Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001.

OBJECTIVES: To summarize the findings relevant to otolaryngology from the annual meeting of the Blood-Brain Barrier Disruption Consortium in Gleneden Beach, Oregon, March 10, 2001. STUDY DESIGN: Summaries are provided by the speakers, as well as related data from the published literature. Findings in otology and oncology regarding ototoxicity that were discussed at the meeting are included. RESULTS: Data considered included physiological research, animal studies, and clinical trials that relate to platinum-based chemotherapy and prevention of toxicity. CONCLUSIONS: The dose-limiting side effects of platinum-based chemotherapy are preventable, but questions about the effect of the protective agents on oncological efficacy remain. Strategies for prevention of chemotherapy-induced toxicity include temporal or anatomical separation of cisplatin or carboplatin from sodium thiosulfate, D-methionine, or N-acetyl-cysteine. Clinical application of these methods has begun. The mechanisms presumably involve free radicals or drug conjugation, or both. Understanding the role of free radicals in medicine is likely to become important in the future.

Cisplatin ototoxicity in the Sprague Dawley rat evaluated by distortion product otoacoustic emissions.

The present study has evaluated the use of distortion product otoacoustic emission (DPOAE) responses in the detection of cisplatin-induced ototoxicity in a Sprague Dawley rat animal model. The cisplatin was administered as a 16 mg/kg, dose introduced by a slow 30-min intraperitoneal infusion. Data from three DP-gram protocols, DPOAE input-output responses at 8 kHz, and auditory brainstem responses (ABRs) at 8, 12 and 16 kHz were collected before and 72 h after treatment. The post-treatment ABRs at 16 kHz showed the greatest mean threshold shift of 33.6 dB. The post-treatment DP-gram data showed significant reduction of the signal to noise ratios in the majority of the frequencies tested, across all tested protocols. The data suggest that the most sensitive DPOAE procedure for the early detection of the cisplatin-induced ototoxic damage is the DPOAE I/O protocol. Morphological analyses indicated that the inner hair cells remained intact, while several types of alterations were observed in the arrangement of the stereocilia in the outer hair cells.

Evaluation of D-methionine as a cytoprotectant in cisplatin treatment of an animal model for ovarian cancer.

BACKGROUND: To evaluate the use of D-methionine(D-met) as a cytoprotectant in the context of clinically relevant doses of cisplatin. MATERIALS AND METHODS: Forty five Fischer rats were injected intraperitoneally with 10(6) NuTu-19 cells and treated as follows: group 1 was the control group and received no treatment, group 2 received cisplatin 4 mg/kg and group 3 received cisplatin 4 mg/kg plus D-met. There were two groups that received high dose cisplatin. Group 4 received cisplatin 8 mg/kg and group 5 received cisplatin 8 mg/kg plus D-met. Treatment was initiated four weeks after injection of the NuTu-19 cells, and consisted of four weekly intraperitoneal injections. Serum BUN and creatinine levels in the high dose groups evaluated nephrotoxicity and clinical outcome was measured by mean survival using Kaplan Meier analysis. RESULTS: There were no significant elevations in serum BUN or creatinine levels in any of the rats treated with high dose cisplatin. In the animals given cisplatin 8 mg/kg plus D-met, death from toxicity was prevented and all animals completed four treatments. In contrast, only two animals in group 4 (cisplatin 8 mg/kg alone) completed 4 treatments. There was a significant improvement in survival for the animals given D-met. (p = .0001) In all treated groups except for group 4, there was an improvement in survival compared to the control group. When comparing groups 2 and 3 (4 mg/kg +/- D-met), there was a subjective decrease in tumor response for group 3 but mean survival was not statistically different. (91 vs. 81 days; p = 0.07) A comparison of groups 2 and 5 revealed no survival benefit using high dose cisplatin with D-met. (91 vs. 79 days; p = 0.10). CONCLUSIONS: Our results indicate that D-methionine provides cytoprotection against cisplatin toxicity without significant compromise of antitumor activity. All though D-methionine allowed for significant dose intensification of cisplatin above standard doses, there was no survival advantage noted in this group of animals. The indications for its use in the treatment of ovarian cancer remain to be determined.

