels, in vivo CTC enrichment, and photoacoustic-guided photothermal ablation of CTCs in the bloodstream. These advances make feasible the early diagnosis of melanoma during the initial parallel progression of primary tumor and CTCs, and laser blood purging using noninvasive or hemodialysis-like schematics for the prevention of metastasis.

Diagnosis and management of hemangiomas and vascular malformations of the head and neck

Vascular anomalies are congenital errors in vascular development. They frequently involve the head, neck, and oral cavity. Subdivided into vascular tumors (hemangiomas) and vascular malformations, vascular anomalies remain poorly understood. However, growing interest and recent advances in the diagnosis, management, and molecular characterization of these lesions are improving treatment strategies. The role of the multidisciplinary team cannot be overstated. This review provides both basic and up-to-date knowledge on the most common vascular anomalies encountered by physicians and practitioners. Because treatment options for vascular anomalies are widely variable and often debated, this report aims to provide a comprehensive approach to these lesions based upon current concepts and practical clinical experience.

Ataxia-telangiectasia-mutated (ATM) gene in head and neck squamous cell carcinoma: promoter hypermethylation with clinical correlation in 100 cases.

The Ataxia-telangiectasia-mutated (ATM) gene product is a well-characterized tumor suppressor that plays a key role in maintenance of genomic stability. We have recently documented that the ATM promoter is a target for epigenetic silencing in cultured tumor cells. Here we show that aberrant methylation of the ATM promoter occurs in a significant percentage (25%) of head and neck squamous cell carcinomas. The presence of methylated ATM promoter shows a statistically significant correlation with an earlier age of initial diagnosis and decreased overall survival, particularly in early-stage tumors. These findings indicate that ATM promoter hypermethylation occurs in head and neck squamous cell carcinoma, and this feature is a potentially useful prognostic marker in this tumor type.

Treatment of hemangiomas of the head and neck

Hemangiomas are a group of pediatric tumors that present at or soon after birth. Rapid proliferation is seen in the neonatal period, and may continue for the first year of life. Involution follows, and may last as long as 12 years. Since hemangiomas invariably involute, the vast majority have been left untreated. At least 10% to 20% of cases, however, will need active intervention, traditionally in the form of oral Prednisone. The frequent occurrence of life‐threatening complications, permanent deformities, and irreversible psychosocial damage in spite of adequate steroid therapy necessitated a fresh look at the management of these lesions. Using recently developed laser technology alone or in combination with surgical excision, the authors have developed guidelines for safe intervention in all stages of the hemangioma cycle. Safe, active intervention in accordance with these guidelines offers an alternative to the more conservative approach previously advocated.

The p16 (CDKN2a/INK4a) tumor-suppressor gene in head and neck squamous cell carcinoma: A promoter methylation and protein expression study in 100 cases

The p16 (CDKN2a/INK4a) gene is an important tumor-suppressor gene, involved in the p16/cyclin-dependent kinase/retinoblastoma gene pathway of cell cycle control. The p16 protein is considered to be a negative regulator of the pathway. The gene encodes an inhibitor of cyclin-dependent kinases 4 and 6, which regulate the phosphorylation of retinoblastoma gene and the G1 to S phase transition of the cell cycle. In the present study, p16 gene promoter hypermethylation patterns and p16 protein expression were analyzed in 100 consecutive untreated cases of primary head and neck squamous cell carcinoma by methylation-specific PCR and immunohistochemical staining. The p16 promoter hypermethylation and apparent loss of p16 protein expression were detected in 27% and 74% of head and neck squamous cell carcinoma, respectively. By χ2 test, history of alcohol or tobacco use was significantly correlated with the loss of p16 protein expression (P = .005 and.05, respectively). When patient follow-up data were correlated with various clinical and molecular parameters, tumor size and nodal and clinical stage were the strongest prognostic predictors for disease-free survival (tumor recurrence) and for cause-specific and overall survival in patients with head and neck squamous cell carcinoma. Neither p16 promoter hypermethylation nor apparent loss of p16 protein expression appears to be an independent prognostic factor, although loss of p16 protein may be used to predict overall patient survival in early-stage head and neck squamous cell carcinoma.

The submental Island flap in head and neck reconstruction

The submental island flap (SIF) is a new alternative in the reconstruction of various head and neck defects. We present our preliminary experience in the use of this flap and describe the surgical technique.

