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There are two promising herpes viral-based anticancer strategies: one involves replication-defective viruses to transfer therapeutic transgenes, and the other involves replication-conditional oncolytic viruses, which selectively infect and destroy cancer cells directly. This study examines a novel dual herpesvirus preparation, which combines the immunostimulatory effects of amplicon-mediated IL2 expression with direct viral-induced oncolysis. The oncolytic virus G207 was used as the helper virus to package a herpes simplex virus (HSV)-amplicon vector carrying the gene IL2 (HSV-IL2), yielding a single preparation with two complementary modes of action. In vivo comparison was carried out in a syngeneic squamous cell carcinoma flank tumor model. We directly injected established tumors with HSV-IL2, G207, G207 mixed with HSV-IL2, or G207-packaged HSV-amplicon carrying the IL2 transgene (G207[IL2]). Significant inhibition of tumor growth was seen at 2 weeks in the G207[IL2]-treated tumors relative to controls (0.57+/-0.44 cm(3) versus 39.45+/-5.13 cm(3), P<0.00001), HSV-IL2 (20.97+/-4.60 cm(3)), and the G207 group (7.71+/-2.10 cm(3)). This unique use of a replication-conditional, oncolytic virus to package a replication-incompetent amplicon vector demonstrates impressive efficacy in vitro and in vivo, and avoids the theoretical concerns of recombination with reversion to wild type.

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Herpes simplex type 2-defective infectious single-cycle (DISC) viruses are attenuated viruses that were originally produced as viral vaccines; however, these viruses are also efficient gene transfer vehicles. The main goals of this study were to examine determinants of the gene transfer by using DISC virus for squamous cancer and to evaluate the antitumoral efficacy of vaccination with tumor cells modified by DISC viruses carrying a combination of immunomodulatory genes (interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor (GM-CSF), B7-1) in a model of squamous cell cancer (SCCVII) in C3H/HeJ mice. SCCVII cells transduced by DISC viruses (multiplicity of infection of 10) carrying the IL-2 or GM-CSF gene produced nanogram quantities of IL-2 or GM-CSF per 10(6) cells. Irradiated (5,000 cGy, 10,000 cGy) cells secreted levels of GM-CSF or IL-2 that were comparable with nonirradiated cells. In vivo vaccination using tumor cells transduced ex vivo with DISC-IL2 or DISC-GMCSF resulted in protection against subsequent tumor challenge (P < .01), with DISC-GMCSF-transduced, irradiated tumor cells showing the greatest effects (P < .001). Marked growth arrest also was noted in established tumors after direct injection of DISC-GMCSF (P < .001). These data demonstrate that (a) DISC virus is capable of efficient gene transfer, (b) GM-CSF-secreting genetically modified tumor vaccine protects against tumor cell challenge and suppresses tumor growth, and (c) intratumoral injection of DISC-GMCSF significantly suppresses the growth of established tumors. These results not only confirm clinically relevant gene transfer but also demonstrate that the gene transfer is an effective anti-cancer therapy.

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OBJECTIVE AND IMPORTANCE: Delayed epistaxis resulting from trauma to branches of the external carotid artery is an infrequent but potentially serious complication of transsphenoidal surgery. We report two cases of severe, delayed epistaxis in patients who had undergone transsphenoidal surgery. In both cases, noninvasive treatment failed, necessitating endovascular intervention. CLINICAL PRESENTATION: The first patient, a 52-year-old woman with a prolactinoma, underwent a second transsphenoidal resection 18 months after the first surgery. She was readmitted on postoperative Day 15 with massive epistaxis. The second patient, a 40-year-old woman, had undergone two transsphenoidal surgeries, 14 years apart, for an adrenocorticotropic hormone-secreting adenoma. She was readmitted with massive epistaxis on postoperative Day 17. INTERVENTION: Both patients were initially treated with nasal balloon packing but experienced recurrent hemorrhage when the balloon was deflated, necessitating referral to the interventional radiology department for embolization. At arteriography, the first patient was found to have a pseudoaneurysm of the medial branch of the left internal maxillary artery, which was subsequently embolized. Arteriography in the second patient revealed an abnormally dilated midline branch of the right internal maxillary artery in the nasal septum; this vessel was occluded at arteriography. CONCLUSION: Delayed massive epistaxis is a rare but significant complication of transsphenoidal surgery. Injury to branches of the external carotid artery, along with injury to the internal carotid artery, should be suspected in patients who present with delayed epistaxis after transsphenoidal surgery. Angiography performed in patients with refractory bleeding should include selective external carotid injections. Epistaxis that is refractory to anterior and posterior nasal packing may be effectively treated with endovascular embolization.

