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A tissue field of somatic genetic alterations precedes the histopathological phenotypic changes of carcinoma. Genomic changes could be of potential use in the diagnosis and prognosis of pre-invasive squamous head and neck carcinoma (HNSCC) lesions and as markers for cancer risk assessment. Studies of sequential molecular alterations and genetic progression of pre-invasive HNSCC have not been clearly defined. Studies have shown recurring alterations at chromosome 9p21 (location of the CDKN2A) and TP53 mutations in the early stages of HNSCC. However, gene silencing via hypermethylation is still a relatively new idea in the development of HNSCC and little is known about the contribution of epigenetics to the development of neoplasia, its transformation, progression, and recurrence in HNSCC. This review examines the role of promoter hypermethylation of tumor suppressor genes in the progression continuum from benign papillomas to malignancy in HNSCC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective/hypothesis: To analyze vocal fold vibration after photofrin-mediated photodynamic therapy (PDT) for the treatment of Tis and T1N0M0 squamous cell carcinoma (SqCCa) tumors of the larynx. It was hypothesized that key attributes of vocal fold vibration would return to baseline within 1-6 months of treatment., Study Design: Retrospective., Methods: Laryngovideostroboscopic data were retrospectively analyzed for eight patients with Tis-T1N0M0 SqCCa tumors of the larynx treated with photofrin-mediated PDT. Baseline and posttreatment videostroboscopy images of select vibratory characteristics of the vocal folds were randomized and analyzed by a speech-language pathologist and fellowship-trained laryngologist specializing in voice disorders., Results: Significant improvement in mucosal wave (P=0.003) and amplitude of vibration (P=0.004) occurred at greater than or equal to 20 weeks post-PDT compared with baseline. Comparing results within 5 weeks postprocedure to 10-19-weeks postprocedure revealed significant improvement in amplitude of vibration (P=0.013) and nonvibrating portion of the vocal fold (P=0.020). Comparing results within 5-weeks postprocedure to 20 or more weeks postprocedure revealed significant improvement in amplitude of vibration (P=0.001), mucosal wave (P=0.001), and nonvibrating portion of the effected fold (P=0.001)., Conclusion: Photofrin-mediated PDT allows for preservation of function and structure of the larynx without systemic toxicity; however, it may take 4-5 months or more for key vibratory characteristics of the vocal folds to recover posttreatment., (Copyright © 2013 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Background: Auditory disorders associated with substance abuse are rare. Hearing loss secondary to heroin and hydrocodone abuse has been described variously as not always responsive to steroid management, as not always reversible, and in some cases, as nonresponsive profound sensorineural hearing loss requiring cochlear implantation. We present a case of a teenager with sudden-onset moderate to severe bilateral sensorineural hearing loss after documented polysubstance "binging." The hearing loss improved substantially after high-dose steroid and vasoactive therapy., Purpose: The purpose of this report is to describe the hearing disorder of a patient who had awakened with a bilateral severe hearing loss following a night of recreational drug abuse., Research Design: Case report and review of the literature., Data Collection and Analysis: The subject of this report is an 18-yr-old patient with a history of substance abuse. Data collected were magnetic resonance /computed tomography brain imaging; metabolic, infectious disease, and autoimmune evaluation; and extensive audiologic evaluation, including pure-tone and speech audiometry, immittance measures, distortion-product otoacoustic emissions, and auditory brainstem response testing. Serial audiograms were collected for 10 mo following the onset of symptoms., Results: Two days of polysubstance abuse (heroin, benzodiazepine, alcohol, and crack [smoked cocaine]) resulted in moderately severe sensorineural hearing loss bilaterally. The loss responded to a 1 mo course of high-dose prednisone and a 10 mo course of pentoxifylline. Hearing sensitivity subsequently improved, leaving only residual high-frequency sensorineural hearing loss., Conclusions: This case report highlights the importance of "recreational" drug abuse in the evaluation of sudden hearing loss. Potential etiologies include altered pharmacokinetics, vascular spasm/ischemia, encephalopathy, acute intralabyrinthine hemorrhage, and genetic polymorphisms of drug-metabolizing enzymes., (American Academy of Audiology.)

INTRODUCTION: This study examined the contribution of promoter hypermethylation to the pathogenesis of respiratory papillomatosis (RP), including recurrences (RRP) and progression to squamous cell carcinoma (SSC). MATERIALS AND METHODS: A retrospective cohort of 25 laryngeal papilloma cases included 21 RRP, two of which progressed to SCC. Aberrant methylation status was determined using the multi-gene (22 tumor suppressor genes) methylation-specific multiplex ligation-dependent probe amplification assay and confirmed using methylation specific PCR. RESULTS: Twenty genes had altered DNA methylation in 22 of 25 cases. Aberrant methylation of CDKN2B and TIMP3 was most frequent. Promoter hypermethylation of BRCA2, APC, CDKN2A and CDKN2B was detected in 2 RRP cases with subsequent progression to SCC. Of the 25 cases, 22 were positive for HPV-6, 2 for HPV-11 and 1 for HPV-16 and 33. CONCLUSIONS: Consistent aberrant methylation of multiple tumor suppressor genes contributes to the pathogenesis of laryngeal papillomas. Persistent aberrant DNA methylation events in 2 RRP cases that progressed to cancer indicate an epigenetic monoclonal progression continuum to SCC.

