[Radiation therapy in veterinary medicine at the University of Liège]. / Radiothérapie en médecine vétérinaire à l'Université de Liège.

Radiation therapy has many indications in veterinary oncology and allows a multidisciplinary approach for the treatment of canine and feline patients. Radiation therapy can be recommended as a sole therapy in case of radiosensitive tumors or can be associated to surgery and/or chemotherapy after marginal excision for example. It can also be recommended as a palliative treatment for patients with an inoperable or painful tumor or disseminated disease. Radiation therapy significantly improves the quality of life and survival time of treated animals and should be part of the therapeutic modalities in veterinary medicine. The University of Liège developed the first veterinary center of radiation therapy in Belgium and can therefore participate in improving therapeutic management of cancerous animal patients.

La radiothérapie présente de nombreuses indications en oncologie vétérinaire et permet une approche multidisciplinaire pour le traitement de nos patients cancéreux canins et félins.La radiothérapie peut être recommandée seule pour le traitement de tumeurs radiosensibles, ou associée à la chirurgie et/ou la chimiothérapie notamment lors d'exérèse marginale. Elle a également sa place dans une prise en charge palliative de certains patients présentant une tumeur inopérable ou douloureuse, ou encore une maladie disséminée. La radiothérapie permet d'améliorer significativement la qualité et l'espérance de vie des animaux traités et à ce titre, doit faire partie de l'arsenal thérapeutique vétérinaire. L'Université de Liège possède, depuis peu, l'unique centre de radiothérapie vétérinaire en Belgique et peut ainsi participer à l'amélioration de la prise en charge des animaux cancéreux.

Effect of pituitary-dependent hypercortisolism on the survival of dogs treated with radiotherapy for pituitary macroadenomas.

BACKGROUND: Radiotherapy (RT) is an effective treatment for dogs presented with neurologic signs caused by pituitary tumors. However, its impact on the outcome of concurrent pituitary-dependent hypercortisolism (PDH) is controversial. OBJECTIVES: Determine whether dogs with PDH have longer survival after pituitary RT compared with dogs with nonhormonally active pituitary masses and to evaluate whether clinical, imaging, and RT variables affect survival. ANIMALS: Ninety-four dogs divided into 2 groups: PDH and non-PDH, based on the presence of hypercortisolism. Forty-seven dogs were allocated to the PDH group and 47 to the non-PDH group. METHODS: Retrospective cohort study in which clinical records of dogs undergoing RT for pituitary macroadenomas between 2008 and 2018 at 5 referral centers were retrospectively evaluated. RESULTS: Survival was not statistically different between PDH and non-PDH groups (median survival time [MST], 590 days; 95% confidence interval [CI], 0-830 days and 738 days; 95% CI, 373-1103 days, respectively; P = .4). A definitive RT protocol was statistically associated with longer survival compared with a palliative protocol (MST 605 vs 262 days, P = .05). The only factor statistically associated with survival from multivariate Cox proportional hazard analysis was total radiation dose (Gy) delivered (P < .01). CONCLUSIONS AND CLINICAL IMPORTANCE: No statistical difference in survival was identified between the PDH and non-PDH groups, and longer survival was associated with higher Gy delivered.

Non-injection-site soft tissue sarcoma in cats: outcome following adjuvant radiotherapy.

OBJECTIVES: Biological behaviour and treatment options of non-injection-site soft tissue sarcomas (nFISS) in cats are less well understood than in dogs. The aim of this retrospective study was to assess the outcomes of cats with nFISS following treatment with adjuvant radiotherapy. METHODS: The medical records of cats with soft tissue sarcomas in locations not associated with, and histology reports not suggestive of, injection-site sarcomas were reviewed. All cats underwent adjuvant radiotherapy, either hypofractionated (32-36 Gy delivered in weekly 8-9 Gy fractions) or conventionally fractionated (48-54 Gy delivered in 16-18 3 Gy fractions) to microscopic disease. RESULTS: In total, 18 cats were included in the study, 17 with extremity nFISS and one with facial nFISS. Nine received radiotherapy after a single surgery and nine after multiple surgeries for recurrent nFISS. Eight cats were treated with a hypofractionated protocol and 10 with a conventionally fractionated protocol. The median follow-up time was 540 days (range 51-3317 days). The tumour recurred in eight (44.4%) cats following adjuvant radiotherapy; it recurred in three (37.5%) cats following a hypofractionated protocol and in five (50%) cats following a conventionally fractionated protocol. The overall median progression-free interval (PFI) for 17/18 cats was 2748 days, while the median PFI for the 7/8 cats with recurrence was 164 days. The recurrence for one cat was reported, but the date was unknown and it was therefore censored from these data. When stratifying based on the protocol, the median PFI for hypofractionated and conventionally fractionated protocols was 164 days and 2748 days, respectively. Statistically, there was no significant difference between the two protocols (P = 0.636). CONCLUSIONS AND RELEVANCE: Adjuvant radiotherapy resulted in good long-term tumour control in 12/18 cats with nFISS. Further studies in larger populations are required to assess the significance of radiation dose and fractionation on tumour control and the effect of multiple surgeries prior to initiation of radiotherapy on outcome.

