This study investigated mobile health enabled surveillance in ototoxicity.

This was a longitudinal study of 32 participants receiving chemotherapy. Baseline and exit audiograms that included conventional and extended high frequency audiometry were recorded within the patient's treatment venue using a validated mobile health audiometer.

Average hearing thresholds at baseline were within the normal range (81.2 per cent left; 93.8 per cent right), reducing at exit testing (71.9 per cent left; 78.1 per cent right). Half of participants presented with a threshold shift according to ototoxicity monitoring criteria. The frequencies affected the most were between 4000 and 16 000 Hz, with left ears significantly more affected than right ears. Noise levels exceeded the maximum permissible ambient noise levels in up to 43.8 per cent of low frequencies (250–1000 Hz).

Mobile health supported audiometry proved to be an efficacious tool for ototoxicity monitoring at the treatment venue. Changes in hearing ability over time could be tracked, improving surveillance in patients with full treatment schedules.

Platinum-based chemotherapy drugs are associated with substantial ototoxicity. The hearing of children treated with these drugs should be closely monitored.

A questionnaire was sent out to the 19 audiology departments associated with national paediatric cancer specialist centres in the UK looking at current practice in ototoxicity monitoring.

Responses were received from 17 of 19 centres (89 per cent). All offered some form of audiometric monitoring service. Extended high-frequency testing (9–20 kHz) was only utilised by 7 services (29 per cent). A majority of respondents were reluctant to consider self-test devices in paediatric ototoxicity monitoring (n = 9; 53 per cent). Provision of long-term audiological follow up is sporadic with only 4 (23 per cent) respondents keeping all children with normal hearing under review once treatment is completed.

While some good practice in paediatric ototoxicity was identified, opportunities exist to improve clinical practice and protocols, promote multidisciplinary team working and to utilise technologies such as extended high frequency and self-test audiometry.

Neurotoxicity is an adverse effect caused by cisplatin due to inflammation and oxidative stress in the central nervous system. The present study aimed to assess the effects of vitamin E injection on the learning and memory of rats with cisplatin-induced cognitive impairment.

Male rats were administered with cisplatin (2 mg/kg/7 day; intraperitoneally [i i.p.]) and/or vitamin E (200 mg/kg/7 day; i.p.) for 1 week, and the control group received saline solution. Spatial memory was evaluated using Morris water maze (MWM). In addition, the hippocampal concentrations of malondialdehyde (MDA), thiol, and superoxide dismutase (SOD) were measured using biochemical methods.

According to the findings, cisplatin significantly increased the escape latency, while decreasing the time spent and travelled pathway in the target quadrant on the final trial day compared to the control group. Furthermore, pre-treatment with vitamin E significantly reversed all the results in the spatial memory test. The biochemical data indicated that vitamin E could decrease MDA activity and increase thiol and SOD activity compared to the control group.

According to the results, vitamin E could improve cisplatin-induced memory impairment possibly through affecting the hippocampal oxidative status.

Weekly low-dose cisplatin is routinely used in concurrent chemoradiation (CCRT) in locally advanced head and neck cancer (LAHNC), despite 3-weekly cisplatin being the standard of care. We compared compliance, toxicity and efficacy in weekly versus 3-weekly cisplatin CCRT in LAHNC.

In this retrospective study, weekly cisplatin 50 mg flat dose was compared with 3-weekly cisplatin 100 mg/m2, when given in CCRT in LAHNC with curative intent. The study outcome was compliance, toxicity, loco-regional control (LRC), disease-free survival (DFS) and overall survival (OS).

Eighty-four patients received CCRT from January 2013 to June 2017, 40 in weekly and 44 in 3-weekly arm. There was no difference between the arms not completing scheduled radiation therapy or chemotherapy. Patient receiving 200 mg/m2 cisplatin is higher in 3-weekly arm compared with weekly arm (75 versus 40·9%; p<0·0015). Compared with 3-weekly arm, more patient in weekly arm developed grade ≥3 mucositis (52·5 versus 15·9%, p=0·0004), day care intravenous hydration (82·5 versus 38·6% <0·0001) and in-patient admission (55·0 versus 18·2%; p=0·0004). The 2-year LRC, DFS and OS in weekly versus 3-weekly arm were: 70 versus 61·4% (p=0·406); 67·5 versus 56·8% (p=0·314); 67·5 versus 61·4% (p=0·558), respectively. The median time to LRR, DFs and OS was not reached.

