Randal S. Weber

Matrix Metalloproteinase 9 Promoter Activity Is Induced Coincident with Invasion during Tumor Progression

Matrix metalloproteinase 9 (MMP-9, also known as gelatinase B or 92-kd Type IV collagenase) is overexpressed in many human and murine cancers. We induced carcinomas in mice carrying a transgene that links the MMP-9 promoter to the reporter ss-galactosidase so that activation of the MMP-9 promoter would be indicated by ss-galactosidase. Mammary carcinomas were induced by mating the MMP-9 promoter reporter transgenic mice with mice carrying a transgene for murine mammary tumor virus promoter linked to polyoma middle T antigen, a transgene that leads to rapid development of mammary tumors in female mice. None of the hyperplastic mammary glands and none of the carcinomas in situ expressed ss-galactosidase. However, all invasive tumors had evidence of ss-galactosidase expression. In addition to the breast carcinomas, a malignant teratoma in a female and a papillary adenocarcinoma in the pelvic region of a male arose and were also ss-galactosidase positive. We also induced skin tumors in the mice with the MMP-9 reporter transgene with 7, 12-dimethylbenz[a]anthracene (DMBA) treatment followed by phorbol 12 myristate 13-acetate (TPA). None of the papillomas or in situ carcinomas showed any ss-galactosidase expression, but expression was seen in invasive carcinoma. Although normal skin epithelial cells did not express ss-galactosidase, we did find staining in a few cells at the duct of the sebaceous gland at the base of the hair follicles. The MMP-9 reporter transgene did not lead to expression in the alveolar macrophages, confirming that additional upstream sequences are required for expression in macrophages. These experiments have revealed that MMP-9 promoter activity is induced coincident with invasion during tumor progression. Furthermore, this indicates that the more proximal upstream elements of the promoter are sufficient for MMP-9 transcription during tumor progression.

Malignant tumors of the nose and paranasal sinuses: Hospital of the University of Pennsylvania experience 1990-1997

We reviewed our experience with sinonasal malignancies, which comprise less than 1% of all cancers, in order to determine the spectrum of disease and outcome after treatment. The medical records of 48 patients with sinonasal malignancies treated between 1990–1997 were reviewed for epidemiologic characteristics, tumor location and histology, treatment modalities, and tumor recurrence. Mean age was 58.5 years and 46% were male. Multiple sites of origin were common, including maxillary sinus (83%), ethmoid sinus (35%), and nasal cavity (40%). The histologic spectrum included squamous cell carcinoma (46%), adenoid cystic carcinoma (6%), and miscellaneous others (48%). Treatment included surgery and adjuvant radiotherapy (XRT) (58%), surgery alone (27%), XRT and chemotherapy (6%), surgery and chemotherapy (4%), and XRT alone (4%). Mean follow-up was 15 months (range 2–58). Recurrence was evident in nine patients (19%), 3 (33%) of whom had prior treatment before presenting to HUP. Of the six who recurred after initial treatment at HUP, five (83.3%) were treated with surgery and XRT and one (16.7%) was treated with surgery alone. Of the three that recurred after undergoing attempts at salvage (prior treatment and then treatment at HUP), one had received surgery alone followed by surgery and XRT, one had surgery and XRT followed by surgery and one had XRT followed by surgery alone. Our experience reveals surgery and XRT to be the modality of choice, particularly for advanced tumors, whereas surgery alone may be sufficient for small, well localized tumors. Neoadjuvant chemotherapy may offer improved local control; the future role of endoscopic surgery warrants further investigation.

Survival impact of planned restaging and early surgical salvage following definitive chemoradiation for locally advanced squamous cell carcinomas of the oropharynx and hypopharynx

Objectives:Patients who have received definitive radiation therapy (RT) for a nonlaryngeal T3/4 head and neck squamous cell carcinoma have a limited opportunity for post-RT surgical salvage. The authors reviewed the practice of planned post-RT restaging to determine its impact on the success of early surgical salvage. Methods:A retrospective review was performed for patients with resectable T3/4 cancers of the oropharynx and hypopharynx treated with RT ± chemotherapy who underwent planned restaging clinically, radiographically (CT or MRI), and by direct laryngoscopy with biopsy at 4 to 8 weeks post-RT. Chemotherapy was given as induction, concurrently, or both. Neck dissection was performed at time of restaging in patients with primary tumor control and initial N2/N3 neck disease or persistent lymphadenopathy. Results:A total of 54 patients had a median follow-up of 34.7 months (range, 7.6–97.8 months). Forty-two patients (78.8%) achieved a complete response (CR) at the primary site immediately after RT. Six developed late local failure at 9 to 61 months, of whom 2 were successfully salvaged. The ultimate 2-year local control among patients with initial CR was 94.8%. The 2-year organ preservation, disease-free survival, and overall survival (OS) rates were was 92.5%, 87%, and 90%, respectively. Twelve patients did not achieve initial CR. Two patients with bulky stage IV disease had unresectable cancers. Ten underwent immediate surgical salvage and 7 achieved local control (1 of whom developed distant metastases) whereas 3 had continued local failure. For patients without initial CR, the 2-year ultimate local control rate was 46.7% and OS was 46.8%. For all patients, overall 2-year local control, organ preservation, and OS rates were 85.6%, 75.6%, and 81.8% respectively. The rate of local failure-free organ preservation was 71.5%. Conclusion:For patients with T3/4 resectable nonlaryngeal head and neck cancers, planned clinical, radiographic, and pathologic restaging at 1 to 2 months after definitive RT provides the opportunity for early surgical salvage in those who fail at the primary site. This practice produces improved overall local control and survival rates compared with the literature reports for delayed attempted salvage with timing based on the findings of routine postradiation clinical surveillance. Future efforts may focus on the improved selection of patients who would be most likely to require early surgical intervention.