The out-of-field dose in radiation therapy induces delayed tumorigenesis by senescence evasion.

A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1-40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient's treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks. Importantly, a few of these senescent cells systematically and spontaneously escape from the cell cycle arrest after a while to generate daughter cells harboring mutations and invasive capacities. These findings highlight single-strand break-induced senescence as the mechanism of second primary cancer initiation, with clinically relevant spatiotemporal specificities. Senescence being pharmacologically targetable, they open the avenue for second primary cancer prevention.

Excisional biopsy and radiotherapy for management of an olfactory neuroblastoma in an axolotl (Ambystoma mexicanum).

CASE DESCRIPTION: A 4-year-old sexually intact male leucistic axolotl (Ambystoma mexicanum) was presented with a 2-week history of dysrexia and difficulty swallowing. CLINICAL FINDINGS: Physical examination revealed a 1-cm-diameter intraoral mass on the rostral aspect of the palate and swelling of the left nasal fossa. Local invasion into the left nasal fossa was suspected during oral examination. The lesion was marginally excised, and an incompletely excised olfactory neuroblastoma was diagnosed histologically. Five weeks later, physical examination revealed persistent erythema, delayed healing of the rostral portion of the palate, and a mild facial deformity associated with a white mass in the nasal cavity. TREATMENT AND OUTCOME: 6 weeks after excision, adjuvant electron (6-MeV) beam radiotherapy was initiated for treatment of the incompletely excised olfactory neuroblastoma and likely presence of a recurrent mass. The protocol consisted of 4 weekly fractions of 8 Gy each (total, 32 Gy) with the axolotl under anesthesia. No acute adverse radiation effects were noted following radiotherapy. The oral erythema resolved after the third session. No recurrence was observed 2 months after treatment, and the owners reported no abnormal signs at home. The axolotl died 3.5 months after radiotherapy was completed (8 months after marginal excision of the tumor) secondary to an environmental management failure. Postmortem histologic evaluation showed no evidence of neoplasia. CLINICAL RELEVANCE: In axolotls, olfactory neuroblastoma should be considered in the differential diagnosis of intraoral palatal masses. This report describes the first application of radiotherapy for treatment of an olfactory neuroblastoma in an axolotl.

Outcomes of adjunctive radiation therapy for the treatment of mast cell tumors in dogs and assessment of toxicity: A multicenter observational study of 300 dogs.

BACKGROUND: Radiation therapy is commonly used as an adjunct to incomplete surgical excision in dogs with mast cell tumors (MCT), but the optimal dose and fractionation regimen have yet to be determined. HYPOTHESIS: We assessed outcomes (time to local recurrence, patient survival and toxicity) of a large population of dogs with MCT that received adjunctive radiation therapy. ANIMALS: Three hundred dogs with 302 MCT treated using adjunctive radiation therapy. METHODS: Retrospective observational study. Clinical records of 4 veterinary radiation centers were reviewed. RESULTS: Local recurrence rates were similar regardless of radiation protocol with 6.6% of patients developing recurrent cutaneous MCT at a median of 526 days. Local recurrence rate was similar between high and low-risk MCT. Mast cell tumor related death was reported in 19% of all dogs, with 13% of dogs with low-risk MCT dying of their disease compared to 29% of dogs with high-risk MCT. No SC MCT (SCMCT) recurred after radiation therapy and only 7% of dogs with SCMCT were reported to have died of their disease. Mild late toxicity was common in both protocols and severe late toxicity occurred in 1.9% of dogs many years after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study supports the use of adjunctive radiation for the long-term control of incompletely or narrowly excised cutaneous and SCMCT in dogs. More moderate dose and fractionation protocols may be appropriate in the adjunctive treatment of low-risk MCT in dogs. Large multicenter prospective studies are required to establish the optimal dose and fractionation for MCT of different risk categories.

