Normal Tissue Response of Combined Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy.

PURPOSE: Proton minibeam radiation therapy, a spatial fractionation concept, widens the therapeutic window. By reducing normal tissue toxicities, it allows a temporally fractionated regime with high daily doses. However, an array shift between daily fractions can affect the tissue-sparing effect by decreasing the total peak-to-valley dose ratio. Therefore, combining temporal fractions with spatial fractionation raises questions about the impact of daily applied dose modulations, reirradiation accuracies, and total dose modulations. METHODS AND MATERIALS: Healthy mouse ear pinnae were irradiated with 4 daily fractions of 30 Gy mean dose, applying proton pencil minibeams (pMB) of Gaussian σ = 222 µm in 3 different schemes: a 16 pMB array with a center-to-center distance of 1.8 mm irradiated the same position in all sessions (FS1) or was shifted by 0.9 mm to never hit the previously irradiated tissue in each session (FS2), or a 64 pMB array with a center-to-center distance of 0.9 mm irradiated the same position in all sessions (FS3), resulting in the same total dose distribution as FS2. Reirradiation positioning and its accuracy were obtained from image guidance using the unique vessel structure of ears. Acute toxicities (swelling, erythema, and desquamation) were evaluated for 153 days after the first fraction. Late toxicities (fibrous tissue, inflammation) were analyzed on day 153. RESULTS: Reirradiation of highly dose-modulated arrays at a positioning accuracy of 110 ± 52 µm induced the least severe acute and late toxicities. A shift of the same array in FS2 led to significantly inducted acute toxicities, a higher otitis score, and a slight increase in fibrous tissue. FS3 led to the strongest increase in acute and late toxicities. CONCLUSIONS: The highest normal-tissue sparing is achieved after accurate reirradiation of a highly dose modulated pMB array, although high positioning accuracies are challenging in a clinical environment. Nevertheless, the same integral dose applied in highly dose-modulated fractions is superior to low daily dose-modulated fractions.

Wound monitoring of pH and oxygen in patients after radiation therapy.

OBJECTIVES: Postradiogenic wound healing disorders are an important clinical problem. While a variety of treatment modalities are available, there is no strategy to objectively judge treatment success. The aim of this study was to evaluate a 2D luminescence imaging system for pH and oxygen in non-healing wounds after radiotherapy. METHODS: Luminescence 2D imaging was performed with the VisiSens (Presens, Regensburg, Germany) 2D imaging systems A1 and A2 for oxygen and pH, respectively. Biocompatible planar luminescent sensor foils were applied to non-irradiated and irradiated skin as well as to radiogenic wounds of five patients and the pH and the oxygen saturation was determined. RESULTS: pH measurements showed significant differences between non-irradiated skin (6.46 ± 0.18) and irradiated skin (6.96 ± 0.26). Radiogenic wounds exhibited the highest pH values (7.53 ± 0.26). Oxygen measurements revealed a mean oxygen saturation of non-irradiated skin of 6.19 ± 0.83 mmHg. The highest value of oxygen saturation (28.4 ± 2.4 mmHg) was found on irradiated skin while irradiated wounds had a poor oxygen saturation (9.4 ± 2.2 mmHg) (mean ± s.e.m.). CONCLUSION: We found that routine measurement of pH and pO2 in patients could be easily integrated into the clinical routine. The results of the measurements show unfavorable pH and oxygen saturation conditions for wound healing in irradiated wounds. Interestingly, irradiated wounds exhibit a more pronounced hypoxia than irradiated skin which is reflected by an altered pH and pO2 compared to unirradiated skin, which has the potential to serve as a prognostic marker in the future. In addition to the objectification of the treatment success of postradiogenic wound healing disorders, the extent of skin toxicity could already be predicted during radiotherapy with this method.

Proton pencil minibeam irradiation of an in-vivo mouse ear model spares healthy tissue dependent on beam size.