Objectives: To evaluate the efficacy of dihematoporphyrin ether (PHOTOFRIN)-mediated photodynamic therapy (PDT) for the treatment of diffuse field cancerization and Tis-T2N0M0 squamous cell carcinoma (SqCCA) of the oral cavity and oropharynx in patients not amenable to or that have failed conventional head and neck cancer treatment., Methods: This is a retrospective study of 30 patients with Tis-T2N0M0 SqCCA of the oral cavity/oropharynx treated with PDT. Intravenous PHOTOFRIN (porfimer sodium) (dose 2.0 mg/kg) was administered outpatient, followed 48-60 hours later by intraoperative photoactivation at 630 nm via fiberoptic microlens surface delivery (light dose 50-100 J/cm(2)) or interstitial implantation via cylindrical diffuser fiberoptic delivery (light dose 50-100 J/cm)., Results: Twenty-four of 30 patients (80%) have demonstrated complete remission (follow-up 3-144 months). There were six patients who had partial remission with recurrence observed at 3, 3, 5, 9, 23, and 26 months subsequently retreated with conventional therapy. Eleven of 24 patients were cancer disease free at 2 years following PDT., Conclusion: PDT provides a surgical oncologic modality for potentially curative treatment of early stage oral cavity and oropharyngeal malignancies either as a primary modality or for treatment in patients that have previously failed surgery and/or radiation therapy.

Benign inverted papillomas have been reported as monoclonal but lacking common genetic alterations identified in squamous cell carcinoma of the head and neck. Epigenetic changes alter the heritable state of gene expression and chromatin organization without change in DNA sequence. We investigated whether epigenetic events of aberrant promoter hypermethylation in genes known to be involved in squamous head and neck cancer underlie the pathogenesis of sinonasal papillomas. Ten formalin-fixed paraffin DNA samples from three inverted papilloma cases, two exophytic (everted) papilloma cases, and two cases with inverted and exophytic components were studied. DNA was obtained from microdissected areas of normal and papilloma areas and examined using a panel of 41 gene probes, designed to interrogate 35 unique genes for aberrant methylation status (22 genes) using the methylation-specific multiplex-ligation-specific polymerase assay. Methylation-specific PCR was employed to confirm aberrant methylation detected by the methylation-specific multiplex-ligation-specific polymerase assay. All seven cases indicated at least one epigenetic event of aberrant promoter hypermethylation. The CDKN2B gene was a consistent target of aberrant methylation in six of seven cases. Methylation-specific PCR confirmed hypermethylation of CDKN2B. Recurrent biopsies from two inverted papilloma cases had common epigenetic events. Promoter hypermethylation of CDKN2B was a consistent epigenetic event. Common epigenetic alterations in recurrent biopsies underscore a monoclonal origin for these lesions. Epigenetic events contribute to the underlying pathogenesis of benign inverted and exophytic papillomas. As a consistent target of aberrant promoter hypermethylation, CDKN2B may serve as an important epigenetic biomarker for gene reactivation studies.

Objective: To investigate the contribution of promoter methylation-mediated epigenetic events in recurrent respiratory papillomatosis tumorigenesis., Design: Archival tissue DNA, extracted from microdissected papilloma lesions, was interrogated for methylation status by means of the novel, multigene methylation-specific multiplex ligation-dependent probe amplification assay., Subjects: Fifteen subjects with recurrent respiratory papillomatosis, 3 females and 12 males, all with adult onset of illness (age range, 23-73 years) except for 1 female patient with juvenile onset (1 year old)., Results: Promoter hypermethylation was recorded in 14 of 15 cases, and 19 of 22 unique methylation-prone cancer genes in the multigene panel had altered DNA methylation in at least 1 laryngeal papilloma biopsy specimen. Identical abnormally methylated genes were found in 5 of 15 recurrent cases, of which the CDKN2B gene was hypermethylated in all 5 cases. Dissimilar epigenetic events were noted in the remaining cases., Conclusions: A clonal origin was derived for 5 of 15 recurrent respiratory papillomatosis biopsy specimens based on identical epigenetic events. The high frequency of epigenetic events, characterized by consistent promoter hypermethylation of multiple tumor suppressor genes, points to the use of gene silencing mechanisms in the pathogenesis of recurrent respiratory papillomatosis.

Background and Objective: To determine the efficacy of PHOTOFRIN-mediated photodynamic therapy (PDT) for treatment of diffuse "field cancerization" of the oral cavity and Cis-T2N0M0 squamous cell carcinoma (SqCCa) of the larynx in patients not amenable or that have failed conventional head and neck treatment., Study Design/materials and Methods: Over the past 15 years 10 patients with early stage Tis-T2N0M0 SqCCa of the oral cavity and oropharynx and 10 patients with Tis-T2N0M0 SqCCa of the larynx were treated. Intravenous PHOTOFRIN (porfimer sodium) (dose 2.0 mg/kg) was administered outpatient, followed 48-60 hours later by intraoperative light photoactivation at 630 nm via fiberoptic microlens (ML) delivery (surgical light dose, 50-100 J/cm(2)) and/or cylindrical diffuser (CD) delivery (80-100 J/cm)., Results: Complete responses (CRs) (follow up 6 months-9 years) were achieved in eight of 10 patients with diffuse field cancerization of the oral cavity. CRs (follow up 6 months-8 years) were achieved in eight of 10 patients with superficial laryngeal cancer obviating the need for total laryngectomy in previously treated radiation therapy patients., Conclusion: PHOTOFRIN-mediated PDT provides a surgical oncologic modality for potentially curative treatment of early stage oral cavity and laryngeal malignancies with minimal side effects, absence of systemic toxicity, preservation of oral function and voice quality, with multiple drug administration, and laser light retreatment capability., (Copyright 2001 Wiley-Liss, Inc.)