Abstract 21: Grading dysphagia as a toxicity of head and neck cancer: Differences in severity classification based on MBS DIGEST and clinical CTCAE grades

Background: Clinician-reported toxicity grading through Common Terminology Criteria for Adverse Events (CTCAE) stages dysphagia based on symptoms, diet, and tube dependence. The new Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) tool offers a similarly scaled 5-point ordinal summary grade of pharyngeal swallowing as determined through results of a modified barium swallow (MBS) study. This study aims to inform clinicians on the similarities and differences between dysphagia severity according to clinical CTCAE and MBS-derived DIGEST grading. Methods: A cross-sectional sample of 95 MBS studies was randomly selected from a prospectively-acquired MBS database among patients treated with organ preservation strategies for head and neck cancer. MBS DIGEST and clinical CTCAE dysphagia grades were compared. Results: DIGEST and CTCAE dysphagia grades had “fair” agreement per weighted k of 0.358 (95% CI .231-.485). Using a threshold of DIGEST ≥3 as reference, CTCAE had an overall sensitivity of 0.50, specificity of 0.84, and area under the curve (AUC) of 0.67 to identify severe MBS-detected dysphagia. At less than 6 months, sensitivity was 0.72, specificity was 0.76, and AUC was 0.75 while at greater than 6 months, sensitivity was 0.22, specificity was 0.90, and AUC was 0.56 for CTCAE to detect dysphagia as determined by DIGEST. Conclusions: Classification of pharyngeal dysphagia on MBS using DIGEST augments our understanding of dysphagia severity according to the clinically derived CTCAE while maintaining the simplicity of an ordinal scale. DIGEST likely complements CTCAE toxicity grading through improved specificity for physiologic dysphagia in the acute-phase and improved sensitivity for dysphagia in the late-phase. Citation Format: Ryan P. Goepfert, Jan S. Lewin, Martha P. Barrow, Carla L. Warneke, Clifton D. Fuller, Stephen Y. Lai, Randal S. Weber, Katherine A. Hutcheson. Grading dysphagia as a toxicity of head and neck cancer: Differences in severity classification based on MBS DIGEST and clinical CTCAE grades [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 21.

Chapter 28 – Thyroid Cancer

Publisher Summary nThis chapter begins with a review of the present understanding of pathogenetic mechanisms leading to thyroid cancer. After a brief review of the risk factors and staging of thyroid carcinomas, it discusses an algorithm for the evaluation of a thyroid nodule and the available diagnostic tools. A review of the different forms of thyroid cancer, ranging from well-differentiated carcinomas to anaplastic and other less common malignancies, is followed by a discussion of surgical management and postoperative adjuvant treatment. Although thyroid cancer is relatively rare, the incidence of thyroid nodules is significantly higher. Exposure to ionizing radiation increases a patients risk for the development of thyroid carcinoma. Although higher doses of ionizing radiation typically lead to the destruction of thyroid tissue, Hodgkins disease patients who receive 4000 cGy also have a higher incidence of thyroid cancer. A patient with a history of radiation exposure who presents with a thyroid nodule has up to a 50% chance of having a malignancy. Similarly, patients exposed to radiation from nuclear weapons and accidents have a higher incidence of thyroid cancer. Surgery is the primary modality for the treatment of thyroid carcinomas. Prior to any thyroid surgery, any voice changes or previous neck surgery should prompt an assessment of vocal-cord mobility by indirect laryngoscopy. Although many patients with thyroid carcinomas are euthyroid, necessary medical therapy should be instituted for patients demonstrating thyrotoxicosis or hypothyroidism to avoid intraoperative metabolic derangements, such as hypertensive crisis. The primary goals of surgical treatment should be to eradicate primary disease, to reduce the incidence of local/distant recurrence, and to facilitate the treatment of metastases, which should be achieved with minimal morbidity.