Regression of tumors by IFN-α electroporation gene therapy and analysis of the responsible genes by cDNA array

The key to success with nonviral gene therapy as a treatment for cancer is to discover effective therapeutic genes and gene delivery methods and to understand how tumors are eradicated. We discovered that electroporation of IFN-α DNA into tumors in the SCCVII tumor-bearing mice led to tumor eradication in 50% of the mice and a more than two-fold increase in survival time when compared with controls (P = 0.0012). Analyses using cDNA array and Northern blot indicated that the genes responsible for the therapeutic effect of electro-IFN-α gene therapy included IRF-7, Granzyme A, Granzyme C, Gjb2, Krt14, Mig, IP-10 and MCP3. Because most of these genes have been known to either inhibit angiogenesis (Mig, IP-10), inhibit tumor growth (Gjb2, MCP3), kill tumor cells (Granzyme A and C), or induce expression of antitumor gene (IRF-7), they may become promising therapeutic gene candidates for a combination gene therapy approach to cancer treatment.

Immunological skin testing and interpretation: a plea for uniformity.

Immunological skin tests are one of the major methods used for the assessment of ones immune status. A review of the literature clearly reveals that there is no uniform method for the administration and interpretation of skin tests. Without uniformity, it is obvious that data are not comparable. Contradictory conclusions may be reached from the same skin test data, depending upon the method of interpretation used. Precedent, rather than rationale, has often determined the method of interpretation. There are studies which suggest that slight induration or erythema, often considered negative, are significant immunologic events. The various methods of skin test administration and interpretation are reviewed. Recommendations for application and interpretation are presented so that uniformity may exist.

Bisphosphonates and jaw osteonecrosis: The UAMS experience

Background Over the past year at least 10 case series and several case reports on osteonecrosis of the jaw (ONJ) have been published with most found in the oral surgery literature. This clinical entity is largely unknown to head and neck surgeons. Methods Retrospective chart review. Results A total of 479 charts were reviewed, identifying 25 individuals meeting inclusion criteria. Mean age was 63.4 (standard deviation, 9.9) years; 40% were female. Multiple myeloma was the most common comorbidity. Twenty-five patients were treated with bisphosphonates for 4.4 years (range, 1 to 8 years); most commonly pamidronate before ONJ diagnosis. Forty-two percent (10) took steroids within the month before diagnosis. Fifty-two percent (11) underwent dental work before developing ONJ. Conclusion These data reflect the importance of awareness of the possibility of ONJ with bisphosphonate therapy.

Induced Expression of Syndecan-1 in the Stroma of Head and Neck Squamous Cell Carcinoma

Syndecan-1 (CD138), a cell-surface heparan sulfate proteoglycan, is involved in cell–cell, cell-matrix interaction and growth factor binding. Loss of expression of syndecan-1 in tumor cells leads to decreased intercellular cohesion, increased potential for tumor invasiveness, and metastatic spread. Furthermore, induction of syndecan-1 expression in the tumor stroma has been postulated to promote tumor angiogenesis via its binding to growth factors such as basic fibroblast growth factor. Although syndecan-1 expression within tumor cells has been investigated in head and neck squamous cell carcinoma, stromal expression has not been studied in detail. We analyzed 38 cases of head and neck squamous cell carcinoma by immunohistochemical staining for syndecan-1 expression within the stroma. The expression of syndecan-1 within tumor cells of various histologic grades of differentiation, squamous cell carcinoma in situ cells, and benign squamous epithelium was also determined. Variable levels of diminished syndecan-1 expression were noted within the dysplastic cells of 9 of 16 (60%) squamous cell carcinoma in situ lesions and in all 38 (100%) invasive squamous cell carcinoma. In general, higher levels of syndecan-1 expression were observed in the well-differentiated tumors, in contrast to significant reduction of expression seen in poorly differentiated tumors. Syndecan-1 expression was observed within the stroma (in fibroblasts) surrounding infiltrating carcinoma cells in 28 of 38 (74%) cases. The intensity of syndecan-1 staining within the stroma showed generally an inverse correlation with the degree of tumor cell differentiation. Syndecan-1 expression was not detected in the stroma beneath normal squamous epithelium or adjacent to areas of squamous cell carcinoma in situ. We conclude that induced expression of syndecan-1 in the stroma surrounding tumor cells of invasive head and neck squamous cell carcinoma is a frequent event. The increased stromal syndecan-1 expression, coupled with its loss from the surface of carcinoma cells, may contribute to tumor cell invasion and the development of metastases.