Background and Objectives: Pretreatment prostate-specific antigen (PSA) levels may be of prognostic significance for patients with prostate cancer. Posttreatment PSA data are more limited. This study was undertaken to examine the prognostic role of pretreatment and posttreatment PSA levels in the radiation treatment of patients with carcinoma of the prostate., Methods: One hundred one patients who received primary radiation therapy at UCLA between 1988 and 1992 for clinical stage A to D1 prostate cancer were analyzed. Included were 4 patients with stage A, 77 with stage B, 16 with stage C, and 4 with stage D. All patients had pretherapy and posttherapy PSA values. Patients received definitive radiation therapy with photons (81), neutrons (13), or interstitial implant (7). Correlations were made with other prognostic factors and treatment outcome., Results: Median follow-up was 28 months. At last follow-up, 64% were without evidence of disease, 17% had rising PSA profiles or failure of PSA to normalize (chemical failure), and 19% had local recurrence and/or distant metastases. The 4-year overall survival was 85%, whereas actuarial survival free of chemical or clinical failure was only 32%. Pretreatment PSA levels and posttreatment PSA level normalization at 6 months correlated significantly with disease-free survival. On univariate analysis, pretreatment PSA levels correlated significantly with stage, high versus low Gleason score, and outcome. Posttreatment PSA level normalization at 6 and 12 months correlated with stage, pretreatment PSA level, and outcome, but not with Gleason score. Only PSA level normalization at 6 months and age were independent variables using multivariate analysis. PSA nadir values differed significantly between patients free of disease and those who failed., Conclusions: In our analysis, posttreatment PSA levels were independently predictive of outcome, whereas pretreatment PSA levels, while correlating with other prognostic factors, were not independently predictive. Given the prognostic value of posttreatment PSA levels, it is appropriate that chemical failures be included in outcome analyses, although this will lower disease-free survival.

Background: Radiation recall refers to a tissue reaction produced by a chemotherapeutic agent in a previously irradiated field that would not occur in a nonirradiated field. A number of agents have been reported to cause radiation recall. Recently, there have been case reports of recall dermatitis from paclitaxel treatment., Methods: A patient with metastatic lung cancer received palliative radiation to her mediastinum and ribs. Because of disease progression, she subsequently received paclitaxel., Results: After paclitaxel administration, the patient became acutely dyspneic. A subsequent chest X-ray revealed a parenchymal opacity in a region that corresponded with the patient's radiation portal. She also developed a severe skin reaction in the previously treated electron field., Conclusions: This is one of few reported cases of recall dermatitis from paclitaxel and is also suggestive of recall pneumonitis, a phenomenon previously unreported to the authors' knowledge. Given paclitaxel's ability to function as a radiosensitizer, this response is not unexpected. As the frequency of paclitaxel administration increases, its potential as a radiation sensitizer and radiation recall should be considered.

This chapter summarizes the reported ototoxicity data on the most clinically important ototoxic chemotherapeutic agents, notably emphasizing the oto(neuro)toxicities of the more commonly administered platinum compounds, cisplatin and carboplatin. Currently, in the United States, the only other marketed ototoxic chemotherapeutic agents are nitrogen mustard, alpha-difluoromethyl ornithine (DFMO), and the vinca alkaloids (vincristine and vinblastine sulfate); for these groups, animal ototoxicity data is sparse, and audiovestibular records of human ototoxicity are not available from most prospective, randomized controlled clinical trials. Future phase I, II, and III clinical oncologic trials of "experimental" chemotherapeutic agents should include methodology for audiovestibular monitoring, just as present FDA-approved cancer protocols with either monotherapy or combined therapy of known "ototoxic" agents should include standardized audiovestibular assessment in the database. Finally, continued clinical application of cisplatin alone or in combination with other chemotherapeutic agents in the successful treatment of solid tumors mandates decreasing or eliminating specifically the dose-dependent sensorineural hearing loss (partially in cases of complete or long-term partial remission) in addition to other common antiproliferation-induced side effects (nephritis, peripheral neuropathy, intractable nausea and vomiting, electrolyte imbalance, anaphylactic-like reactions, and myelosuppression). Because of the chemotherapeutic superiority of cisplatin, it is essential to continue to investigate methods of altering the dose-limiting oto(neuro)toxicity without causing a "counterproductive" reduction of the antitumor activity of cisplatin (or other second- or third-generation ototoxic platinum agents).

