Photoimmunotherapy of residual disease after incomplete surgical resection in head and neck cancer models.

Antibody-based photodynamic therapy, or photoimmunotherapy (PIT), is a novel, targeted cancer therapy, which can serve as both a diagnostic and a therapeutic agent. The primary objective of this study was to evaluate the capacity of panitumumab-IRDye700DX (Pan-IR700) to eliminate microscopic tumor remnants in the postsurgical setting, which was accomplished using novel in vitro and in vivo models of residual disease after incomplete resection. Additionally, PIT was evaluated in fresh human-derived cancer tissue. To determine a threshold for cellular regrowth after PIT, an in vitro assay was performed using a range of cells representing microscopic disease quantities. Long-term growth inhibition was induced after treatment of 5 × 10(3) and 1 × 10(4) cells at 6 J. A novel in vivo mouse model of subtotal tumor resection was used to assess the effectiveness of Pan-IR700 mediated PIT to eliminate residual disease and inhibit recurrence in the post-surgical wound bed. Mice receiving surgical treatment plus adjuvant PIT showed a threefold and fourfold reduction in tumor regrowth at 30 days post PIT in the 50% and 90% subtotal resection groups, respectively (as measured by bioluminescence imaging), demonstrating a significant (P < 0.001) reduction in tumor regrowth. To determine the translatability of epidermal growth factor receptor (EGFR)-targeted PIT, SCCHN human tissues (n = 12) were treated with Pan-IR700. A significant reduction (P < 0.001) in ATP levels was observed after treatment with Pan-IR700 and 100 J cm(-2) (48% ± 5%) and 150 J cm(-2) (49% ± 7%) when compared to baseline. Targeting EGFR with Pan-IR700 has robust potential to provide a tumor-specific mechanism for eliminating residual disease in the surgical setting, thereby increasing therapeutic efficacy, prolonging progression-free survival, and decreasing morbidity.

On the horizon: Optical imaging for cutaneous squamous cell carcinoma.

BACKGROUND: Surgical resection with negative margins remains the standard of care for high-risk cutaneous squamous cell carcinoma (SCC). However, surgical management is often limited by poor intraoperative tumor visualization and inability to detect occult nodal metastasis. The inability to intraoperatively detect microscopic disease can lead to additional surgery, tumor recurrence, and decreased survival. METHODS: A comprehensive literature review was conducted to identify studies incorporating optical imaging technology in the management of cutaneous SCC (January 1, 2000-December 1, 2014). RESULTS: Several innovative optical imaging techniques, Raman spectroscopy, confocal microscopy, and fluorescence imaging, have been developed for intraoperative surgical guidance. Fifty-seven studies review the ability of these techniques to improve cutaneous SCC localization at the gross and microscopic level. CONCLUSION: Significant advances have been achieved with real-time optical imaging strategies for intraoperative cutaneous SCC margin assessment and tumor detection. Optical imaging holds promise in improving the percentage of negative surgical margins and in the early detection of micrometastatic disease. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2204-E2213, 2016.

Frozen section: guiding the hands of surgeons?

Frozen section (FS) analysis is a powerful tool that can provide a rapid diagnosis, directing operative management. However, FSs can also be misused. We consider an FS to be "inappropriate" when it does not influence operative management or immediate patient care. Not only can inappropriate FSs compromise diagnostic material, they can impact turnaround time of other FSs. We evaluated the utilization of FSs at our institution and assessed influence on intraoperative management. Frozen sections performed at the University of Alabama at Birmingham Hospital in 2013 were stratified by surgical subspecialty. Operative, clinical, and pathology notes were reviewed to determine the rationale for sending each FS and to determine impact on intraoperative management. Cases lacking operative notes were excluded. A total of 4104 FSs were performed in 1896 cases. Surgical subspecialties included cardiothoracic, otolaryngology, breast, surgical oncology, gynecology, gastrointestinal, hepatobiliary, urology, transplant, and orthopedics. 42.5% of FSs evaluated margin status, 34.8% confirmed or excluded malignancy, 9.5% were for tumor classification, 6.7% assessed adequacy for diagnosis, 1.9% were to confirm or exclude infection, 2.8% were for transplant, and 1.8% were for lymphoma workup. Twelve percent (491/4104) of FSs did not influence operative management. This was most common among cardiothoracic surgeries (34%). No inappropriate FSs were sent for any transplant surgeries. Otolaryngology used the most FSs and had less than 1% that were inappropriate. Most FSs influence operative management. The rationale for sending an FS and its influence on operative management was subspecialty dependent. Interdepartmental discussions of FS utilization might be helpful in the elimination of unnecessary FSs.