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INTRODUCTION: Radiation therapy is an integral part of the treatment of head and neck cancer. Factors predicting radiation response are ill defined. The aim of this study was to identify genetic aberrations associated with radiation response in cell lines derived from head and neck squamous cell carcinomas (HNSCC) using comparative genomic hybridization (CGH) for genome-wide screening. METHODS: Five cell lines derived from HNSCC were subjected to a single course of radiation (400 cGy) in parallel with a similarly handled, untreated control. Cellular response to radiation was determined on posttreatment days 1, 2, 3, 4, and 5 using a cell viability assay (MTT assay). Radiation response was defined as 35% or greater decrease in cell survival relative to control. Tumor doubling time was determined by cell counts performed at day 0 and 1 for each cell line. All experiments were done in quadruplicate. CGH analysis was performed by differentially labeling DNA from tumor and normal tissue with fluorescent agents. The labeled DNAs were simultaneously hybridized to normal metaphase chromosomes. Image analysis for fluorescence intensity along the entire length of each metaphase chromosome allowed generation of a color ratio, which was used to detect copy number changes. RESULTS: Radioresistance was identified in two of five cell lines. The tumor doubling time was not a predictor of radiation response. CGH identified a complex pattern of aberrations, with gain of 3q common to all cell lines. The number of genetic aberration was higher in radiation-sensitive cell lines than in radiation-resistant ones. No recurrent aberrations were unique to the radiation-resistant cell lines. Recurrent gains at 7p and 17q and losses at 5q, 7q, and 18q were unique to the radiation-sensitive cell lines. CONCLUSIONS: The number of aberrations identified by CGH analysis may be a predictor of radiation response. A large study of primary tumors is warranted to confirm this association and identify specific genetic aberrations associated with radiation response.

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BACKGROUND: This study was performed to assess the relationship between Hashimoto's thyroiditis and the development, presentation, management, and outcome of papillary thyroid carcinoma. METHODS: Two complementary analytic methods were used. The clinical study was a retrospective case-control study, including patients seen with papillary thyroid carcinoma presenting during a 12-year period. We also used a systematic literature review to identify suitable reports and meta-analysis to statistically combine published results. RESULTS: The prevalence of Hashimoto's thyroiditis is significantly higher in patients with papillary thyroid cancer (odds ratio, 1.89; 95% CI, 1.02-3.50). These patients typically have a dominant nodule, 44% of which are discovered incidentally on routine examinations. Fine-needle aspiration has a sensitivity of 91% for the identification of papillary cancer. The prognostic variables at the time of a diagnosis of papillary cancer and the approach to management are not altered by the presence of coexistent Hashimoto's thyroiditis. In addition, the rate of surgical complications was not higher in patients with coexistent Hashimoto's disease. Meta-analysis suggested a positive correlation between Hashimoto's disease and disease-free survival (r = 0.09; 95% CI, 0.05-0.12) and overall survival (r = 0.11; 95% CI, 0.07-0.15). CONCLUSIONS: There is an increased prevalence of Hashimoto's thyroiditis in patients with papillary thyroid carcinoma. The presence of coexistent Hashimoto's thyroiditis does not affect the diagnostic evaluation or management of papillary thyroid cancers. The survival of patients who have papillary thyroid cancers may be superior in coexistent Hashimoto's thyroiditis.

