Vanessa G. Schweitzer

Cisplatin-Induced Ototoxicity: The Effect of Pigmentation and Inhibitory 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.

Osteolytic sinusitis and pneumomediastinum: Deceptive otolaryngologic complications of cocaine abuse

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.

Ototoxicity of cisplatin vs. platinum analogs CBDCA (JM-8) and CHIP (JM-9).

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)-0,01-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.

Ototoxic and nephrotoxic effects of combined treatment with cis-diamminedichloroplatinum and kanamycin in the guinea pig.

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.

Sarcoidosis, Hypercalcemia and Primary Hyperparathyroidism The Vicissitudes of Diagnosis

Abstract Two cases of coexistent sarcoidosis and primary hyperparathyroidism are reported from the University of Michigan Medical Center from a series of 600 consecutive cases of primary hyperparathyroidism. The histopathologic finding of noncaseating granulomas within a parathyroid adenoma in one patient has not been previously reported. Two additional patients with suspected primary hyperparathyroidism had sarcoidosis detected by paratracheal lymph node biopsy done at the time of neck exploration.

Waardenburg's syndrome: a case report with CT scanning and cochleovestibular evaluation.

The Waardenburgs 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 Hirshsprungs 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 Waardenburgs 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.

Free Amino Acid Analysis of Guinea Pig Perilymph: A Possible Clinical Assay for the PLF Enigma?

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.

Perilymphatic Fistula: Analysis of Free Amino Acids in Middle Ear Microaspirates:

High-performance liquid chromatography was used to determine 19 free amino acid concentrations in perilympyh, 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 > 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.

Disparate Molecular, Histopathology, and Clinical Factors in HNSCC Racial Groups

Objective: Causes of differences in the higher incidence of and mortality from squamous head and neck cancer (HNSCC) in African American (AA) vs Caucasian Americans (CA) lack a consensus. We examined a comprehensive array of risk factors influencing health and disease in an access to care, racially diverse, primary HNSCC cohort. Method: The study cohort of 673 primary HNSCC comprised 391 CA and 282 AA. Risk variables included demographic, histopathology, and clinical/epidemiologic risk factors. Tumor DNA was interrogated for loss and gain of 113 genes with known involvement in HNSCC/cancer. Univariate analysis was followed by multivariate modeling with determination of c-index. Results: Of the 39 univariate differences in race as AA and CA, multivariate modeling (c-index = 0.81) retained 6 variables (pCDKN2A) and aneupoidy of SCYA3 than CA tumors. AA were more likely to be unmarried, to have radiation treatment, and be more likely to be current and past smokers. Insurance type as HAP (Health Alliance Plan), Blue Cross, Medicaid, Medicare, and other was a significant determinant of race. AA were more likely to have Medicaid and Medicare. Insurance status by stage and radiation by stage were not significant. Conclusion: Molecular modeling indicated significant differences between AA and CA for histopathology, patient factors, and tumor gene copy number alterations. Our data reiterate that for HNSCC, as in the case of other complex diseases, tumor genetics or biology is only one of many potential contributors to differences among racial groups.

Photodynamic therapy for treatment of superficial oral cavity and laryngeal malignancies

incidence of between 0.4% and 5% for all cases being reported. A retrospective review of patients with tumors at the Department of Otolaryngology-Head and Neck Surgery of the Portsmouth Naval Medical Center was undertaken to assess the presentation, risk factors, treatment, and outcomes of patients between the ages of 18 and 45 years who had SCCA of the oral cavity and oropharynx. Methods: Four hundred seventy-eight patients with tumors were entered into our departments tumor database between 1975 and the end of 1996. Of the 127 patients with oral and oropharyngeal SCCA, 20 were between the ages of 18 and 45 years. Thirteen patients (10 men and three women) comprise the present series. All subjects were Caucasian. Histories were reviewed for tobacco and alcohol use. Nine of the 13 patients had oral cavity lesions; the remainder had oropharyngeal lesions. All patients had confirmed SCCA and the lesions were clinically staged according to American Joint Committee on Cancer criteria. Results: Among patients with oral cavity lesions, six had earlystage lesions and three had late-stage lesions, whereas patients with oropharyngeal lesions were evenly divided. Follow-up ranged from none/lost to 120 months. Twelve of the 13 patients had no evidence of disease at the time of their last visit; one died of his disease within 32 months of his initial treatment. Overall, 15% of patients with oral or oropharyngeal SCCA seen in our department were between the ages of 18 and 45 years. Conclusions: Our findings are consistent with those of others, which established a higher than expected incidence of oral SCCA in young adult women. However, they fail to support the commonly advanced View that SCCA has a tendency to be more aggressive in young adults compared with older patients. These findings emphasize the need for continued aggressive promotion of the prevention and cessation of tobacco and alcohol abuse among young people. Health care providers who encounter a young patient with a suspicious head or neck lesion must include malignancy in their differential diagnosis and seek early consultation with an otolaryngologist.