Cis-diamminedichloroplatinum II (cisplatin), a divalent platinum compound and potent cell-cycle nonspecific chemotherapeutic agent, produces a dose-limiting, permanent, high-frequency sensori-neural hearing loss and peripheral neuropathy, and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. The potential for dose-limiting and permanent cochlear (neuro) toxicity remains despite present methods of hypertonic saline, prehydration, and mannitol diuresis prior to drug administration. The exact mechanism(s) of ototoxicity and/or nephrotoxicity are still unknown. Continued aggressive high-dose cisplatin chemotherapy necessitates the investigation of ways to decrease the dose-limiting side effects that inhibit the administration of cisplatin at therapeutic and tumoricidal doses. This multifaceted project investigates two categories of potential inhibitors of cisplatin toxicity that, when coadministered with a known tumoricidal and ototoxic dose of cisplatin, will decrease or inhibit the ototoxicity: 1. phosphonic acid antibiotics (fosfomycin; 1,2 epoxypropylphosphonic acid); 2. nonglucocorticoid 21-aminosteroids, which are free oxygen radical scavengers (LAZAROIDS: U74006F and U78517F). This project also investigates the role of pigmentation as a variable affecting the evaluation of platinum-induced ototoxicity in the guinea pig animal model. Identification of an optimal animal model for future cisplatin toxicity research should be based on previously established species-specific differences in total drug dose, systemic toxicity, and morphological and functional evidence of cochlear toxicity, as affected by differences in pigmentation and drug tolerance. Cytocochleography, brainstem auditory evoked response (BSER), scanning and transmission electron microscopy of organ of Corti and the stria vascularis, double-blind light microscopy of renal, small intestine, and peripheral nerve tissue, and gamma-emission analysis of 195Mplatinum localization in inner ear neuroepithelium and the stria vascularis are used in the global evaluation of the ototoxic effects of cisplatin in both the adult albino and pigmented guinea pig.

The purpose of this study was to assess the protective effects of allopurinol, a blocker of free oxygen radical (FOR) formation, and superoxide dismutase-polyethylene glycol (SOD-PEG), a scavenger of FORs, on ischemic and reperfusion-induced cochlear damage. Fifteen Wistar Kyoto rats (WKY) were randomly assigned to three groups: (1) a control group (5 animals) that was exposed to 15 minutes of cochlear ischemia by clamping the anterior inferior cerebellar artery (AICA), followed by 15 minutes of reperfusion as documented by laser Doppler flowmetry; (2) a drug-treated group (5 animals) that received allopurinol before ischemia/reperfusion; and (3) a drug-treated group (5 animals) that received SOD-PEG before ischemia/reperfusion. In the control group, the tone burst-evoked compound action potential (CAP) recorded from the round window (RW) of the cochlea was abolished, and the cochlear microphonic (CM) was reduced after ischemia. In contrast, both allopurinol and SOD-PEG-treated animals showed post-reperfusion sensitivity in CAP and CM measures. We interpret these results to indicate that damage to the cochlear from ischemia and subsequent reperfusion can be attenuated by pretreatment with allopurinol or SOD-PEG. This provides indirect evidence that FORs may be partially responsible for cochlear damage resulting from ischemic conditions.

High-performance liquid chromatography was used to determine 19 free amino acid concentrations in perilymph, serum/plasma, and red blood cell intracellular fluid. Significant differences were found between perilymph and these fluids. Free amino acid analysis was then used to quantitatively analyze middle ear microaspirates in order to test the hypothesis that perilymph is a potential source of clear fluid in perilymphatic fistulas (PLF). Fourteen unknown samples from patients with visually identified PLF, including patients with no identifiable otic capsule defect, were studied. Six samples on amino acid pattern analysis were correlated most similarly with perilymph (rrho greater than 0.95). Four of these six samples were scored on the basis of quantitative amino acid values as similar to perilymph. However, three samples of clear fluid were more similar to serum/plasma than to perilymph on both amino acid pattern and quantitative amino acid score analysis. These results objectively suggest perilymph as a potential source of clear fluid in some patients with a diagnosis of PLF. Not all clear fluid observed in the middle ear, however, is potentially perilymph.

The most common complication resulting from cochlear implant surgery involves the skin flap: scalp breakdown, flap necrosis, and implant exposure requiring explantation. A 5.4 percent flap complication rate has been reported with the C-shaped postauricular flap (anteriorly-based on the superficial temporal and occipital arteries) in contrast to a 0 percent flap complication rate with the Australian inverted U-flap (inferiorly-based on the occipital artery). The literature is scant concerning detailed management of flap necrosis in order to obviate cochlear implant removal. Presented is an illustrative case of full thickness C-shaped flap necrosis with resultant exposure of a Nucleus multichannel implant. Successful wound management required pre- and postoperative hyperbaric oxygen in conjunction with a transposition flap closure of the scalp defect. Cochlear explantation was not necessary and rehabilitation and implant function were excellent 18 months postoperatively.