Proton radiotherapy using minibeams of sub-millimeter dimensions reduces side effects in comparison to conventional proton therapy due to spatial fractionation. Since the proton minibeams widen with depth, the homogeneous irradiation of a tumor can be ensured by adjusting the beam distances to tumor size and depth to maintain tumor control as in conventional proton therapy. The inherent advantages of protons in comparison to photons like a limited range that prevents a dosage of distal tissues are maintained by proton minibeams and can even be exploited for interlacing from different beam directions. A first animal study was conducted to systematically investigate and quantify the tissue-sparing effects of proton pencil minibeams as a function of beam size and dose distributions, using beam widths between σ = 95, 199, 306, 411, 561 and 883 µm (standard deviation) at a defined center-to-center beam distance (ctc) of 1.8 mm. The average dose of 60 Gy was distributed in 4x4 minibeams using 20 MeV protons (LET ~ 2.7 keV/µm). The induced radiation toxicities were measured by visible skin reactions and ear swelling for 90 days after irradiation. The largest applied beam size to ctc ratio (σ/ctc = 0.49) is similar to a homogeneous irradiation and leads to a significant 3-fold ear thickness increase compared to the control group. Erythema and desquamation was also increased significantly 3-4 weeks after irradiation. With decreasing beam sizes and thus decreasing σ/ctc, the maximum skin reactions are strongly reduced until no ear swelling or other visible skin reactions should occur for σ/ctc < 0.032 (extrapolated from data). These results demonstrate that proton pencil minibeam radiotherapy has better tissue-sparing for smaller σ/ctc, corresponding to larger peak-to-valley dose ratios PVDR, with the best effect for σ/ctc < 0.032. However, even quite large σ/ctc (e.g. σ/ctc = 0.23 or 0.31, i.e. PVDR = 10 or 2.7) show less acute side effects than a homogeneous dose distribution. This suggests that proton minibeam therapy spares healthy tissue not only in the skin but even for dose distributions appearing in deeper layers close to the tumor enhancing its benefits for clinical proton therapy.

Beam size limit for pencil minibeam radiotherapy determined from side effects in an in-vivo mouse ear model.

Side effects caused by radiation are a limiting factor to the amount of dose that can be applied to a tumor volume. A novel method to reduce side effects in radiotherapy is the use of spatial fractionation, in which a pattern of sub-millimeter beams (minibeams) is applied to spare healthy tissue. In order to determine the skin reactions in dependence of single beam sizes, which are relevant for spatially fractionated radiotherapy approaches, single pencil beams of submillimeter to 6 millimeter size were applied in BALB/c mice ears at a Small Animal Radiation Research Platform (SARRP) with a plateau dose of 60 Gy. Radiation toxicities in the ears were observed for 25 days after irradiation. Severe radiation responses were found for beams ≥ 3 mm diameter. The larger the beam diameter the stronger the observed reactions. No ear swelling and barely reddening or desquamation were found for the smallest beam sizes (0.5 and 1 mm). The findings were confirmed by histological sections. Submillimeter beams are preferred in minibeam therapy to obtain optimized tissue sparing. The gradual increase of radiation toxicity with beam size shows that also larger beams are capable of healthy tissue sparing in spatial fractionation.

Dose-response relationship and normal-tissue complication probability of conductive hearing loss in patients undergoing head-and-neck or cranial radiotherapy: A prospective study including 70 ears.

PURPOSE: Head-and-neck (H&N) and cranial radiotherapy may cause hearing loss. Little has been published on the dose-response relationship and normal-tissue complication probability (NTCP) of the conductive subtype of hearing loss. The aims were to observe the incidence of hearing loss in patients undergoing non-intensity-modulated H&N or cranial radiotherapy, obtain the relationship between dose and conductive hearing loss (CHL) and test the current Lyman-Kutcher-Burman (LKB) NTCP model parameters. METHODS: The dose-response in the peripheral auditory system (PAS) of 35 patients (70 ears) was prospectively studied using mean dose and the current LKB model parameters. A wide dose range was obtained by conducting the study at a clinic without advanced treatment techniques. The patients underwent routine external-beam treatments following 3D treatment planning. Hearing status was evaluated by pure-tone audiometry one day before the start and one day and 30 days after the end of radiotherapy. RESULTS: Nineteen ears (27%) experienced hearing loss. Sixteen (23%) had CHL and three (4%) the sensorineural subtype. On average, mean doses of the PAS structures and V95%, V40Gy and V30Gy volumes of the middle-ear planning-organ-at-risk volume (PRV) were significantly greater in ears that suffered CHL. The modelled 50% NTCP of CHL occurred at approximately 30-40 Gy mean dose to middle ear planning organ-at-risk volume. CONCLUSIONS: Incidence of conductive hearing loss in non-intensity-modulated radiotherapy of H&N and brain can be significant. CHL exhibits a dose-effect. This suggests that the PAS should be considered in treatment plan optimization. The LKB NTCP model was reasonably accurate but modifications are indicated.

