Equivalence of cell survival data for radiation dose and thermal dose in ablative treatments: analysis applied to essential tremor thalamotomy by focused ultrasound and gamma knife.

Thermal dose and absorbed radiation dose have historically been difficult to compare because different biological mechanisms are at work. Thermal dose denatures proteins and the radiation dose causes DNA damage in order to achieve ablation. The purpose of this paper is to use the proportion of cell survival as a potential common unit by which to measure the biological effect of each procedure. Survival curves for both thermal and radiation doses have been extracted from previously published data for three different cell types. Fits of these curves were used to convert both thermal and radiation dose into the same quantified biological effect: fraction of surviving cells. They have also been used to generate and compare survival profiles from the only indication for which clinical data are available for both focused ultrasound (FUS) thermal ablation and radiation ablation: essential tremor thalamotomy. All cell types could be fitted with coefficients of determination greater than 0.992. As an illustration, survival profiles of clinical thalamotomies performed by radiosurgery and FUS are plotted on a same graph for the same metric: fraction of surviving cells. FUS and Gamma Knife have the potential to be used in combination to deliver a more effective treatment (for example, FUS may be used to debulk the main tumour mass, and radiation to treat the surrounding tumour bed). In this case, a model which compares thermal and radiation treatments is valuable in order to adjust the dose between the two.

The use of high-intensity focused ultrasound as a novel treatment for painful conditions-a description and narrative review of the literature.

High-intensity focused ultrasound (HIFU) is a non-invasive technique that allows a small, well-circumscribed thermal lesion to be generated within a tissue target. Tissue destruction occurs due to direct heating within the lesion and the mechanical effects of acoustic cavitation. HIFU has been used in a broad range of clinical applications, including the treatment of malignancies, uterine fibroids and cardiac arrhythmias. Interest in the use of the technique to treat pain has recently increased. A number of painful conditions have been successfully treated, including musculoskeletal degeneration, bone metastases and neuropathic pain. The exact mechanism by which HIFU results in analgesia remains poorly understood, but it is thought to be due to localised denervation of tissue targets and/or neuromodulatory effects. The majority of studies conducted investigating the use of HIFU in pain are still at an early stage, although initial results are encouraging. Further research is indicated to improve our understanding of the mechanisms underlying this treatment and to fully establish its efficacy; however, it is likely that HIFU will play a role in pain management in the future. This narrative review provides a synthesis of the recent, salient clinical and basic science research related to this topic and gives a general introduction to the mechanisms by which HIFU exerts its effects.

Treatment of age-related hearing loss in dogs with the vibrant soundbridge middle ear implant: short-term results in 3 dogs.

BACKGROUND: Age-related hearing loss (ARHL), or presbycusis, is the most common form of acquired hearing loss in dogs. Middle ear implants have been used successfully in people with ARHL who cannot benefit from conventional hearing aids. HYPOTHESIS: Audibility improves in dogs with ARHL after implantation of the Vibrant Soundbridge (VSB) middle ear implant. ANIMALS: Three Beagle dogs with ARHL, mean age 11.1 years. METHODS: The dogs were assessed pre- and postoperatively by brainstem-evoked response audiometry (BERA), otoscopy, and computed tomography scans of the ears. A VSB middle ear implant was implanted unilaterally. Three months later the functionality of the implants was assessed by auditory steady-state responses (ASSRs), after which the dogs were euthanized for histopathological examination. RESULTS: The VSB was implanted successfully in all dogs. Recovery from surgery was uneventful, except for transient facial nerve paralysis in 2 dogs. ASSRs showed that hearing improved after activation of the implants with a mean of 20.7, 13, and 16.3 dB at 1, 2, and 4 kHz, respectively. The implantation procedure did not affect residual hearing (with inactive implants) as measured by BERA. CONCLUSIONS AND CLINICAL IMPORTANCE: Implantation of the VSB resulted in lower ASSR thresholds, but only at the higher gain settings of the audioprocessor. As in humans, a more powerful audioprocessor is required to treat sensorineural hearing loss exceeding 20 dB in dogs. A substantial improvement in patient-owner communication will have to be demonstrated in future studies before the procedure can be recommended in clinical practice.