Controversy prevails regarding the accuracy of the clinical diagnosis of perilymphatic fistula (PLF). The diagnosis of PLF has been based on the subjective evaluation of vestibular function tests and the intraoperative macroscopic visualization of "clear fluid" from the oval/round windows at the time of exploratory tympanotomy. However, the subjective visual characterization of PLF varies among observing surgeons. Furthermore, perilymph can be "contaminated" with serum, blood, cerebrospinal fluid (CSF), and local anesthesia. This article presents a scientific biochemical microassay for the free amino acid profile of perilymph. Microaliquots of uncontaminated perilymph were sampled from the bilateral round windows (scala tympani) of 20 guinea pigs and analyzed for 19 free amino acid concentrations (FAAC) by high-performance liquid chromatography (HPLC). These samples were compared with the FAAC of guinea pig serum samples. Perfect predictor value ranges were nonoverlapping for 12 of 19 free amino acids in perilymph vs. plasma. Amino acid microassay of middle ear fluid for verification of "true" perilymph vs. nonperilymph fluids by the identification of nonoverlapping FAA markers may allow scientific verification of the existence of PLF in "suspected" patients.

Hyperbaric oxygen (HBO) has proven efficacious in the adjunct management of selected otolaryngologic problems: radiation therapy-induced osteoradionecrosis of the temporal bone, malignant external otitis, mandibular osteoradionecrosis and refractory osteomyelitis, soft tissue head and neck necrotizing fasciitis, compromised skin flaps and grafts, acute air or gas embolism, and otologic barotrauma. Herein is described the management of an insidious Staphylococcus aureus osteomyelitis of the temporal bone by pre- and postoperative HBO in conjunction with surgical debridement. The possible application of angiogenic agents and tetracycline bone-labeling in combination with hyperbaric oxygen therapy in the management of refractory neurotologic disease will be discussed.

Angioedema is a disorder characterized by well-demarcated nonpitting edema involving the tongue, floor of the mouth, larynx, lips, and face. This condition can progress to upper airway obstruction and death. Angiotensin-converting enzyme inhibitors (ACEIs), relatively new antihypertensive agents, act by blocking the formation of angiotensin II, a potent vasoconstrictor and stimulator of aldosterone formation. ACEIs also retard the breakdown of bradykinin, a potent vasodilator, which may lead to the edema seen in nonhereditary angioedema. These ACEIs include enalapril, captopril, lisinopril, saralasin acetate, and a combination of ACEI with diuretics (for example, Capozide). From August 1987 to January 1989, we treated six patients with a nonhereditary form of angioedema related to ingestion of angiotensin-converting enzyme inhibitors. Symptoms developed in all patients within 12 hours after their initial dose of an ACEI. They presented with shortness of breath and dysphagia associated with tongue and floor of the mouth edema. Two of the six required intubation and monitoring in the surgical intensive care unit for 36 to 48 hours. Three required supportive treatment and observation in an intermediate care unit, and one received supportive care in the clinic and was discharged the same day. Specifically, treatment consisted of cessation of inciting agent, steroids, antihistamines, and epinephrine, if not otherwise contraindicated. Assays of C1 esterase inhibitor levels and C4 were normal in all six patients; this was important in order to rule out hereditary forms of angioedema. These cases will be discussed, including a review of the literature, methods of diagnosis, pathophysiology, and treatment of angioedema.

Since 1975, Phase I and II studies have demonstrated the successfulness of hematoporphyrin derivative photodynamic therapy in the treatment of various malignancies of the skin, eye, bladder, lung, and head and neck. Moreover, two cases of traditional Western cutaneous Kaposi's sarcoma (TKS) have been treated with photodynamic therapy with both early and late complete response. To date, attempts at cure and palliation of the more aggressive AIDS-related oral Kaposi's sarcoma with conventional radiation, chemotherapy or immunotherapy, or surgical excision have been limited and often associated with debilitating mucositis and further immunosuppression. Certain aspects of photodynamic therapy may be efficacious for treatment of Kaposi's sarcoma: (1) the selective retention of hematoporphyrin derivative by neoplastic lesions; (2) a tumor-specific cytotoxic agent (i.e., free oxygen radical); (3) absence of systemic toxicity from immunosuppression; and (4) the potential for retreatment without increasing side effects. Herein we present five cases of AIDS-related KS (EKS) with diffuse, superficial, and nodular oral lesions treated with dihematoporphyrin derivative and photodynamic therapy with subsequent dramatic early partial and complete responses.

Since 1975, photodynamic therapy has reportedly been effective in a variety of head and neck malignancies that failed traditional (conventional) therapy, including surgery, cryotherapy, chemotherapy, hyperthermia, and radiation therapy. Photodynamic therapy consists of the intravenous administration of (di)hematoporphyrin ether, a chemosensitizing drug selectively retained by neoplastic and reticuloendothelial tissues which, when exposed to a 630-nm argon laser, catalyzes a photochemical reaction to release free oxygen radicals, "the cytotoxic" agents responsible for cell death and tumor necrosis. Preliminary investigations have assessed the efficacy of photodynamic therapy in treatment of: (1) superficial "condemned mucosa" or "field cancerization" of the oral cavity and (2) stage III and IV head and neck carcinomas that had unsuccessful conventional therapy. Complete and/or partial remissions were obtained in 11 of 12 patients (16 treatments) with a variety of carcinomas of the nasopharynx, palate and uvula, retromolar trigone, temporal bone, cervical esophagus, and AIDS-related Kaposi's sarcoma of the oral cavity.