Early intervention of fractional carbon dioxide laser on fresh traumatic scar.

To determine the combined therapeutic effect of fractional carbon dioxide laser and silicone gel on fresh traumatic scars using a rabbit ear hypertrophic scar (EHS) model, as well as on human subjects. The rabbit EHS model was established by punching four circular wounds in each ear and respectively treated with carbon dioxide laser, silicone gel, and the combination of both, while one wound was left untreated. In addition, a validation group of five rabbits was also included wherein the wounds were treated with triamcinolone, IFN-α, and normal saline, with one untreated control. The gross hyperplasic changes and the histological features were analyzed, and the scar elevation index (SEI) was calculated for each treatment group. In the rabbit model, the untreated control wounds showed hypertrophic growth, whereas triamcinolone or IFN-α showed an inhibitory effect, similar to that on hypertrophic scars in humans, thereby proving the feasibility of our animal model. The SEI peaked 2 months after treatment and was respectively 2.28 ± 0.56, 1.85 ± 0.33, 1.91 ± 0.34, and 1.45 ± 0.22 in the untreated control, and the silicone, laser, and combined treatment groups, clearly indicating a significant therapeutic effect of the combined treatment modality (p < 0.01). The fibroblast and microvascular counts also showed similar trends in each group. Early application of fractional carbon dioxide laser can prevent hypertrophic scars; the combined use of laser and silicone gel was more effective with less recovery time, thereby worthy of clinical promotion.

Is intensity-modulated radiotherapy superior to conventional techniques to prevent late ear complications of nasopharyngeal cancer?

PURPOSE: This study analyzed the late ear complications of radiotherapy for nasopharyngeal cancer (NPC) and compared the conventional and intensity-modulated radiotherapy (2D-RT and IMRT, respectively). METHODS: At 2-21 years after the end of NPC treatment, 104 ears of 52 patients were evaluated with the otoscopic examination, pure tone audiometry test, tympanometry, and subjective complaints by being blinded to the radiotherapy technique. RESULTS: There were no differences in terms of the pathology of the external, middle or inner ear, air and bone-conduction hearing thresholds, and the air-bone (A-B) gap at 500, 1000, 2000, and 4000 Hz, and tympanometry types between 2D-RT and IMRT groups (p > 0.05). There were positive correlations between the values of A500 and A1000 thresholds; gap 500, 4000, and mean cochlear RT dose (p < 0.05). There were positive correlations between the values of A500, A1000, and A4000 thresholds; gap 500, 1000, 2000, 4000, and maximum cochlear RT dose (p < 0.05). CONCLUSION: IMRT was not found to be superior to 2D-RT to prevent RT-induced ear complications. The solution of the middle ear problems must be the goal of the strategies for complications treatment.

Irradiated ears in nasopharyngeal carcinoma survivors: A review.

This article reviews the literature on otological complications in nasopharyngeal carcinoma (NPC) survivals after irradiation during the past three decades. Symptoms of the irradiated ears were assessed from the external ear canal, through the middle ear cavity including the Eustachian tube, and to the inner ear compartments. The development of radioimaging diagnostic techniques, the introduction from adjuvant chemotherapy to concurrent chemoradiotherapy, and the invention of radiotherapeutic equipment to intensity-modulated radiotherapy (IMRT) have increased the survival rate of NPC patients during the past 30 years. The prevalence of cochlear and vestibular deficits has decreased a lot, whereas middle ear complications (i.e., otitis media with effusion and radiation-induced otitis media) do not decline in NPC survivors even in the IMRT era, probably because the medial half of the Eustachian tube receives > 95% of the total dose despite 2DRT or IMRT. Laryngoscope, 129:637-642, 2019.

Effects of Synchrotron X-Ray Micro-beam Irradiation on Normal Mouse Ear Pinnae.