Early Oral Tongue Squamous Cell Carcinoma: Sampling of Margins From Tumor Bed and Worse Local Control.

IMPORTANCE: Positive margins are associated with poor prognosis among patients with oral tongue squamous cell carcinoma (SCC). However, wide variation exists in the margin sampling technique. OBJECTIVE: To determine the effect of the margin sampling technique on local recurrence (LR) in patients with stage I or II oral tongue SCC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study was conducted from January 1, 1986, to December 31, 2012, in 5 tertiary care centers following tumor resection and elective neck dissection in 280 patients with pathologic (p)T1-2 pN0 oral tongue SCC. Analysis was conducted from June 1, 2013, to January 20, 2015. INTERVENTIONS: In group 1 (n = 119), tumor bed margins were not sampled. In group 2 (n = 61), margins were examined from the glossectomy specimen, found to be positive or suboptimal, and revised with additional tumor bed margins. In group 3 (n = 100), margins were primarily sampled from the tumor bed without preceding examination of the glossectomy specimen. The margin status (both as a binary [positive vs negative] and continuous [distance to the margin in millimeters] variable) and other clinicopathologic parameters were compared across the 3 groups and correlated with LR. MAIN OUTCOMES AND MEASURES: Local recurrence. RESULTS: Age, sex, pT stage, lymphovascular or perineural invasion, and adjuvant radiation treatment were similar across the 3 groups. The probability of LR-free survival at 3 years was 0.9 and 0.8 in groups 1 and 3, respectively (P = .03). The frequency of positive glossectomy margins was lowest in group 1 (9 of 117 [7.7%]) compared with groups 2 and 3 (28 of 61 [45.9%] and 23 of 95 [24.2%], respectively) (P < .001). Even after excluding cases with positive margins, the median distance to the closest margin was significantly narrower in group 3 (2 mm) compared with group 1 (3 mm) (P = .008). The status (positive vs negative) of margins obtained from the glossectomy specimen correlated with LR (P = .007), while the status of tumor bed margins did not. The status of the tumor bed margin was 24% sensitive (95% CI, 16%-34%) and 92% specific (95% CI, 85%-97%) for detecting a positive glossectomy margin. CONCLUSIONS AND RELEVANCE: The margin sampling technique affects local control in patients with oral tongue SCC. Reliance on margin sampling from the tumor bed is associated with worse local control, most likely owing to narrower margin clearance and greater incidence of positive margins. A resection specimen-based margin assessment is recommended.

In Vivo Fluorescence Immunohistochemistry: Localization of Fluorescently Labeled Cetuximab in Squamous Cell Carcinomas.

Anti-EGFR (epidermal growth factor receptor) antibody based treatment strategies have been successfully implemented in head and neck squamous cell carcinoma (HNSCC). Unfortunately, predicting an accurate and reliable therapeutic response remains a challenge on a per-patient basis. Although significant efforts have been invested in understanding EGFR-mediated changes in cell signaling related to treatment efficacy, the delivery and histological localization in (peri-)tumoral compartments of antibody-based therapeutics in human tumors is poorly understood nor ever made visible. In this first in-human study of a systemically administered near-infrared (NIR) fluorescently labeled therapeutic antibody, cetuximab-IRDye800CW (2.5 mg/m(2), 25 mg/m(2), and 62.5 mg/m(2)), we show that by optical molecular imaging (i.e. denominated as In vivo Fluorescence Immunohistochemistry) we were able to evaluate localization of fluorescently labeled cetuximab. Clearly, optical molecular imaging with fluorescently labeled antibodies correlating morphological (peri-)tumoral characteristics to levels of antibody delivery, may improve treatment paradigms based on understanding true tumoral antibody delivery.