Hyperbaric oxygen (HBO) is an effective adjunct in the management of selected otolaryngologic problems including radiation-induced necrosis of the temporal bone, malignant external otitis, mandibular osteoradionecrosis and refractory osteomyelitis, soft tissue head and necrotizing fasciitis, compromised skin flaps and grafts, acute air or gas embolism, and otologic barotrauma. We describe the management of a patient with insidious Staphylococcus aureus osteomyelitis of the temporal bone by the use of HBO preoperatively and postoperatively in conjunction with surgical debridement. The possible application of angiogenic agents and tetracycline bone-labeling in combination with HBO therapy in the management of refractory neurotologic disease is discussed.

Otosclerosis classically describes an osteodystrophic change in the bony labyrinth and stapes footplate, of autosomal dominant inheritance, reported rare under the age of 5, extremely "rare" in the Oriental and Black race, "non-existent" in the American Indian, and with a clinical incidence of 5 per 1000 Caucasians. The differential diagnosis of a non-effusion conductive hearing loss in a child should include otosclerosis, congenital malleus or footplate fixation, tympanosclerotic fixation, congenital cholesteatoma, lysis of the incus long process, Paget's disease, osteogenesis imperfecta, and fibromuscular hyperplasia of the renal artery. Presented is a case report of a 14-year-old black male with bilateral clinical otosclerosis and a persistent stapedial artery. Preoperative multiple-frequency tympanometry and Zwislocki acoustic reactance and resistance analysis demonstrated absence of the "W" resonance pattern on high-frequency tympanometry and the classic friction and stiffness patterns of otosclerotic fixation. Repeat multiple-frequency tympanometry testing post-stapedectomy demonstrated prosthesis articulation. Prosthesis position can be monitored postoperatively by these acoustic impedance studies.

The continued chemotherapeutic application of cisplatin (cis-diamminedichloroplatinum [II]) necessitates reduction of its dose-limiting toxicity without decreasing its tumoricidal effect. This research project evaluated the efficacy of fosfomycin, a phosphonic acid antibiotic, in decreasing or ameliorating the ototoxicity (high frequency sensorineural hearing loss) and nephrotoxicity (renal tubular necrosis and interstitial nephritis) of cisplatin. Experimentally, fosfomycin effectively inhibits aminoglycoside-induced ototoxicity and nephrotoxicity in animals and humans. The efficacy of fosfomycin in blocking platinum-induced toxicity in the guinea pig was evaluated histologically and functionally using cytocochleography and light microscopy of the organ of Corti and the auditory brain stem evoked response (ABR), and light microscopy of renal corticomedullary tissues, small bowel, liver, lung, and peripheral nerve. The results demonstrate that fosfomycin ameliorates the acute renal tubular necrosis and interstitial nephritis and markedly inhibits the elevation of ABR thresholds and simultaneous outer hair cell loss that can result from cisplatinum administration. Fosfomycin should be considered a potential antidote for the dose-limiting ototoxicity and nephrotoxicity of cisplatin chemotherapy.

Synthetic second generation chemotherapeutic platinum analogs are presently being tested to identify an analog with greater antitumor activity, but less ototoxicity and nephrotoxicity than cisplatin. The objective of this study was to analyze potential vestibular effects of cisplatin and of the two platinum analogs, CBDCA (cis-diammine 1,1-cyclobutane dicarboxylato [2]-0,0(1) platinum or JM-8) and CHIP (cis-dichlorotrans-dihydroxy-bis(isopropylamine) platinum [IV] or JM-9) using scanning and transmission electron microscopy of vestibular neuroepithelium from the albino guinea pig. Vestibular neuroepithelial damage was not demonstrated in either cisplatin- or the analog-treated animals when administered at equitoxic doses.

Thirty-two cases of sudden, symmetrical, high-frequency, sensorineural hearing loss associated with intravenous (IV) and oral erythromycin therapy have been published since 1973. We treated a patient with reversible ototoxicity associated with IV erythromycin for the treatment of legionnaire's disease.

Guinea pigs were pretreated IP with cisplatin (10 mg/kg) for various times before IV administration of 195mPt-labeled cisplatin. Concentrations of 195mplatinum were greater in tissues of pretreated animals than in those of control animals. Amounts of 195mplatinum in subcellular fractions from pretreated rabbits were similarly greater in pretreated animals. Amounts of radioactivity appeared to be greatest in animals receiving a larger number of pretreatment injections, even though the total amount of cisplatin administered was equal in all groups. BUN was elevated on day 1 after the radioactive dose only in those animals which had been pretreated. Urinary excretion of platinum was significantly less in pretreated than in control animals. It appears that pretreatment with cisplatin damages the kidney severely enough for subsequent doses of cisplatin not to be excreted as efficiently, thus leading to a greater tissue deposition of platinum in pretreated animals.