PURPOSE: To analyze the effects of micro-beam irradiation (MBI) on the normal tissues of the mouse ear. METHODS AND MATERIALS: Normal mouse ears are a unique model, which in addition to skin contain striated muscles, cartilage, blood and lymphatic vessels, and few hair follicles. This renders the mouse ear an excellent model for complex tissue studies. The ears of C57BL6 mice were exposed to MBI (50-µm-wide micro-beams, spaced 200 µm between centers) with peak entrance doses of 200, 400, or 800 Gy (at ultra-high dose rates). Tissue samples were examined histopathologically, with conventional light and electron microscopy, at 2, 7, 15, 30, and 240 days after irradiation (dpi). Sham-irradiated animals acted as controls. RESULTS: Only an entrance dose of 800 Gy caused a significant increase in the thickness of both epidermal and dermal ear compartments seen from 15 to 30 dpi; the number of sebaceous glands was significantly reduced by 30 dpi. The numbers of apoptotic bodies and infiltrating leukocytes peaked between 15 and 30 dpi. Lymphatic vessels were prominently enlarged at 15 up to 240 dpi. Sarcomere lesions in striated muscle were observed after all doses, starting from 2 dpi; scar tissue within individual beam paths remained visible up to 240 dpi. Cartilage and blood vessel changes remained histologically inconspicuous. CONCLUSIONS: Normal tissues such as skin, cartilage, and blood and lymphatic vessels are highly tolerant to MBI after entrance doses up to 400 Gy. The striated muscles appeared to be the most sensitive to MBI. Those findings should be taken into consideration in future micro-beam radiation therapy treatment schedules.

High-precision, non-invasive anti-microvascular approach via concurrent ultrasound and laser irradiation.

Antivascular therapy represents a proven strategy to treat angiogenesis. By applying synchronized ultrasound bursts and nanosecond laser irradiation, we developed a novel, selective, non-invasive, localized antivascular method, termed photo-mediated ultrasound therapy (PUT). PUT takes advantage of the high native optical contrast among biological tissues and can treat microvessels without causing collateral damage to the surrounding tissue. In a chicken yolk sac membrane model, under the same ultrasound parameters (1 MHz at 0.45 MPa and 10 Hz with 10% duty cycle), PUT with 4 mJ/cm2 and 6 mJ/cm2 laser fluence induced 51% (p = 0.001) and 37% (p = 0.018) vessel diameter reductions respectively. With 8 mJ/cm2 laser fluence, PUT would yield vessel disruption (90%, p < 0.01). Selectivity of PUT was demonstrated by utilizing laser wavelengths at 578 nm or 650 nm, where PUT selectively shrank veins or occluded arteries. In a rabbit ear model, PUT induced a 68.5% reduction in blood perfusion after 7 days (p < 0.001) without damaging the surrounding cells. In vitro experiments in human blood suggested that cavitation may play a role in PUT. In conclusion, PUT holds significant promise as a novel non-invasive antivascular method with the capability to precisely target blood vessels.

Ototoxicity and cancer therapy.

Ototoxicity is a well-established toxicity associated with a subgroup of antineoplastic therapies that includes platinum chemotherapy, radiation or surgery involving the ear and auditory nerve, and supportive care agents such as aminoglycoside antibiotics and loop diuretics. The reported prevalence of ototoxicity in patients who have received potentially ototoxic therapy ranges from 4% to 90% depending on factors such as age of the patient population, agent(s) used, cumulative dose, and administration techniques. The impact of ototoxicity on subsequent health-related and psychosocial outcomes in these patients can be substantial, and the burden of morbidity related to ototoxic agents is particularly high in very young children. Considerable interindividual variability in the prevalence and severity of ototoxicity has been observed among patients receiving similar treatment, suggesting genetic susceptibility as a risk factor. The development and testing of otoprotective agents is ongoing; however, to the author's knowledge, no US Food and Drug Administration-approved otoprotectants are currently available. Prospective monitoring for ototoxicity allows for comparison of auditory outcomes across clinical trials, as well as for early detection, potential alterations in therapy, and auditory intervention and rehabilitation to ameliorate the adverse consequences of hearing loss. Cancer 2016;122:1647-58. © 2016 American Cancer Society.