Ultrasound bioeffects and safety.

The main mechanisms by which ultrasound can induce biological effects as it passes through the body are thermal and mechanical in nature. The mechanical effects are primarily related to the presence of gas, whether drawn out of solution by the negative going ultrasound pressure wave (acoustic cavitation), a naturally occurring gas body (such as lung alveoli), or deliberately introduced into the blood stream to increase imaging contrast (microbubble contrast agents). Observed biological effects are discussed in the context of these mechanisms and their relevance to ultrasound safety is discussed.

Effects of aging on inner ear morphology in dogs in relation to brainstem responses to toneburst auditory stimuli.

BACKGROUND: Age-related hearing loss (ARHL) is the most common form of hearing loss in humans and is increasingly recognized in dogs. HYPOTHESIS: Cochlear lesions in dogs with ARHL are similar to those in humans and the severity of the histological changes is reflected in tone audiograms. ANIMALS: Ten geriatric dogs (mean age: 12.7 years) and three 9-month-old dogs serving as controls for histological analysis. METHODS: Observational study. Auditory thresholds were determined by recording brainstem responses (BERA) to toneburst auditory stimuli (1, 2, 4, 8, 12, 16, 24, and 32 kHz). After euthanasia and perfusion fixation, the temporal bones were harvested and processed for histological examination of the cochleas. The numbers of outer hair cells (OHCs) and inner hair cells (IHCs) were counted and the spiral ganglion cell (SGC) packing density and stria vascularis cross-sectional area (SVCA) were determined. RESULTS: A combination of cochlear lesions was found in all geriatric dogs. There were significant reductions (P .001) in OHC (42%, 95% confidence interval [CI]; 24-64%) and IHC counts (21%, 95% CI; 62-90%) and SGC packing densities (323, 95% CI; 216-290) in the basal turn, SVCA was smaller in all turns. The greatest reduction in auditory sensitivity was at 8-32 kHz. CONCLUSIONS AND CLINICAL IMPORTANCE: ARHL in this specific population of geriatric dogs was comparable histologically to the mixed type of ARHL in humans. The predominance of histological changes in the basal cochlear turn was consistent with the large threshold shifts observed in the middle- to high-frequency region.

Surgical management of chronic otitis secondary to craniomandibular osteopathy in three West Highland white terriers.

Three West Highland white terriers were presented for investigation of left-sided para-aural abscessation. CT revealed chronic otitis media with extensive osseous proliferation surrounding the horizontal and vertical ear canals contiguous with the expanded temporal bone, consistent with a unilateral variant of craniomandibular osteopathy. A left total ear canal ablation with lateral bulla osteotomy was performed in all dogs. An ultrasonic bone curette (Sonopet; Stryker) proved useful when removing the osseous proliferation in two dogs. Histopathological examination of the ear canals was consistent with craniomandibular osteopathy and the treatment led to resolution of the presenting clinical signs in all dogs. To our knowledge, this is the first report of craniomandibular osteopathy engulfing the external ear canal, presumably leading to chronic otitis media and para-aural abscess formation. This is also the first reported use of an ultrasonic bone curette in canine otic surgery.

Gait analysis in French bulldogs with and without vertebral kyphosis.

The study objective was to compare temporal-spatial and kinetic gait variables in neurologically normal French bulldogs with and without vertebral kyphosis. French bulldogs presented to a dedicated brachycephalic clinic were prospectively enrolled. All dogs underwent general physical, orthopaedic, and neurological examination prior to study inclusion. The presence of vertebral kyphosis was evaluated by computed tomography and kyphosis was defined as a Cobb angle exceeding 10°. Gait variables were collected using a pressure-sensitive GAITRite walkway with GAITFour software and included measurement of total pressure index (TPI) defined as the sum of peak pressure values recorded from each activated sensor by a paw during mat contact. Fifteen French bulldogs with (n=8) and without kyphosis (n=7) were included. Cobb angle in kyphotic dogs ranged from 14.9° to 39.5°. Univariate analyses were initially performed to examine the association between kyphosis and 16 gait variables. When those variables found to be associated (P<0.2) were taken forward into multivariate generalised linear mixed models (accounting for dog, velocity and side), kyphosis had a significant effect upon TPI of the forelimbs and TPI symmetry ratio (P<0.05); however, the size of these effects was small. Although vertebral kyphosis is rarely associated with neurological deficits, it was associated with subtle alterations in kinetic gait variables (TPI forelimbs and TPI symmetry ratio). Further studies are needed to evaluate the clinical importance of altered gait variables in French bulldogs with kyphosis.