Weekly cisplatin is comparable with 3-weekly cisplatin in terms of compliance, disease control and survival, but with increased grade 3 mucositis and higher admissions for supportive care.

This study aimed to compare the efficacies of intratympanic dexamethasone and methylprednisolone in preventing in cisplatin-induced ototoxicity in rats.

Experimental groups of rats (n = 8 each) received intratympanic isotonic saline, intraperitoneal cisplatin and intratympanic isotonic saline, intraperitoneal cisplatin and intratympanic dexamethasone, or intraperitoneal cisplatin and intratympanic methylprednisolone. Distortion product otoacoustic emission thresholds were compared on days 0 and 10 in all rats, and correlations between drug effects and changes in cochlear histology were evaluated.

Distortion product otoacoustic emission thresholds were comparable in groups III and IV (p > 0.05). Significant protection against cisplatin-induced ototoxicity was seen in groups III and IV compared with group II (p < 0.05). Dexamethasone and, to a lesser extent, methylprednisolone protected against cellular apoptosis in cisplatin-induced ototoxicity.

Dexamethasone (and possibly methylprednisolone) may be clinically useful as an intratympanic chemopreventive agent to treat cisplatin ototoxicity. Future clinical studies should investigate the use of dexamethasone for this purpose in adult patients.

Epidermal growth factor receptor (EGFR) overexpression and prognostic value in head and neck squamous cell cancer is the basis for targeting by anti-EGFR antibodies, which increase the efficacy of radiotherapy. In order to evaluate the best therapeutic schedule, the effects of cetuximab (C225) on Hep-2 cell proliferation, alone and in combination with cisplatin, were studied.

Hep-2 cells were treated with cetuximab alone or in combination with cisplatin. After determining cell viability with trypan blue, morphological features of apoptotic degeneration were analysed by fluorescence microscopy with Hoechst 33258 stain.

Cetuximab alone mildly inhibited Hep-2 proliferation and showed no pro-apoptotic effects. When administered concomitantly with cisplatin, cetuximab synergistically increased inhibition of proliferation and apoptosis.

The antiproliferative activity of cetuximab is consistent with its hypothesised role in inhibiting repopulation. However, the increase in the effects of pro-apoptotic agents induced by cetuximab may be even more relevant to its clinical effectiveness than the inhibition of repopulation.

Ototoxicity due to cisplatin therapy interferes with treatment and often forces a reduction in the dosage, duration and frequency of the cisplatin therapy. (-)-Epigallocatechin-3-gallate is known to have the highest antioxidant potency among all tea catechins. This study aimed to investigate the effect of (-)-epigallocatechin-3-gallate on cisplatin ototoxicity in an auditory cell line: House Ear Institute-Organ of Corti 1 cells.

Cultured House Ear Institute-Organ of Corti 1 cells were exposed to cisplatin with or without pre-treatment with (-)-epigallocatechin-3-gallate. Cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hoechst 33258 staining was used to identify cells undergoing apoptosis. Western blot analysis was conducted to determine whether (-)-epigallocatechin-3-gallate inhibited cisplatin-induced caspase activation. Intracellular reactive oxygen species production was examined to investigate whether (-)-epigallocatechin-3-gallate was capable of scavenging cisplatin-induced reactive oxygen species accumulation.

Cell viability significantly increased in cells pre-treated with (-)-epigallocatechin-3-gallate compared with cells exposed to cisplatin alone. Cisplatin increased cleaved caspase-3 on Western blot analysis; however, pre-treatment with (-)-epigallocatechin-3-gallate inhibited the expression of caspase-3. (-)-Epigallocatechin-3-gallate attenuated reactive oxygen species production and apoptosis in House Ear Institute-Organ of Corti 1 cells.

(-)-Epigallocatechin-3-gallate protected against cisplatin cytotoxicity through anti-apoptotic and anti-oxidative effects. Therefore, (-)-epigallocatechin-3-gallate could play a preventive role in cisplatin-induced ototoxicity.

Cisplatin is an effective chemotherapeutic agent commonly used in the treatment of malignant tumours, but ototoxicity is a significant side effect.

To discuss the mechanisms of cisplatin ototoxicity and subsequent cell death, and to present the results of experimental studies.

We conducted a systematic search for data published in national and international journals and books, using the Medline, SciELO, Bireme, LILACS and PubMed databases.

The nicotinamide adenine dinucleotide phosphate oxidase 3 isoform (also termed NOX3) seems to be the main source of reactive oxygen species in the cochlea. These reactive oxygen species react with other molecules and trigger processes such as lipid peroxidation of the plasma membrane and increases in expression of the transient vanilloid receptor potential 1 ion channel.