Surgical margins in head and neck cancer: a contemporary review.

Adequate resection margins are critical to the treatment decisions and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). However, there are numerous controversies regarding reporting and interpretation of the status of resection margins. Fundamental issues relating to the basic definition of margin adequacy, uniform reporting standards for margins, optimal method of specimen dissection, and the role of intraoperative frozen section evaluation, all require further clarification and standardization. Future horizons for margin surveillance offer the possible use of novel methods such as "molecular margins" and contact microscopic endoscopy, However, the limitations of these approaches need to be understood. The goal of this review was to evaluate these issues to define a more rational, standardized approach for achieving resection margin adequacy for patients with HNSCC undergoing curative resection.

A study of TRAIL receptors in squamous cell carcinoma of the head and neck.

OBJECTIVE: To determine the potential immediate applicability of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and TRAIL-R2, the apoptotic forms of TRAIL-Rs, for preclinical testing. DESIGN AND SETTING: Head and neck squamous cell carcinoma (HNSCC) tumors were studied for TRAIL-R1 and TRAIL-R2 expression by immunohistochemical analysis. In addition, matched tumor and peripheral blood DNA samples were screened for 2 known TRAIL-R1 coding single nucleotide polymorphisms (C626G and G422A). Subjects Tumor samples taken from 43 patients (37 samples for immunohistochemical analysis and 6 additional ones included for polymorphism analysis). MAIN OUTCOME MEASURES: The expression of TRAIL-R1 and TRAIL-R2 and the presence of the TRAIL-R1 polymorphisms C626G and G422A. RESULTS: Fewer than 25% of HNSCC tumor cells expressed TRAIL-R1 and TRAIL-R2. Surrounding tumor-infiltrating polymorphonuclear cells expressed TRAIL-R1 and TRAIL-R2 in 12 (32%) and 14 (38%) of cases, respectively. The TRAIL-R1 polymorphisms C626G and G422A were present in 36 (88%) and 33 (89%) cancer cases, respectively. Compared with control groups from another study, these polymorphism frequencies were statistically significant (P = .01 and .003, respectively). CONCLUSIONS: TRAIL-R expression was detected in less than half of the tumor specimens studied but not in any surrounding normal tissue and was found in a higher frequency on tumor-infiltrating polymorphonuclear cells than on tumor cells. These findings support the idea that the presence of TRAIL-Rs on some HNSCC tumors may make them more susceptible to apoptosis, and they also suggest that TRAIL-R-associated mechanisms may result in immune-modulatory effects on tumor-infiltrating polymorphonuclear cells. Furthermore, the significant association of somatic TRAIL-R1 genetic polymorphisms in this sample of patients with HNSCC suggests a potential association between constitutive TRAIL-R1 polymorphisms and development of HNSCC. Defining TRAIL-R expression and genetic polymorphisms in HNSCC represents the first step in examining TRAIL-related mechanisms for their potential as therapeutic targets.

Spindle cell transformation of papillary carcinoma: an aggressive entity distinct from anaplastic thyroid carcinoma.

Spindle cells are not routinely encountered in the context of thyroid pathology and are most often present in anaplastic thyroid carcinoma, medullary thyroid carcinoma, and benign conditions such as Riedel struma or de Quervain granulomatous thyroiditis. Only a few publications have reported papillary thyroid carcinoma admixed with a prominent spindle cell component. While these tumors are clearly distinct from anaplastic thyroid carcinoma, prognostication as to their oncologic potential is not yet established. We describe a unique case of spindle cell transformation of papillary thyroid carcinoma. The blandness of the spindle cells was so impressive as to dissuade us from a malignant diagnosis on preoperative biopsies. However, this patient unfortunately died shortly after transformation of this papillary thyroid carcinoma. We conclude that this peculiar and rare spindle cell transformation should be regarded as a potentially lethal variant of papillary thyroid carcinoma.