The gender differences in the inhibitory action of UVB-induced melanocyte activation by the administration of tranexamic acid.

BACKGROUND: Tranexamic acid has an inhibitory action on ultraviolet (UV) B-induced melanocyte activation. This study examined the sex differences in the inhibitory action of tranexamic acid on UVB-induced melanocyte activation. METHODS: We irradiated the eye and ear of male and female mice with UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp. We orally administered tranexamic acid (750 mg/kg/day) at 30 min before UVB exposure. RESULTS: Tranexamic acid inhibited the UVB-induced epidermal melanocyte activation, and the effect was more remarkable under UVB eye irradiation than under UVB ear irradiation. Furthermore, the melanocyte activity suppression effect was stronger in female mice than in male mice. Following the administration of tranexamic acid, the female displayed increased blood levels of ß-endorphin and µ-opioid receptor and estradiol receptor ß expression in comparison with the male. Furthermore, the effect of melanocyte activity suppression in the female mice was decreased by the administration of tamoxifen (antagonist of estrogen receptor) or naltrexone (antagonist of µ-opioid receptor). CONCLUSIONS: These results suggest that the suppression by tranexamic acid of the UVB-induced melanocyte activation (UVB sensitivity) is stronger in female mice than in male mice and that female hormones and ß-endorphin play an important role in this sex difference.

A Mouse Ear Model for Bystander Studies Induced by Microbeam Irradiation.

Radiation-induced bystander effects have been observed in vitro and in cell and tissue culture models, however, there are few reported studies showing these effects in vivo. To our knowledge, this is the first reported study on bystander effects induced by microbeam irradiation in an intact living mammal. The mouse ear was used to investigate radiation-induced bystander effects in keratinocytes, utilizing a 3 MeV proton microbeam (LET 13.1 keV/µm) with a range in skin of about 135 µm. Using a custom-designed holder, the ear of an anesthetized C57BL/6J mouse was flattened by gentle suction and placed over the microbeam port to irradiate cells along a 35 µm wide, 6 mm long path. Immunohistochemical analysis of γ-H2AX foci formation in tissue sections revealed, compared to control tissue, proton-induced γ-H2AX foci formation in one of the two epidermal layers of the mouse ear. Strikingly, a higher number of cells than expected showed foci from direct irradiation effects. Although the proton-irradiated line was ~35 µm wide, the average width spanned by γ-H2AX-positive cells exceeded 150 µm. Cells adjacent to or in the epidermal layer opposite the γ-H2AX-positive region did not exhibit foci. These findings validate this mammalian model as a viable system for investigating radiation-induced bystander effects in an intact living organism.

Mobile telephone use effects on perception of verticality.

Low-level radiofrequency (RF) signals may produce disorientation and nausea. In experiment I, we assessed mobile phone effects on graviception in nine symptomatic subjects after mobile telephone use and 21 controls. The mobile handset was strapped to each ear for 30 min in pulsed emission, continuous RF emission, or no emission test mode, respectively. The subjective visual vertical and horizontal (SVV/SVH) were tested from min 25 of exposure. There was no exposure effect; however, there was an ear effect, with the SVV/SVH being shifted to the opposite direction of the ear exposed. This could be due to thermal or RF effects or handset weight. In experiment II, we assessed the handset weight effect on 18 normal controls. After baseline SVV/SVH, the switched off handset was strapped to either ear; the SVV/SVH was repeated 25 min later. A significant ear effect was found. We compared the observed ear effect SVV/SVH change in the experiment II group to the continuous exposure ear effect change in the experiment I group, and the difference was not significant. The ear effect was attributed to a minor head tilt due to the handset weight, or proprioceptive stimulation of neck muscle affecting the perception of verticality.

Therapeutic effects of full spectrum light on the development of atopic dermatitis-like lesions in NC/Nga mice.