A semiquantitative analysis of the effects of cisplatin on the rat stria vascularis.

Cisplatin (CDDP) is a very effective chemotherapeutic agent but is highly ototoxic. Most studies have focused on the effects of CDDP on the outer hair cells. The purpose of this study was to examine changes in the stria vascularis in cisplatin treated male Wistar rats and to provide semiquantitative analysis of the results. We removed a section of the stria vascularis from the basal turn of five control and five CDDP (16 mg/kg) treated rats. Using transmission electron microscopy (TEM) we analyzed: (1) changes to the strial tissue as a whole; and (2) intracellular changes in the marginal cells. We also subjected the samples to semiquantitative analysis using the MCID, focusing on three aspects of strial profile abnormalities; the number of abnormal marginal cells in CDDP treated tissue, intracellular strial edema and densitometry. Controls appeared normal, but many pathologic changes were apparent in the experimental group. Results from the semiquantitative analysis indicate cisplatin has a deleterious effect on the stria vascularis including strial edema; bulging, rupture and/or compression of the marginal cells and depletion of the cytoplasmic organelles.

D-methionine provides excellent protection from cisplatin ototoxicity in the rat.

Cisplatin (CDDP) is a widely used chemotherapeutic agent. Unfortunately, CDDP is highly ototoxic. We tested D-methionine (D-Met), a sulfur containing compound, as an otoprotectant in male Wistar rats. Complete data sets were obtained for five groups of five animals each, including a treated control group (16 mg/kg CDDP), an untreated control group (administered an equivalent volume of saline) and three groups that received either 75, 150, or 300 mg/kg D-Met 30 min prior to the 16 mg/kg CDDP dosing. Auditory brainstem response (ABR) thresholds were obtained in response to clicks, and 1 kHz, 4 kHz, 8 kHz, and 14 kHz toneburst stimuli, before and 3 days after drug administration. Scanning electron microscopy (SEM) was used to examine the outer hair cells of the apical, middle and basal turns of the cochlea. Animal weight was measured on the first and final day. D-Met provided excellent otoprotection even at the lowest level with complete otoprotection obtained for the 300 mg/kg dosing as measured by both ABR and SEM. D-Met also markedly reduced weight loss and mortality. All animals receiving D-Met (15/15) survived to the end of the study period as opposed to only 5/10 of the treated controls.

Technical and editorial administration of a World-Wide-Web site during a period of rapid growth: the OncoLink experience.

OncoLink is a cancer information resource on the World-Wide-Web (WWW) that provides a wide variety of information for cancer patients and healthcare providers. Since its introduction in March, 1994 it has enjoyed success as demonstrated by an over 31-fold increase in usage as of February, 1996. Current utilization exceeds 1.1 million accesses per month. The content of OncoLink has also expanded greatly, with new items being added daily. In addition, OncoLink has been the recipient of numerous awards from a variety of agencies and organizations. During this period of rapid growth, the complexity of managing and maintaining OncoLink has likewise increased. This work may be divided into three categories: content editing, technical (or production) editing, and web site maintenance. Consequently, we have developed numerous administrative procedures to handle this workload. After implementing these new administrative strategies, we were able to greatly reduce the need for face-to-face meetings of our Editorial and Production Staffs. This paper describes our experience with developing efficient strategies for managing the daily operation of OncoLink during a period of rapid growth.

Electrocochleography with postural changes in perilymphatic fistula and Menière's disease: case reports.

Perilymphatic fistula can be difficult to diagnose differentially prior to exploratory surgery. In this study, we investigated a new test technique in four case studies of subjects with perilymphatic fistula and compared our findings to results obtained in 20 normally hearing subjects with no history of vertigo and 10 subjects with Meniere's disease. Recordings from an eardrum electrode were obtained with the subject in an upright position, after the subject had been lying in a horizontal position for 30 minutes with the test ear up and after 15 minutes with the test ear down. Stimuli consisted of high level clicks and tonebursts. Neither the summating potential (SP) and action potential (AP) amplitudes nor the SP/AP amplitude ratio were significantly affected by postural change in either the normal or Meniere's disease group. The perilymphatic fistula subjects, in general, showed greater changes in the SP/AP, particularly for the 6000 Hz tonebursts, than did the other two groups. More data will be needed to determine if these findings are consistent in a large population of perilymphatic fistula patients.