Effects of aging on brainstem responses to toneburst auditory stimuli: a cross-sectional and longitudinal study in dogs.

BACKGROUND: It is assumed that the hearing of dogs becomes impaired with advancing age, but little is known about the prevalence and electrophysiologic characteristics of presbycusis in this species. HYPOTHESIS: As in humans, hearing in dogs becomes impaired with aging across the entire frequency range, but primarily in the high-frequency area. This change can be assessed quantitatively by brainstem-evoked response audiometry (BERA). ANIMALS: Three groups of 10 mixed-breed dogs with similar body weights but different mean ages were used. At the start of the study, the mean age was 1.9 years (range, 0.9-3.4) in group I, 5.7 years (3.5-7) in group II, and 12.7 years (11-14) in group III. METHODS: In a cross-sectional study, the BERA audiograms obtained with toneburst stimuli were compared among the 3 groups. In a longitudinal study, changes in auditory thresholds of group II dogs were followed for 7 years. RESULTS: Thresholds were significantly higher in group III than in groups I and II at all frequencies tested, and higher in group II than in group I at 4 kHz. The audiograms in group II indicated a progressive increase in thresholds associated with aging starting around 8-10 years of age and most pronounced in the middle- to high-frequency region (8-32 kHz). CONCLUSIONS AND CLINICAL IMPORTANCE: Age-related hearing loss in these dogs started around 8-10 years of age and encompassed the entire frequency range, but started and progressed most rapidly in the middle- to high-frequency area. Its progression can be followed by BERA with frequency-specific stimulation.

Lingual abscesses in three dogs.

Lingual abscessation is a rare condition in dogs. Very little information is available on the diagnosis and treatment of lingual abscesses in the major surgical textbooks and current veterinary literature. The common clinical signs of lingual abscesses are macroglossia, hypersalivation and a reluctance to open the mouth, but these can vary depending on the time course of the disease and the location of the abscess. This article presents three cases of tongue abscess in the dog outlining treatment and outcomes. A thorough diagnostic work up, consisting of anamnesis, clinical and haematological examinations, oral inspection under sedation and the use of diagnostic imaging techniques should be mandatory before surgical exploration of the abscess. Surgery is followed by drainage and systemic antibiotics, complemented by systemic fluid support and pain management. Conservative management of lingual abscesses can be fatal. Sharp trauma from an unknown object is suspected to be the underlying cause for the abscesses in the present cases.

Relationship between brachycephalic airway syndrome and gastrointestinal signs in three breeds of dog.

OBJECTIVES: To assess the breed-specific prevalence of, and effects of corrective airway surgery on, gastrointestinal signs in French bulldogs, English bulldogs and pugs presenting with brachycephalic airway syndrome to a referral teaching hospital. MATERIALS AND METHODS: In this retrospective study, ptyalism, regurgitation and vomiting were graded at presentation using a previously established scoring system. Staphylectomy and nares resection were performed on all dogs. Gastrointestinal signs were re-assessed via telephone follow-up at least 6 weeks after surgery. RESULTS: Ninety-eight dogs were included: French bulldogs (n=43), English bulldogs (n=12) and pugs (n=43). Overall population prevalence of all gastrointestinal signs was 56%. Breed-specific prevalence for French bulldogs was 93%, English bulldogs 58% and pugs 16%. There was post-surgical clinical improvement in gastrointestinal signs for the whole study population, especially in French bulldogs. CLINICAL SIGNIFICANCE: The prevalence of gastrointestinal signs in dogs presenting with brachycephalic airway syndrome and improvement in these clinical signs following corrective surgery may vary between breeds.