Full spectrum light (FSL) includes UVA, visible light and infrared light. Many studies have investigated the application of FSL in severe cases of atopic dermatitis (AD) in humans; however, FSL has not yet been studied in an animal model. The purpose of this study was to evaluate the therapeutic effects of FSL on AD-like skin lesions using NC/Nga mice, with the aim of mitigating itching and attenuating the expression of adhesion molecules. We examined the effects of FSL on mite allergen-treated NC/Nga mice by assessing skin symptom severity, ear thickness, serum IgE levels, and the cytokine expression. We examined the histology of lesions using hematoxylin-eosin, toluidine blue and immunohistochemical staining. Our findings suggest that FSL phototherapy exerts positive therapeutic effects on Dermatophagoides farinae (Df)-induced AD-like skin lesions in NC/Nga mice by reducing IgE levels, thus promoting recovery of the skin barrier. The mechanisms by which FSL phototherapy exerts its effects may also involve the inhibition of scratching behavior, reduction of IL-6 levels and reductions in adhesion molecule expression. The present study indicates that FSL phototherapy inhibits the development of AD in NC/Nga mice by suppressing cytokine, chemokine and adhesion molecule expression, and thus, could potentially be useful in treating AD.

Assessment of intermittent UMTS electromagnetic field effects on blood circulation in the human auditory region using a near-infrared system.

The aim of the present study was to assess the potential effects of intermittent Universal Mobile Telecommunications System electromagnetic fields (UMTS-EMF) on blood circulation in the human head (auditory region) using near-infrared spectroscopy (NIRS) on two different timescales: short-term (effects occurring within 80 s) and medium-term (effects occurring within 80 s to 30 min). For the first time, we measured potential immediate effects of UMTS-EMF in real-time without any interference during exposure. Three different exposures (sham, 0.18 W/kg, and 1.8 W/kg) were applied in a controlled, randomized, crossover, and double-blind paradigm on 16 healthy volunteers. In addition to oxy-, deoxy-, and total haemoglobin concentrations ([O(2) Hb], [HHb], and [tHb], respectively), the heart rate (HR), subjective well-being, tiredness, and counting speed were recorded. During exposure to 0.18 W/kg, we found a significant short-term increase in Δ[O(2) Hb] and Δ[tHb], which is small (≈17%) compared to a functional brain activation. A significant decrease in the medium-term response of Δ[HHb] at 0.18 and 1.8 W/kg exposures was detected, which is in the range of physiological fluctuations. The medium-term ΔHR was significantly higher (+1.84 bpm) at 1.8 W/kg than for sham exposure. The other parameters showed no significant effects. Our results suggest that intermittent exposure to UMTS-EMF has small short- and medium-term effects on cerebral blood circulation and HR.

Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy.

BACKGROUND: Hearing loss is common following chemoradiotherapy for children with medulloblastoma. Compared to photons, proton radiotherapy reduces radiation dose to the cochlea for these patients. Here we examine whether this dosimetric advantage leads to a clinical benefit in audiometric outcomes. METHODS: From 2006-2009, 23 children treated with proton radiotherapy for medulloblastoma were enrolled on a prospective observational study, through which they underwent pre- and 1 year post-radiotherapy pure-tone audiometric testing. Ears with moderate to severe hearing loss prior to therapy were censored, leaving 35 ears in 19 patients available for analysis. RESULTS: The predicted mean cochlear radiation dose was 30 60Co-Gy Equivalents (range 19-43), and the mean cumulative cisplatin dose was 303 mg/m2 (range 298-330). Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (P < 0.05). There was partial sparing of mean post-radiation hearing thresholds at low-to-midrange frequencies and, consequently, the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was favorable (5%). Ototoxicity did not correlate with predicted dose to the auditory apparatus for proton-treated patients, potentially reflecting a lower-limit threshold for radiation effect on the cochlea. CONCLUSIONS: Rates of high-grade early post-radiation ototoxicity following proton radiotherapy for pediatric medulloblastoma are low. Preservation of hearing in the audible speech range, as observed here, may improve both quality of life and cognitive functioning for these patients.

Prospective study on the dose distribution to the acoustic structures during postoperative 3D conformal radiotherapy for parotid tumors: dosimetric and audiometric aspects.