Outcome After Radiation Therapy in Canine Intracranial Meningiomas or Gliomas.

AIM: To characterize a group of dogs diagnosed with meningioma or glioma treated with radiation therapy and assess the clinical impact of diagnosis and radiation protocol on survival time. PATIENTS AND METHODS: Canine patient records from a single veterinary referral hospital, between 2011 and 2015, were searched for intracranial tumour cases treated with radiation therapy, as a sole modality. Thirty-two dogs were included. RESULTS: Median survival times were 524 days [95% confidence interval (CI)=287-677] in total, 512 days (95% CI=101-682) for the glioma group and 536 days (95% CI=249-677) for the meningioma group. No significant difference in survival was detected when using a definitive or a palliative protocol (p=0.130), nor other prognostic factors were found. CONCLUSION: Our results highlight the efficacy of radiation therapy in the treatment of canine meningioma, as well as glioma, suggesting a change in the current perception of the response of glial tumours to radiation.

Influence of External Beam Radiotherapy on the Properties of Polymethyl Methacrylate-Versus Silicone-Induced Membranes in a Bilateral Segmental Bone Defect in Rats.

INTRODUCTION: Standard care for malignant tumors arising next to a bone structure is surgical removal with safety margins, followed by external beam radiotherapy (EBRT). Complete tumor removal can result in large bone defects. A two-step bone reconstruction technique using the induced membrane (IM) technique has proven its efficacy to bridge gap nonunion. During the first step, a spacer is placed in the bone gap. The spacer then is removed and the IM around it is filled with autologous cancellous bone graft. However, the feasibility of this technique with the addition of adjuvant EBRT between the two reconstruction steps has not yet been studied. Polymethyl methacrylate (PMMA) used to be the standard spacer material for the first step. Silicone spacers could replace them owing to their good behavior when submitted to EBRT and their easier removal from the surgical site during the second step. The aim of this study was to evaluate the influence of EBRT on the histological and biochemical properties of IM induced using PMMA or silicone as spacer. MATERIALS AND METHODS: The analyses were performed on PMMA- or silicone-IM with and without EBRT in a 6-mm bilateral femoral defect in 32 rats. Thickness and vessel content were measured in both groups. Bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF) content in lysates of the crushed membranes were measured by enzyme immunoassay. Finally, alkaline phosphatase activity was analyzed in human bone marrow stromal cell cultures in contact with the same lysates. RESULTS: EBRT did not change the histological structure of the cellular internal layer or the fibrous outer layer. The nature of the spacer only influenced IM thickness, PMMA-IM with external radiotherapy being significantly thicker. EBRT decreased the vascular density of IM but was less effective on VEGF/BMP2 production. In vitro, IM could have an osteoinductive potential on human bone marrow stem cells. CONCLUSION: EBRT did not modify the histological properties of IMs but decreased their vascular density. VEGF and BMP2 production within IMs was not affected by EBRT. Silicone spacers are able to induce membranes with similar histological characteristics to PMMA-IM.

RETROSPECTIVE COMPARISON OF THREE-DIMENSIONAL CONFORMAL RADIATION THERAPY VS. PREDNISOLONE ALONE IN 30 CASES OF CANINE INFRATENTORIAL BRAIN TUMORS.