Cisplatin ototoxicity proceeds via the formation of reactive oxygen species in cochlear tissue, with apoptotic cell death as a consequence.

Cisplatin, an effective therapeutic agent for various human cancers, has dose-limiting side effects of ototoxicity and nephrotoxicity. Cisplatin ototoxicity is thought to result from increased amounts of toxic free radicals or cell membrane changes leading to increased intracellular calcium content. Ginkgo biloba extract prevents lipid peroxidation, decreases intracellular free oxygen radical levels, regulates the cell membrane calcium transport mechanism and prevents cell death. This study aimed to investigate the protective effect of Ginkgo biloba extract against cisplatin-induced ototoxicity in rats.

Twenty Wistar albino rats with normal hearing (confirmed by distortion product otoacoustic emission testing prior to cisplatin application) were randomly allocated to two groups. Both groups received a single intraperitoneal dose of cisplatin (12 mg/kg). Group two also received daily intraperitoneal doses of Ginkgo biloba extract (100 mg/kg) for 10 days. Distortion product otoacoustic emission measurements were repeated on days 10 and 17 and signal-to-noise ratios were compared.

Compared with group one, group two had significantly better distortion product otoacoustic emission results at 3, 4, 6 and 8 kHz on days 10 and 17.

These findings suggest that Ginkgo biloba extract protects the inner ear against cisplatin-induced ototoxicity.

Klotho protein is involved in insulin-signalling and ageing. Klotho mutation causes premature ageing and significantly shortens the lifespan. The anti-neoplastic drug cisplatin promotes ototoxicity at higher doses by inducing apoptosis. This study aimed to clarify the effect of klotho expression on cisplatin ototoxicity, using an auditory cell line.

Expressions of klotho messenger RNA and protein were analysed by reverse-transcription polymerase chain reaction and western blotting. Auditory cells (HEI-OC1 line) were pretreated with 2 nM klotho protein for 2 hours; 15 µM cisplatin was then applied. After 48 hours incubation, assessment of cell viability (via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay), apoptosis (via Hoechst 33258 staining) and reactive oxygen species was performed.

Klotho protein expression increased in cisplatin-treated auditory cells. Cells treated with both klotho protein and cisplatin showed a viability of 67.7 per cent, versus 59.4 per cent in cisplatin-treated cells. Klotho significantly attenuated the cisplatin-induced increase in reactive oxygen species, and increased the viability of cells with cisplatin-induced cytotoxicity.

Klotho protein is protective against cisplatin-induced auditory cell cytotoxicity; inhibition of reactive oxygen species may be the main mechanism.

This experimental study aimed to investigate the effects of vitamins E, B and C and l-carnitine in preventing cisplatin-induced ototoxicity.

Twenty-five adult, male, Wistar albino rats were randomly allocated to receive intraperitoneal cisplatin either alone or preceded by vitamins B, E or C or l-carnitine. Auditory brainstem response (i.e. hearing thresholds and wave I–IV intervals) and distortion product otoacoustic emissions (i.e. signal-to-noise ratios) were recorded before and 72 hours after cisplatin administration.

The following statistically significant differences were seen: control group pre- vs post-treatment wave I–IV interval values (p < 0.05); control vs vitamin E and B groups' I–IV interval values (p < 0.05); control vs other groups' hearing thresholds; vitamin E vs vitamin B and C and l-carnitine groups' hearing thresholds (p < 0.05); and vitamin B vs vitamin C and l-carnitine groups' hearing thresholds (p < 0.05). Statistically significant decreases were seen when comparing the initial and final signal-to-noise ratios in the control, vitamin B and l-carnitine groups (2000 and 3000 Hz; p < 0.01), and the initial and final signal-to-noise ratios in the control group (at 4000 Hz; p < 0.01).

Vitamins B, E and C and l-carnitine appear to reduce cisplatin-induced ototoxicity in rats. The use of such additional treatments to decrease cisplatin-induced ototoxicity in humans is still under discussion.

Although most studies on animal ototoxicity employ scanning electron microscopy, all cochlear structures may be identified with light microscopy. This paper describes a simple method of histological assessment of cisplatin-induced ototoxicity in rats, and relates morphological changes to functional changes in hearing detected by distortion product evoked otoacoustic emissions.

