Robert A. Weisman

A targeted supradose cisplatin chemoradiation protocol for advanced head and neck cancer

BACKGROUND Hypothesizing that cisplatin (DDP) drug resistance is dose dependent and the radiosensitizing effect of DDP is clinically beneficial, we conducted a chemoradiation protocol using extremely high doses of DDP delivered intra-arterially (IA) to locally advanced head and neck tumors. PATIENTS AND METHODS Twenty-nine patients with untreated stage IV disease received 4 weekly infusions of 150 mg/m2, simultaneous systemic DDP neutralization with intravenous (IV) bolus sodium thiosulfate, and concomitant radiotherapy (180 to 200 cGy/day x 35 fractions). RESULTS The complete response rate of the 24 evaluable patients as determined with repeat biopsies was 23/24 (96%). Of the 29 patients evaluable for toxicity, central nervous system complications related to the infusion technique occurred with 2/110 infusions, both of which were reversible. The rate of grade III to IV chemotoxicity was 13%. The median length of follow-up was 22 months. There have been 6 recurrences: 1 local; 3 regional; and 2 at distant sites. The projected overall and disease-free 3-year survival was 88% and 53%, respectively. CONCLUSION We conclude that the combination of rapid selective delivery of supradose DDP/IV thiosulfate neutralization and concomitant radiotherapy can be safely and effectively applied to patients with advanced head and neck cancer. Preliminary survival analysis indicates that this approach may improve the prognosis for patients with an otherwise devastating disease.

Metastases to the Thyroid: A Review of the Literature from the Last Decade

BACKGROUND Although clinically evident metastases of nonthyroid malignancies (NTMs) to the thyroid gland are uncommon, it is important to suspect them in patients who present with a new thyroid mass and a history, however far back, of prior malignancy. In fact, metastases from NTMs to the thyroid gland have been reported in 1.4%-3% of all patients who have surgery for suspected cancer in the thyroid gland. Here we review the literature over the last decade regarding this topic. SUMMARY Based on recent literature, the most common NTMs that metastasize to the thyroid gland are renal cell (48.1%), colorectal (10.4%), lung (8.3%), and breast carcinoma (7.8%), and sarcoma (4.0%). Metastases of NTMs to the thyroid are more common in women than men (female to male ratio=1.4 to 1) and in nodular thyroid glands (44.2%). The mean and median intervals between diagnosing NTMs and their metastases to thyroid gland are 69.9 and 53 months, respectively. In 20% of cases the diagnosis of the NTM and its metastases to the thyroid was synchronous. Recent reports indicate that there is a higher frequency of sarcoma metastasizing to the thyroid gland than reported in prior years. Fine-needle aspiration biopsy (FNAB) of thyroid masses is useful in diagnosis of thyroid metastases. However, this requires information about the NTM so that the proper antibodies can be used for immunohistochemical analysis; therefore it is of lesser utility if the NTM is occult. In patients with preexisting thyroid pathology the FNAB diagnosis can be more difficult due to more than one lesion being present. CONCLUSIONS It is important to keep in mind that the thyroid gland can be a site of metastases for a variety of tumors when evaluating a thyroid nodule, especially in a patient with a prior history of malignancy. In patients with thyroid lesions and a history of malignant disease, regardless of time elapsed since the initial diagnosis of the primary neoplasm, disease recurrence or progression of malignancy must be considered until proven otherwise.

Expression of Protein Tyrosine Kinases in Head and Neck Squamous Cell Carcinomas

Protein tyrosine kinases (TKs) are overexpressed in many carcinomas and sarcomas. We studied the expression of the following TKs in head and neck squamous cell carcinoma (HNSCC): platelet-derived growth factor receptor (PDGFR), c-kit, epidermal growth factor receptor (EGFR), and a serine-threonine kinase, Akt. Formalin-fixed, paraffin-embedded tumor blocks from 44 consecutive patients with primary HNSCC and 5 specimens of benign pharyngeal and laryngeal mucosa were retrieved for immunohistochemical analysis. Of the specimens, 38 had enough material to stain for all 4 antibodies. The study included 21 pharyngeal (base of tongue, 14; tonsil, 6; soft palate, 1), 16 laryngeal, and 1 floor of the mouth carcinoma. All 4 kinases in the tumor samples were expressed highly (PDGFR, 95%-100%; EGFR, 38%-43%; c-kit, 50%-86%; p-Akt, 57%-81%), with EGFR, c-kit, and p-Akt significantly higher than in benign samples. None of the kinase expressions correlated with disease-free survival. The expression of the kinases raises the possibility of treatment of HNSCC by tyrosine and serine-threonine kinase inhibitors.