Sinus histiocytosis with massive cervical lymphadenopathy (SHML) was originally described in 1969 as a benign clinicopathologic entity characterized by massive bilateral cervical lymphadenopathy, fever, leukocytosis, elevated ESR, and hypergammaglobulinemia, usually occurring within the first two decades of life. We present an illustrated case of an elderly patient with polyclonal hypergammaglobulinemia and a 2-year history of multilobulated cervical and submandibular lymphadenopathy. The etiology and pathogenesis of SHML are not known. Diagnosis requires lymph node biopsy to exclude other causes of cervical lymphadenopathy such as malignant lymphoma, malignant histiocytosis, metastatic carcinoma, and tuberculous lymphadenitis. Histologic examination shows marked dilatation of subcapsular and medullary lymph node sinuses containing large, foamy or vacuolated histiocytes. Although no curative treatment is known, corticosteroids, radiation therapy, vinblastine and oral cyclophosphamide, and surgery have been used to palliate constitutional symptoms and mechanical obstruction from massive lymphadenopathy. Since one third of SHML patients have evidence of disease for 5 years, and a mortality rate of 7% exists with benign histologic disease, all patients with SHML should be carefully screened for evidence of immunodeficiencies that may precipitate a fatal outcome.

Recreational cocaine abuse via intranasal "snorting," "free-base" smoking, "body-packing," or intravenous injection can be lethal. Increasing illicit use of cocaine hydrochloride and the misuse of legal over-the-counter (OTC) nasal drugs are known causative agents of nasal septal perforation with loss of taste and smell. Although 2 to 3 mg/kg is the recommended maximum dose for topical anesthesia, cocaine snorters may use 1,000 mg or more daily on a "run." Furthermore, the newer route of smoking the extracted volatile "free-base" form of the adulterated street drug provides a plasma concentration producing the same physiological and subjective effects of intravenous cocaine. Presented are two cases exemplifying unusual complications of cocaine abuse: 1. total nasal septal bony and cartilaginous necrosis with resultant saddle-nose deformity and osteolytic sinusitis secondary to chronic intranasal "snorting" and 2. tracheobronchial rupture with pneumomediastinum secondary to smoking "free-base" cocaine.

Cis-diamminedichloroplatinum (cisplatin), a divalent platinum compound and cell-cycle nonspecific chemotherapeutic agent, produces a permanent high-frequency sensorineural hearing loss and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. Synthetic platinum analogs are presently being tested to identify an analog with greater antitumor activity, but less ototoxicity and nephrotoxicity than cisplatin. The objectives of this study were to analyze the potential cochlear and nephrotoxic effects of two synthetic platinum analogs presently in phases I and II of clinical trials, CBDCA [JM-8 or cis-diammine, 1,1-cyclobutane dicarboxylato (2)-0,0(1)-platinum (NSC-241240)] and CHIP [JM-9 or cis-dichloro-trans-dihydroxybisisopropylamine platinum IV (NSC-256927)]. Cytocochleography, auditory brain-stem evoked response (ABR), double-blind light microscopy of renal tissues, and gamma emission analysis of 195mpt localization in viscera and inner ear were employed in the evaluation of cisplatin and platinum analogs (JM-8 and JM-9) in adult guinea pigs. Final results indicate that the investigational chemotherapeutic analogs CBDCA (JM-8) and CHIP (JM-9) do not produce the ototoxicity and nephrotoxicity characteristic of cisplatin. Furthermore, these findings demonstrate 195mpt localization in the vestibular labyrinth and confirm previous platinum distribution studies in the organ of Corti and stria vascularis tissues.

The Waardenburg's syndrome, a congenital ectodermal germ layer defect of autosomal dominant inheritance with variable phenotypic expressivity consists of 6 major characteristics: dystopia canthorum, broad nasal root, hypoplasia of the medial eyebrow, heterochromia irides, white forelock, and congenital deafness. Twelve additional characteristics have been reported including meningocele, atresia of the esophagus, and Hirshsprung's disease supporting an early hypothesis that the neural crest is the embryonic site linking defects of the cervical sympathic system with pigmentary abnormalities and inner ear anomalies. Congenital deafness reported in 20% of Waardenburg patients, and the most disabling characteristic, has been associated with ENG abnormalities in 30% of these deaf patients. A congenitally deaf young person with Waardenburg's syndrome is examined for basic cause of episodic vertiginous symptoms. Diagnostic assistance from previous investigations is lacking because they have not involved state-of-the-art functional evaluations or correlations of behavioral and radiographic findings. In this patient, high-resolution computerized tomography failed to demonstrate bony labyrinthine anomalies. Functional cochleovestibular analysis revealed a bilateral profound sensorineural hearing loss and a unilateral weakness in oculomotor responses to caloric stimulations. Repeated measurements of ocular counterroll show variations compatible with intermittent otolithic dysfunctioning. These findings are consistent with a diagnosis of an acquired active unilateral peripheral vestibular disorder. Some of the technical issues underlying the derivation of this conclusion are discussed.

Covalent binding of platinum from the anticancer drug cisplatin has been determined in subcellular organelles from kidney and liver of guinea pig strains sensitive and resistant to the systemic toxicity of cisplatin. Organ distribution of platinum was similar between the two strains, but the sensitive animals (pigmented) excreted only half as much platinum in 24 hr as did the resistent animals (albino). Subcellular distribution of platinum in mitochondria, microsomes, and cytosol was approximately equal for both strains, but the sensitive animals had twice as much platinum bound covalently to cytosolic acid-insoluble protein as did the resistant animals. In the albino guinea pigs, concentrations of total platinum and of covalently bound platinum were greater in kidney subcellular organelles than in either liver or lung organelles, which may help explain the sensitivity of the kidney to the toxic effects of cisplatin.