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Recurrent pleomorphic adenomas (RPAs) of the parotid gland are an uncommon but challenging problem. The records of 31 patients with RPAs were reviewed to assess the clinical presentation and treatment results. More than half of these patients underwent total parotidectomy. Local control was achieved in 94% of patients at 7 years (median follow-up 7.3 years). Patients who had surgery for recurrence after a formal parotidectomy were more likely to have another recurrence (63% local control at 7 years) than patients whose initial procedure was a limited excision (100% local control at 7 years; P < 0.01). Better local control was seen in 11 patients who received postoperative irradiation (100% at 10 years) than in 20 patients who did not (71% at 10 years; P < 0.28). Adequate surgical resection yields an acceptable local control rate in patients with RPAs. Postoperative radiation therapy may improve control in patients at high risk for another recurrence.

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OBJECTIVE/HYPOTHESIS: Hemangiopericytomas are uncommon neoplasms of vascular origin that may arise in the head and neck. Their rare occurrence and variable malignant potential have limited attempts to characterize their clinical behavior. This study reviews the experience in treating hemangiopericytomas of the head and neck at a single institution. STUDY DESIGN: Retrospective. METHODS: The records of 12 patients with hemangiopericytomas of the head and neck presenting between 1979 and 1995 were reviewed. Site of origin included the neck (4), oral cavity (3), parotid (2), orbit (1), maxillary sinus (1) and mandible (1). Five patients had lesions characterized as high or intermediate grade histologically, and six had lesions characterized as low grade. RESULTS: Nine patients were treated with curative intent; three presented either with pulmonary metastasis (2) or unresectable primaries (1) and were treated with radiation therapy and/or palliative Adriamycin-based chemotherapy. Patients treated with curative intent underwent a variety of surgical resections dictated by tumor location and size. Four patients received postoperative radiation therapy to a median dose of 60 Gy, for positive surgical margins (2), high-grade histology (1) or a recurrent lesion (1). Five-year overall survival in patients treated surgically was 87.5%. A single mortality occurred in a patient with a recurrent high-grade lesion who failed at local, regional, and distant sites. Median follow-up of survivors was 73 months. CONCLUSION: The clinical behavior of hemangiopericytomas appears to be related to their histological grade. Aggressive local therapy including surgery and radiation therapy appears to be effective in providing tumor control.

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Unilateral vocal cord paralysis following pneumonectomy has profound effects on deglutition, phonation, protection of the airway, and generation of an adequate cough. If untreated in patients with limited pulmonary reserve, these detrimental effects can have devastating consequences. Several techniques are currently available which allow adequate medialization and rehabilitation of the paralyzed vocal cord. Adequate diagnosis and treatment can minimize the negative consequences associated with vocal cord paralysis following pneumonectomy.

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BACKGROUND: The preservation of viable parathyroid tissue, either by preserving parathyroid glands in situ with an intact blood supply or by autotransplantation, is an integral element of thyroid surgery. There is a general impression that nonviable parathyroid glands can be recognized on the basis of black or purple-black discoloration of the gland. We came to believe that this is not a reliable way to assess the viability of parathyroid glands because we observed that when we excised parathyroid glands (with the intention of reimplanting them) in situations where it was not feasible to preserve their blood supply, they did not become discolored. METHODS: To assess the status of the parathyroid blood supply, we performed incisional biopsies of suspected parathyroid glands during 14 consecutive thyroid operations (9 hemithyroidectomies, 1 completion thyroidectomy, 4 total thyroidectomies), and observed the biopsy site for evidence of active bleeding. RESULTS: Thirty-four of 36 possible parathyroid glands were histologically confirmed. Seventeen bled actively from the biopsy site and were preserved in situ. The other 17 were felt to be nonviable: 5 were severely discolored (black) and either no bleeding or minor venous oozing was seen when they were biopsied; 12 with normal coloration (3 were harvested prior to biopsy), did not bleed actively following an incisional biopsy. Parathyroid glands that were judged to be devascularized were autotransplanted into the sternocleidomastoid muscle. CONCLUSIONS: The absence of discoloration is not a reliable way to determine whether the parathyroid blood supply is intact. Biopsy of the parathyroid glands during thyroid surgery facilitates the identification of devascularized parathyroid glands that can be salvaged with autotransplantation.