EGFR regulates the side population in head and neck squamous cell carcinoma.

Objective: To identify the presence of side population (SP) cells in established head and neck squamous carcinoma cell (HNSCC) lines and to determine the role of EGFR in the regulation of the side population of these cells.

Pseudotumor of the head and neck masquerading as neoplasia.

Four unusual cases of pseudotumor, which had clinical and radiographic findings suggesting neoplasia, are presented. One involved the maxillary sinus, destroying the lateral wall, and extending to the infratemporal fossa and the orbit. The second presented as an enlarging lacrimal gland tumor with ipsilateral parotid adenopathy, and the third as a large parapharyngeal mass that was diagnosed as a lymphoma on aspiration cytology. The fourth case documented the rare occurrence of a congenital pseudotumor, manifesting as proptosis in a neonate and thought to be a fibrosarcoma on frozen section study. Aggressive pseudotumors must be distinguished from malignancy to avoid unnecessary surgery or irradiation. Some cases can be distinguished from neoplasms by their dramatic response to oral steroid therapy, and others by characteristic features on CT or MRI. Due to the diverse cellular proliferation, aspiration cytology is infrequently helpful and diagnosis can be difficult on frozen section study. An approach to the diagnosis and management of pseudotumors is detailed.

A new autologous fibrinogen-based adhesive for otologic surgery.

Many middle ear reconstructive procedures would be facilitated by use of a relatively safe surgical adhesive. A fibrinogen-based adhesive (Tisseel) has been effective in otologic surgery in Europe, but because it is derived from pooled human blood, it carries a risk of transmitting hepatitis, acquired immune deficiency syndrome, and other illnesses. This report details a new procedure for creating an autologous fibrinogen-based adhesive, obviating these risks. The fibrinogen and factor XIII component of the adhesive was isolated by polyethylene glycol precipitation from human plasma within a few hours, and was used either immediately or frozen for use up to 3 weeks later. Fifteen chinchillas had either the single donor adhesive, the commercial European adhesive, or saline placed on the oval and round windows, and no evidence of cochlear, mucosal, or ossicular damage was seen by light microscopy 30 days later. Auditory brain stem response thresholds remained stable, except in three animals that developed otitis media. Based on this investigation, autologous fibrinogen-based adhesive appears promising as a relatively safe, biological bonding material for otologic surgery, and is worthy of further study.

EGFR Kinase Promotes Acquisition of Stem Cell-Like Properties: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma Stem Cells

Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of “stemness” in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC.

Biochemical characterization of autologous fibrinogen adhesive

Fibrinogen‐based adhesive, derived from pooled human plasma, has been used in Europe with great success in otologic surgery, but has not been approved for use in the U.S. because of the risk of transmitting hepatitis. Autologous fibrinogen, derived by polyethylene glycol precipitation from the blood of an individual patient would avoid this risk, and has been shown to be relatively safe to the ear in animal studies. A study of the biochemical composition of this autologous fibrinogen concentrate derived from 15 human volunteer donors was performed. The mean starting plasma fibrinogen was 2.12 mg/ml (range 1.59–3.22 mg/ml). When 10% polyethylene glycol was used to precipitate the fibrinogen, the concentrate contained, on the average, 31.8 mg of fibrinogen/ml. The percent yield averaged 54.9%, and the protein in the final product was 91.9% fibrinogen. Increasing the polyethylene glycol concentration in the precipitation process to as high as 15% resulted in an increased yield as high as 91%, but the protein in the final product was only 42.5% fibrinogen. Polyacrylamide gel electrophoresis confirmed that the predominant protein in the 10% polyethylene glycol precipitate was fibrinogen.

Resorbable fixation in facial plastic and head and neck reconstructive surgery: an initial report on polylactic acid implants.

Objectives The purpose of this study was to evaluate and report our initial experience with a resorbable fixation system in facial cosmetic and head and neck reconstructive surgery. The specific goals were to determine in which settings the absorbable system could be used, to evaluate the outcome of its use, to detail complications that occurred, and to report our observations on advantages and disadvantages of the system compared with traditional methods of osteosynthesis and fixation.

Head and neck manifestations of scleroderma.

— Scleroderma has rarely been discussed in the otolaryngologic literature. A review of the records of 71 scleroderma patients admitted to UCLA Hospital during the past five years indicates that head and neck manifestations are common, occurring in 80% of these patients. The initial symptoms in 30% among them were related to the head and neck. It is the purpose of this paper to familiarize otolaryngologists with scleroderma. Although it has not been emphasized in the past, this is a disease whose early symptoms and findings may require otolaryngologic consultation and whose later course is characterized by head and neck symptoms and findings in the overwhelming majority of patients.