Primary thyroid abscess arising from acute suppurative thyroiditis is an unusual type of head and neck infection. Only 39 cases of thyroid abscess have been reported in the medical literature since 1950. Sixteen of these cases (41%) were in children. This presentation reports in detail two additional adult patients with thyroid abscesses. In addition, the incidence, etiology, signs and symptoms, complications, aids to diagnosis, and management are reviewed. Systemic antimicrobials combined with prompt surgical intervention will prevent the serious complications possible with this disease.

Ototoxic and nephrotoxic potentiation with concomitant cis-diamminedichloroplatinum, or cis-platinum II (CSP), and aminoglycoside therapy was investigated in the guinea pig. We evaluated possible potentiation of the toxic effects of CSP and kanamycin compared with CSP alone in the inner ear and kidney and quantitatively localized CSP in the cochlea with gamma emission analysis of 195mPt. Kanamycin-treated animals demonstrated cytocochleograms and ABR waveforms, absolute latencies, and interwave latencies for waves I, II, and III similar to control animals at our maximum level of acoustic stimulation. CSP treatment produced 60% to 70% mean outer hair cell (OHC) loss in the basal turn of the cochlea, a reduction in ABR waveform and amplitude, and an increase in latencies of ABR waves I, II, and III. Combined CSP and kanamycin treatment produced 90% to 100% mean OHC loss in all rows of the basal turn of the cochlea, with no discernible ABR waveform corresponding to the region stimulated by a 4500 to 7000 Hz acoustic click. Combined treatment produced the most significant cortical medullary tubular necrosis and interstitial nephritis. Furthermore, this study reports for the first time localization of platinum in the inner ear.

A rare congenital autosomal dominant syndrome of thickened bilateral lop auricles, conductive hearing loss, ossicular anomalies, and micrognathia is reported. The anomaly is presumably a defect in the first and second branchial arch development during the sixth and seventh weeks of gestation with an auricle abnormality (first and second arch), abnormal incus and malleus (first and second arch), abnormal stapes (second arch), and micrognathia (first arch). Recognition of low-set or malformed auricles with a unilateral or bilateral conductive hearing loss should alert the otolaryngologist to possible middle ear abnormalities and other associated branchial cleft anomalies. Surgical correction of the congenital conductive hearing loss may include prosthetic ossicular reconstruction and otoplasty. The possibility of associated congenital anomalies of other systems (for example, vestibular, cardiac, genitourinary, reproductive, and so on) should be evaluated. An accurate pedigree and family medical and genetic history should be obtained to screen for other involved family members and for assessment of genetic passage of the trait.

This is a first report of primary hyperparathyroidism (HPT) masquerading as a destructive fibrous sphenoid sinus "Brown tumor" associated with progressive blindness and hypercalcemia. Diagnosis of a Brown tumor was delayed despite serial computerized tomography of the head and repeated transnasal and transethmoid sphenoid biopsies demonstrating diffuse fibrosis. Only detection and medical evaluation of hypercalcemia, demonstrating elevation of both serum calcium and C-terminal parathyroid hormone with an elevated chloride/phosphate ratio, prompted neck exploration, thus confirming a solitary left superior parathyroid adenoma. Postoperative normocalcemia occurred synchronously with the return of light perception and the arrest of sphenoid sinus and parasellar erosion. Although maxillary Brown tumors of secondary HPT have been reported, this is the first report of osteitis fibrosa of the sphenoid sinus. Differential diagnosis of an erosive sphenoid lesion with cranial nerve dysfunction, exclusive of inflammatory or vascular disease, should include sarcoidosis, primary and metastatic sphenoid carcinoma, fibrous dysplasia, giant cell reparative granuloma, midline lethal granuloma, chordoma, and chondrosarcoma. Furthermore, the bony destructive lesions with concomitant hypercalcemia of sarcoidosis and HPT are distinguishable by radiographic and laboratory analyses and by the Dent corticosteroid suppression test. Hypercalcemia of primary HPT is associated with elevated serum C-terminal parathormone, osteitis fibrosa, a negative Dent test, and a chloride/phosphate ratio greater than 33 in 94% of primary HPT patients. Hypercalcemia of sarcoidosis is associated with a normal or decreased C-terminal parathormone assay and a positive Dent test, as well as elevated serum immunoglobulins and erythrocyte sedimentation rate, and a positive angiotensin-converting enzyme assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypercalcemic crisis is a rare but often fatal complication of hyperparathyroidism (HPT). The reported mortality of 60% has been related to delay in diagnosis and appropriate treatment. During a 16-year period (1961 to 1977), 29 patients with severe symptomatic hypercalcemia caused by primary HPT were treated at the Surgical Service at the University of Michigan Hospital. This group represents 6% of the patients with primary HPT treated during this period. All but one patient had an exploration of the neck when the serum calcium level had been decreased to 12 mg/100 ml by intravenous hydration with saline, furosemide diuresis, and mithramycin when a hypocalcemic agent was required. One comatose patient died of irreversible shock. All of the 28 patients who had parathyroidectomies survived the early postoperative period. One patient died three weeks later of a myocardial infarction. This study demonstrates that emergent nonoperative care of parathyroid crisis, followed promptly by parathyroidectomy, can be successful in nearly all cases.