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G207 is a multi-mutated, replication-competent type-1 herpes simplex virus designed to target, infect, and lyse neurological tumors. This study examines the feasibility of using G207 in the treatment of human colorectal cancer and defines the biological determinants of its antitumor efficacy. This virus was tested on five human colorectal cancer cell lines in vitro to determine efficacy of infection and tumor cell kill. These results were correlated to measures of tumor cell proliferation. In vivo testing was performed through direct injections of G207 into xenografts of human colorectal cancer tumors grown in flanks of athymic rats. To evaluate an alternate method of administration, hepatic portal vein infusion of G207 was performed in a syngeneic model of liver metastases in Buffalo rats. Among the five cell lines tested, infection rates ranged between 10% and 90%, which correlated directly with S-phase fraction (8.6%-36.6%) and was proportional to response to G207 therapy in vitro (1%-93%). Direct injection of G207 into nude rat flank tumors suppressed tumor growth significantly vs. control (0.58 +/- 0.60 cm(3) vs. 9.16 +/- 3.70 cm(3), P<0. 0001). In vivo tumor suppression correlated with in vitro effect. In the syngeneic liver tumor model, portal infusion resulted in significant reduction in number of liver nodules (13 +/- 10 nodules in G207-treated livers vs. 80 +/- 30 nodules in control livers, P<0.05). G207 infects and kills human colorectal cancer cells efficiently. In vitro cytotoxicity assay and tumor S-phase fraction can be used to predict response to treatment in vivo. This antineoplastic agent can be delivered effectively by both direct tumor injection and regional vascular infusion. G207 should be investigated further as therapy for colorectal cancer and liver metastases.

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This study evaluates inhibition of human squamous cell carcinomas (SCCs) by a replication-competent multimutated herpes simplex virus type 1 (G207). Infectivity and cytotoxicity of the G207 virus were evaluated in vitro in seven human SCC cell lines. In vivo effects of the G207 virus on human tumor xenografts in an athymic rat model were then investigated by injecting established tumors with 1 x 10(7) virus particles and monitoring tumor growth. In addition, oral cavity tumors in immunocompetent hamster were infected with the G207 virus by selective intraarterial perfusion and the tumor response was monitored. In vitro studies demonstrated infection rates, measured 24 hr after exposure, exceeding 40% at an MOI of 2 in five of seven human SCC cell lines. Cytotoxic effects, as measured by percent cell death on day 5, exceeded 90% in five of seven SCC cell lines. In vivo inhibition of tumor growth in an athymic rat model was seen (p < 0.005) and in two of the cell lines a complete clinical response was seen in 12 of 14 tumors. In the hamster model, selective intraarterial perfusion with G207 virus showed selective infection of the tumor cells, with sparing of the adjacent normal mucosa, which leading to significant suppression of tumor growth (p < 0.005). The G207 virus displayed efficient and selective cytotoxicity and tumor growth inhibition against human SCC and may prove useful as a therapeutic agent for head and neck SCC.

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Combined induction chemotherapy and external beam radiation therapy is an effective treatment for selected patients with advanced-stage laryngeal cancer. The larynx can be preserved in two-thirds of patients receiving this treatment. Investigations continue to evaluate the ideal treatment regimen, the delivery of chemotherapy, patient selection, biologic markers predicting response, functional outcome, and the effectiveness of this treatment at other sites.

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OBJECTIVE: To characterize clinical presentation and prognostic factors in patients with histologically proven regional lymph node metastasis from cutaneous squamous cell carcinoma of head and neck origin. DESIGN: Retrospective, nonrandomized case series. SETTING: Tertiary referral center. PATIENTS: Forty-five patients treated between 1984 and 1995 with regional metastatic squamous cell carcinoma of cutaneous head and neck origin. INTERVENTION: Forty-one patients underwent neck dissection (20 with parotidectomy) and 4 patients underwent parotidectomy alone. Thirty-six patients (80%) received postoperative radiation therapy with a mean dose of 60 Gy (range, 34-71 Gy). MAIN OUTCOME MEASURES: Recurrences and survival by univariate analysis using the Kaplan-Meier product-limit method. The log-rank test was used to evaluate prognostic significance of clinical variables. RESULTS: Follow-up ranged from 2 months to 10 years (mean, 21 months). Compared with historical controls, a greater percentage of patients in our population with regional lymph node metastasis had primary lesions greater than 2 cm in diameter and 4 mm deep. Overall 2- and 5-year survival rates were 33% and 22%, respectively, while 5-year disease-free survival rate was 34%. Clinical staging of the neck proved to be the only factor of prognostic value (P<.01). Treatment failures occurred in 22 patients. CONCLUSIONS: For the small subset of patients with regional metastasis from cutaneous squamous cell carcinoma, survival remains poor despite multimodality treatment. Clinical stage of the neck was the only factor that predicted outcome.