Complications following laryngeal sacculectomy in brachycephalic dogs.

OBJECTIVES: To evaluate the effect of sacculectomy on the immediate postoperative complication rate in dogs affected with brachycephalic obstructive airway syndrome. MATERIALS AND METHODS: Retrospective review of clinical records of brachycephalic dogs with everted saccules that underwent surgery for brachycephalic obstructive airway syndrome between 2009 and 2014. Dogs were grouped as those having nares resection and staphylectomy only and those having nares resection, staphylectomy and laryngeal sacculectomy. Complications were scored as mild, moderate or severe. RESULTS: In total, 37 dogs were included in the sacculectomy group and 44 in the comparator group. Dogs that had undergone sacculectomy were more likely to develop postoperative complications, with 18 of 37 developing complications, nine of which were moderate to severe. In the group without sacculectomy, nine of 44 dogs developed complications, of which one was severe. Different breed distribution between groups might also impact this outcome. CLINICAL SIGNIFICANCE: The results suggest that sacculectomy might increase morbidity following brachycephalic airway surgery, but repeat studies are required to confirm this result. Further information is also required to determine whether the short-term risks of sacculectomy are outweighed by superior long-term functional outcome.

Combining radiation with hyperthermia: a multiscale model informed by in vitro experiments.

Combined radiotherapy and hyperthermia offer great potential for the successful treatment of radio-resistant tumours through thermo-radiosensitization. Tumour response heterogeneity, due to intrinsic, or micro-environmentally induced factors, may greatly influence treatment outcome, but is difficult to account for using traditional treatment planning approaches. Systems oncology simulation, using mathematical models designed to predict tumour growth and treatment response, provides a powerful tool for analysis and optimization of combined treatments. We present a framework that simulates such combination treatments on a cellular level. This multiscale hybrid cellular automaton simulates large cell populations (up to 107 cells) in vitro, while allowing individual cell-cycle progression, and treatment response by modelling radiation-induced mitotic cell death, and immediate cell kill in response to heating. Based on a calibration using a number of experimental growth, cell cycle and survival datasets for HCT116 cells, model predictions agreed well (R2 > 0.95) with experimental data within the range of (thermal and radiation) doses tested (0-40 CEM43, 0-5 Gy). The proposed framework offers flexibility for modelling multimodality treatment combinations in different scenarios. It may therefore provide an important step towards the modelling of personalized therapies using a virtual patient tumour.

Evaluation of Quality of Life Outcomes Following Palliative Treatment of Bone Metastases with Magnetic Resonance-guided High Intensity Focused Ultrasound: An International Multicentre Study.

AIMS: To determine quality of life (QoL) outcomes after palliation of pain from bone metastases using magnetic resonance-guided high intensity focused ultrasound (MR-guided HIFU), measured using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL and the QLQ-BM22 questionnaires. MATERIALS AND METHODS: Twenty patients undergoing MR-guided HIFU in an international multicentre trial self-completed the QLQ-C15-PAL and QLQ-BM22 questionnaires before and on days 7, 14, 30, 60 and 90 post-treatment. Descriptive statistics were used to represent changes in symptom and functional scales over time and to determine their clinical significance. QoL changes were compared in pain responders and non-responders (who were classified according to change in worst pain score and analgesic intake, between baseline and day 30). RESULTS: Eighteen patients had analysable QoL data. Clinically significant improvements were seen in the QoL scales of physical functioning, fatigue, appetite loss, nausea and vomiting, constipation and pain in the 53% of patients who were classified as responders at day 30. No significant changes were seen in the 47% of patients who were non-responders at this time point. CONCLUSION: Local treatment of pain from bone metastases with MR-guided HIFU, even in the presence of disseminated malignancy, has a substantial positive effect on physical functioning, and improves other symptomatic QoL measures. This indicated a greater response to treatment over and above pain control alone. MR-guided HIFU is non-invasive and should be considered for patients with localised metastatic bone pain and poor QoL.