Male Wistar rats were injected with 8 mg/kg/day cisplatin, or with an equivalent volume of saline solution, for three consecutive days. They underwent distortion product evoked otoacoustic emission testing at baseline and at 24 or 48 hours after the last administration. At the end of the experiment, the animals were sacrificed and their cochleae were retrieved and prepared for haematoxylin and eosin staining.

A four-point scoring system was used to grade injury to the external ciliated cells, as indicated by the number of cells absent from the basal turn of the cochlear duct. A four-point scoring system was also used to grade stria vascularis injury, as indicated by the degree of shrinkage of the intermediate cells. Scores were significantly higher in groups treated with cisplatin compared with controls. Morphological changes were confirmed by decreased distortion product evoked otoacoustic emission amplitudes in animals treated with cisplatin.

This method is simple to perform with routine histology equipment and is appropriate for the study of acute, cisplatin-induced ototoxicity in rats.

The influence of the combined application of cisplatin and sevoflurane on a variety of cell types of healthy mice or mice bearing Ehrlich ascites tumour has been investigated in an in vivo study.

The alkaline comet assay method was carried out on peripheral blood leucocytes, brain, liver, kidney and tumour cells of healthy mice or mice bearing Ehrlich ascites tumour. Groups of mice were treated intraperitoneally with cisplatin, exposed to sevoflurane or by combined treatment of sevoflurane after treatment with cisplatin for 3 consecutive days.

The in vivo exposure to sevoflurane induced genotoxicity to all assayed cells. A strong synergistic genotoxic effect to peripheral blood leucocytes, liver and kidney cells was found in mice receiving both cisplatin and sevoflurane. In contrast, a decrease of the comet tail lengths of brain cells in the combined treatments was found as compared to cisplatin alone in both healthy (P < 0.001) and Ehrlich ascites tumour-bearing mice (P < 0.05), respectively. In addition, Ehrlich ascites tumour cells of mice treated with combined treatments showed a decrease in tail lengths (P < 0.001). These findings indicate an antagonistic effect of combined treatments.

Treatment of mice with cisplatin and sevoflurane induced genotoxic effect in peripheral blood leucocytes, liver, kidney, brain and Ehrlich ascites tumour cells; synergistic effect of combined treatments was expressed in all cells but brain and Ehrlich ascites tumour cells.

The ototoxic effects of cisplatin include loss of outer hair cells, degeneration of the stria vascularis and a decrease in the number of spiral ganglion cells. Scanning microscopy has shown balloon-like protrusions (blebs) of the plasma membrane of inner hair cells following cisplatin administration. The present study was undertaken to identify the possible role of inner and outer hair cell blebs in the pathogenesis of cisplatin-induced ototoxicity.

Twenty-five guinea pigs were injected with cisplatin and their hearing tested at different time-points, before sacrifice and examination with scanning electron microscopy.

Seven animals showed blebs in the inner hair cells at different stages. Hearing thresholds were lower in animals showing blebs.

Cisplatin seems to be able to induce changes in inner hair cells as well as in other structures in the organ of Corti. Blebbing observed in animals following cisplatin administration could play a specific role in the regulation of intracellular pressure.

This study was performed to assess the efficacy and safety profile of combination treatment with S-1 and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck.

Eligibility criteria comprised: histologically confirmed squamous cell carcinoma of the head and neck; stage three or four disease with no evidence of distant metastasis; evaluable lesions; adequate organ function; age 20–80 years; and a performance status of two or less. Cisplatin was infused over one hour on day one (75 mg/m2) and S-1 was administered orally for 14 consecutive days (days two to 15). The dosages of S-1 were calculated according to the patients' body surface area: 50 mg twice a day (body surface area <1.5 m2) or 60 mg twice a day (body surface area >1.5 m2). Each course was repeated every three weeks. After two courses, tumour response was evaluated by computed tomography and laryngoscopy. If a response was evident (either complete or partial), the patient received one more course of chemotherapy, before undergoing radical treatment such as radiotherapy or surgery.

All 30 patients were assessable for toxicity, and 29 patients for treatment response. The overall response was 89.7 per cent (complete response: nine; partial response: 17). The two-year estimated overall survival rate was 79.2 per cent. Adverse reactions occurred 128 times during 81 courses in the 30 cases. The most common grade three to four adverse event was neutropenia, which occurred in eight patients. Cases of non-haematological grade three or four toxicity included nausea and vomiting in four patients, stomatitis in two and diarrhoea in one.

S-1 plus cisplatin combination chemotherapy is effective against locally advanced squamous cell carcinoma of the head and neck, with only mild toxicity.