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OBJECTIVE: Evaluate wound healing of incisions created by the scalpel, electrocautery, CO2 laser, and potassium titanyl phosphate (KTP) laser in the upper aerodigestive tract in an animal model. STUDY DESIGN: Prospective randomized study in an animal model. METHODS: Postoperative oral intake, histologic depth of injury, and tensile mechanical strength were measured in rat tongues after creating incisions using a scalpel, electrocautery, CO2 laser, and KTP laser. An unpaired, two-tailed Student's t-test was used to compare results between the experimental groups. RESULTS: Oral intake, indirectly assessed by postoperative weight loss, by the third postoperative day was significantly decreased in the electrocautery (P = 0.004), CO2 laser (P = 0.001), and KTP laser (P = 0.0001) groups as compared with the scalpel group. The depth of the wound healing, as assessed by histologic examination, was successively greater for the scalpel (75 +/- 13 microm), electrocautery (110 +/- 10 microm), CO2 laser (145 +/- 10 microm), and KTP laser (195 +/- 23 microm) groups. However, this difference was only statistically significant for the CO2 laser (P = 0.006) and KTP laser (P = 0.01) groups relative to the scalpel group. Wounds created by the KTP laser had the lowest strength (76.5 +/- 6.9 kPa) as compared with the CO2 laser (156 +/- 28.4 kPa), electrocautery (153 +/- 15.7 kPa), and scalpel groups (249 +/- 61.8 kPa). This difference was only statistically significant for the KTP laser group (P = 0.02) when compared with the scalpel group. CONCLUSIONS: Wounds created in the upper aerodigestive tract of rats by scalpels result in the least postoperative weight loss, tissue destruction, and decrease in tensile strength, whereas wounds created by the KTP laser demonstrated a significantly greater postoperative weight loss, depth of wounding, and decrease in tensile strength.

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BACKGROUND: This study evaluates the efficiency of herpes simplex virus (HSV) mediated gene transfer in human squamous cell carcinoma (SCC) cell lines in vitro and in vivo when delivered by selective intra-arterial perfusion. METHODS: Human head and neck SCC were exposed to HSV-LacZ and HSV-interleukin-2 (IL-2) and gene transfer and expression assessed by X-gal staining and enzyme-linked immunosorbent assay, respectively. Hamster cheek pouch tumors were perfused with HSV-LacZ or HSV-IL-2, by microcannulating the external carotid artery, and gene transfer determined. RESULTS: A ratio of 5 viral particles per tumor cell achieved gene transfer rates exceeding 50%. Interleukin-2 levels of 287 +/- 17 to 424 +/- 8.4 ng per million cells were achieved at a ratio of 2 viral particles per tumor cell. Selective intra-arterial perfusion of the HSV-IL-2 vector yielded IL-2 levels of 45.8 +/- 17.0 pg per g tumor. CONCLUSIONS: HSV amplicon vectors are efficient vehicles for gene transfer in vitro in human head and neck SCC cell lines and in vivo when introduced by selective intra-arterial perfusion.

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BACKGROUND: This study defines the clinical settings in which extended radical neck dissection (ERND) was performed and determines its impact on control of disease in the neck and on survival. METHODS: We reviewed the records of 106 patients undergoing ERND between 1984 and 1993. Most (76) had metastatic squamous cell carcinoma (SCC) that had extended to extranodal structures in the upper neck. RESULTS: Five-year disease-free survival was 39%, and disease was controlled in the neck in 72 patients (68%) with a median follow-up of 5.5 years. A trend toward better survival was seen in patients with SCC (47% at 5 years), compared with those with other histologies (24% at 5 years; P <0.12). Patients with levels I, II, or III involved had better survival (46% at 5 years) than those with level IV, V, or multiple levels involved (14% at 5 years; P <0.0088). Finally, when prior radiation therapy precluded additional irradiation of the neck, survival was only 22% at 5 years, compared with 47% for those who received postoperative radiation (P <0.017). CONCLUSIONS: Although advanced neck disease invading adjacent structures remains an ominous sign, neck control and 5-year survival were achieved in nearly one half of these patients when multimodality therapy was possible.