BACKGROUND AND PURPOSE: To analyze dose distribution in the hearing organ and to evaluate the dose effect on the hearing thresholds in patients treated with post-parotidectomy 3-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: A total of 17 patients received post-parotidectomy 3D-CRT (median dose: 63 Gy). The audiometric evaluation comprised pure tone audiometry and tympanometry performed before radiotherapy (RT) and 3, 6, and 24 months after RT. The ear structures were delineated on planning computer tomography scans. Mean and maximum doses were calculated and dose-volume histograms were plotted. RESULTS: Before RT, the median baseline audiometric thresholds were normal. At 3 months post-RT, 3 patients were diagnosed as having middle ear underpressure and/or effusion that resolved completely by 6 months. During 2-year follow-up, none of the ears showed perceptive hearing loss at speech frequencies. The mean doses at ipsilateral external auditory canal, mastoids cells, tympanic case, Eustachian tube, semicircular canals, and cochlea were 44.8 Gy, 39.0 Gy, 30.9 Gy, 33.0 Gy, 19.6 Gy, and 19.2 Gy, respectively. The doses to the contralateral ear were negligible, except for the Eustachian tube (up to 28.2 Gy). CONCLUSION: Post-parotidectomy 3D-CRT is associated with relatively low doses to the ear and the surrounding structures. Post-RT audiometry did not show any permanent (neither conductive nor perceptive) hearing impairment. Only in 3 patients were there signs of transient unilateral dysfunction of the Eustachian tube observed during the first few months after RT. Longer follow-up and larger patient series are warranted to confirm these preliminary findings.

An ear punch model for studying the effect of radiation on wound healing.

PURPOSE: Radiation and wound combined injury represents a major clinical challenge because of the synergistic interactions that lead to higher morbidity and mortality than either insult would produce singly. The purpose of this study was to develop a mouse ear punch model to study the physiological mechanisms underlying radiation effects on healing wounds. MATERIALS AND METHODS: Surgical wounds were induced by a 2 mm surgical punch in the ear pinnae of MRL/MpJ mice. Photographs of the wounds were taken and the sizes of the ear punch wounds were quantified by image analysis. Local radiation to the ear was delivered by orthovoltage X-ray irradiator using a specially constructed jig that shields the other parts of body. RESULTS: Using this model, we demonstrated that local radiation to the wound area significantly delayed the healing of ear punch wounds in a dose-dependent fashion. The addition of sublethal whole body irradiation (7 Gy) further delayed the healing of ear punch wounds. These results were replicated in C57BL/6 mice; however, wound healing in MRL/MpJ mice was accelerated. CONCLUSIONS: These data indicate that the mouse ear punch model is a valuable model to study radiation and wound combined injury.

Incidence of long-term ipsilateral and contralateral ototoxicity following radiotherapy for nasopharyngeal carcinoma.

OBJECTIVE: To characterize the long-term adverse effects of radiotherapy on the ears in patients with nasopharyngeal carcinoma (NPC), we investigated ipsilateral and contralateral ototoxicities in the external, middle, and inner ear. METHODS: The records of 48 ears in 24 radiotherapy-treated NPC patients were retrospectively analyzed. Radiotherapy doses varied between 60 and 70 Gy in 2-Gy fractions at 5 fractions/week. Ototoxicities were identified by otoscope and pure-tone audiograms conducted at 2-3 month intervals for ≥12 months. The relationship between radiation dosage and sensorineural threshold deterioration was statistically compared using the Mann-Whitney U-test. RESULTS: Post-radiotherapy, 50% of all ears (3 of 6) that developed severe otitis externa were on the contralateral side. There was a post-radiotherapy increase in contralateral otitis media with effusion (OME) (1-7 ears), but a decrease in ipsilateral cases (16-12 ears), with 2 ears on either side subsequently developing chronic otitis media (COM). All ears that showed sensorineural hearing loss (SNHL) before radiotherapy exhibited a further threshold deterioration of more than 15 dB. No statistically significant difference (p=0.086) in average radiation dose was seen between ears with sensorineural threshold deterioration (50.0 Gy) and those without (48.2 Gy). CONCLUSION: Long-term ototoxicity following radiotherapy for NPC can occur in either the ipsilateral or contralateral ears. Pathophysiology varies between and within each side. The post-therapy increase in OME on the contralateral side was thought to be due to radiotherapy-induced Eustachian tube damage, and the sensorineural threshold deterioration in at least 4 ears was thought to be due to chronic cochlea damage secondary to COM.