Noninvasive electrodes for electrocochleography in the chinchilla.

This study compares noninvasive vs invasive electrodes for electrocochleography in chinchillas. Summating potential (SP) amplitude, action potential (AP) amplitude, and AP threshold, recorded with five types of noninvasive electrodes, were compared with simultaneous bulla recordings. Noninvasive electrodes included a needle electrode over the bulla, gold Tiptrode (Etymotic Research, Elk Grove Village, Ill), Enhancer I (Nicolet Instrument Corp, Madison, Wis), Coats (Lifetech Inc, Austin, Tex) electrode, and a locally constructed tympanic membrane (TM) electrode. Stimuli included 100-microsecond clicks and 6000-Hz tone bursts (with a 1 millisecond rise/fall time and a 5 millisecond plateau). Stimuli were initially presented at 110 dB peak equivalent sound pressure level for the clicks and 100 dB peak equivalent sound pressure level for the tone bursts. Intensity was then decreased in 10-dB decrements until no replicable AP activity was observed. The TM damping for the TM electrode was measured with 0.5, 1, 2, 4, and 6 kHz and click stimuli. The AP was clear and replicable for all electrodes used in the study, although the amplitude was substantially less for the noninvasive electrodes as opposed to the invasive electrode. The invasive electrode provided the largest amplitude SP recording, but SP could generally be clearly recorded with the needle electrode, Enhancer I, and the Coats electrode. The TM electrode and gold Tiptrode provided SP recordings less consistently. The AP threshold could be recorded with all the electrodes in the study and was generally within 10 dB of threshold recorded invasively. Electrode variables, including ease of electrode placement and potential injury, were examined. The Tiptrode and Enhancer I electrodes posed relatively few problems during placement.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrocochleographic recordings in acute and healed perilymphatic fistula.

In this study, the summating potential (SP) and action potential (AP) amplitude ratio was measured in 15 guinea pigs before and after surgical induction of a round window fistula. The round window fistula was then allowed to heal, and recordings were obtained after 1 month. Stimuli included 8000-Hz and 2000-Hz tone bursts and click stimuli at levels ranging from 100-dB peak equivalent sound pressure level to AP threshold. Immediately after fistula induction, a statistically significant enlargement in the SP/AP amplitude ratio occurred in response to the click and the 8000-Hz tone-burst stimuli. No change in the SP/AP amplitude ratio was observed for the 2000-Hz stimuli. After healing, the SP/AP amplitude ratio generally returned to prelesion values. No unhealed perilymphatic fistulas were observed in any of the 15 guinea pigs at 1 month after fistula induction. Considering the difficulty of diagnosing perilymphatic fistula in humans, it is encouraging to note that, at least in animals, noninvasive electrophysiologic recordings may perhaps be sensitive to the presence of patent perilymphatic fistula.

The effect of stimulus repetition rate on the auditory brainstem response in tumor and nontumor patients.

Auditory brainstem responses were recorded in two groups of adult subjects with asymmetric sensorineural hearing loss. Clicks were presented at repetition rates of 9.7, 39.7, 49.7, and 59.7/s. One group was composed of 20 patients with no known otoneurologic lesion (cochlear group), and one group was composed of 8 patients with a surgically confirmed acoustic neuroma in the ear with poorer hearing sensitivity (retrocochlear group). Detection of wave V at different repetition rates was not significantly different between the two groups. Average wave-V latency shift was not significantly different between the two groups as repetition rate increased from 9.7/s to 39.7/s but was significantly greater for the retrocochlear group as repetition rate increased from 9.7/s to 49.7/s and 59.7/s. However, the wave-V latency shift showed no improvement over the slow-rate interaural wave-V latency difference in discriminating between the two groups of patients. No significant correlation between the amount of wave-V latency shift and hearing loss at 2000 Hz or 4000 Hz was found for the ears with poorer hearing sensitivity.