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The pathobiology of salivary neoplasms can best be studied in a model system that reflects the native state of the tumor. The present study describes the use of a three-dimensional collagen gel (organoid) system in which pleomorphic adenomas of the parotid gland were propagated in vitro. Five pleomorphic adenoma cultures were established as organoid gels and compared with touch-preparations or cryopreserved specimens of native tumor. The organoid cultures demonstrated normal DNA content, the expression of myoepithelial cell proteins, and the production of sulfated acid mucins; these cellular and secretory features mimicked those found in the archival specimens. Further, organoid cultures of pleomorphic adenoma could be initiated after monolayer culture, demonstrating that culture on a plastic support does not alter the nature of the cells. Development of an in vitro culture system that maintains the native state of pleomorphic adenoma is an important tool for studying the pathobiology of these tumors.

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HYPOTHESIS: The hypothesis tested in this article is that if cholesteatomas are a low-grade squamous cell neoplasm, then evidence of genetic instability, in the form of abnormal or aneuploid amounts of DNA, should be evident. BACKGROUND: Cholesteatoma is a destructive lesion of the middle ear and/or mastoid process that produces complications by erosion of the temporal bone. The clinical hallmarks of cholesteatomas, namely invasion, migration, uncoordinated proliferation, altered differentiation, aggressiveness, and recidivism, are traits typically associated with the neoplastic cell. However, there is little evidence to support or refute the speculation that cholesteatomas are a low-grade squamous cell neoplasm. the existence of defects in the genetic complement of the major cellular constituents comprising a cholesteatoma, fibroblasts and keratinocytes, would support the speculation that cholesteatomas are a neoplasm, since cancers commonly manifest quantitative and qualitative alterations in the normal euploid complement of genetic information, resulting in a cell that has an abnormal or aneuploid amount of DNA. METHODS: DNA content (ploidy) within cholesteatoma tissues was measured by flow cytometry and image analysis. RESULTS: The DNA content of 11 human cholesteatomas and nine postauricular skin specimens was analyzed using flow cytometry, while the DNA content of 10 cholesteatoma specimens was analyzed using image analysis. Interpretable data was obtained from 10 cholesteatoma specimens and six postauricular skin specimens. One cholesteatoma specimen demonstrated an abnormal aneuploid DNA content, whereas the remaining nine cholesteatomas and the six postauricular skin specimens demonstrated a normal euploid DNA content. CONCLUSIONS: We conclude that, due to the lack of overt genetic instability, as evidenced by the presence of a normal euploid DNA content, cholesteatomas are not low-grade neoplasms.

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Anterior rerouting of the intratemporal facial nerve in the infratemporal fossa approach is employed to access to the jugular bulb, hypotympanum, and lateral skull base, whereas posterior rerouting of the facial nerve, as employed in the transcochlear craniotomy, is most frequently used for surgery of the posterior fossa, cerebellopontine angle, prepontine region, and petrous apex. Facial nerve rerouting may lead to facial paresis or paralysis. This review of the literature is intended to define the physiologic "cost" of these procedures, so that the neurotologic surgeon can determine if the morbidity incurred in these techniques is worth the resultant exposure. Inconsistencies in reporting facial function places into question the validity of some of the cumulative data reported. Postoperatively, grades I-II facial nerve function was seen in 91% of patients undergoing short anterior rerouting, 74% of patients undergoing long anterior rerouting, and 26% of patients undergoing posterior complete rerouting. Although facial nerve rerouting allows unhindered exposure to previously inaccessible regions, it is achieved at the cost of facial nerve function. Facial nerve dysfunction increases with the length of facial nerve rerouted.

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