Infratentorial tumors are relatively infrequent in dogs and a lack of data makes it difficult to offer prognostic information. Untreated, dogs with these neoplasms have shorter survival times than those with supratentorial tumors. The role of radiation therapy (RT) in the management of infratentorial tumors is poorly defined and tumoral/peritumoral swelling in this site is a potential cause of serious acute side effects. The aim of this retrospective, cohort study was to describe cases of infratentorial tumors treated with fractionated three-dimensional conformal RT (3D CRT) and glucocorticoids (GC), and compare outcomes and survival with dogs affected by tumors in the same location that received GC alone. Thirty patients with a MRI diagnosis of infratentorial tumors were recruited (15 received RT and GC and 15 GC alone). None had mentation changes at presentation. For both groups, MRI and medical records were reviewed; and factors associated with survival were evaluated with Kaplan-Meier product limit survival and Cox regression analysis. Overall median survival time (MST) was 294 days (95% CI 42-545). The MST in the RT group was 756 days (95% CI 209-1302) vs. 89 days (95% CI 34.7-143.3 days) for those dogs treated palliatively with GC alone. This difference was statistically significant (P = 0.001). No other factors (including neurological signs, MRI features, tumor volume and total RT dose) were statistically associated with survival in the RT group. This study suggests that 3D CRT offers a survival advantage for dogs with infratentorial tumors compared to GC alone, and significant complications are uncommon.

Evaluation of an Accelerated Chemoradiotherapy Protocol for Oropharyngeal Squamous Cell Carcinoma in 5 Cats and 3 Dogs.

Accelerated radiation therapy protocols address the specific biology of aggressive oropharyngeal squamous cell carcinoma and this approach was applied in 5 feline and 3 canine oropharyngeal squamous cell carcinoma patients where surgery was not possible (4/5 feline and 2/3 canine cases) or was declined (1/5 feline and 1/3 canine cases). A protocol using 14 fractions of 3.5 Gy over 9-days, combined with carboplatin chemotherapy as a radiosensitiser (total dose 180 mg/m2 in feline and 300 mg/m2 in canine cases) resulted in a complete tumor response in most cases (4/5 feline and 3/3 canine cases) with acceptable acute and long-term side effects. Results achieved in feline cases correspond with published data where these specific radiotherapy protocols were employed. A complete response and long-term survival (> 2-years) was achieved in all canine patients. Although no standardized chemoradiotherapy protocols currently exist, this therapeutic approach can be a useful addition for the management of oropharyngeal squamous cell carcinoma of cats and dogs when the goals of treatment include maximizing tumor control while maintaining function and quality of life.

Thyroid carcino-sarcoma in a dog.

An adult male greyhound was diagnosed with a thyroid carcino-sarcoma by means of histopathology and positive immuno-histochemistry staining for cytokeratin and vimentin. Surgery and radiotherapy of the area were successful in local tumour control. Adjuvant chemotherapy was recommended to treat and prevent further metastasis. The use of carboplatin, metronomic cyclophosphamide chemotherapy and toceranib failed to control the progression of distant metastasis. The survival time was seven months from the time of diagnosis. This is the eighth case of carcino-sarcoma of the thyroid documented in veterinary medicine and the first one treated with a multimodal approach based on surgery, radiotherapy and chemotherapy. As documented in human medicine, chemotherapy appeared to be ineffective to prevent or delay the progression of the metastatic disease in this case.

The effect of curcumin on the stability of Aß dimers.

Aß oligomers are potential targets for the diagnosis and therapy of Alzheimer's disease (AD). On the other hand, the molecule curcumin has been shown to possess significant therapeutic potential in many areas. In this paper, we use all-atom explicit solvent molecular dynamics simulations to study the effect of curcumin on the stability of Aß amyloid protein oligomers. We observed that curcumin decreases the ß-sheet secondary structural content within the Aß oligomers without reducing the contacts between the monomers. The breaking of the ß-sheet is found to be preceded by a deformation of the ß-sheet structure due to hydrophobic interaction from the nearby curcumin. Furthermore, the π-stacking interaction between curcumin (keto ring and enol ring) and the aromatic residues of Aß, which exists throughout the simulations, has also contributed to the diminishing of the ß-sheet structure. Our analysis of the underwrapped amide-carbonyl hydrogen bonds reveals several stable dehydrons of the oligomer, especially the dehydron pair 34L and 41I, which curcumin tends to hover over. We have examined the paths of curcumin on the Aß proteins and determined the common routes where curcumin lingers as it traverses around the Aß. In consequence, our study has provided a detailed interaction picture between curcumin and the Aß oligomers.

Amyloid ß peptides aggregation in a mixed membrane bilayer: a molecular dynamics study.

The aggregation of amyloid ß peptides resulting in neurotoxic oligomers is an important but yet mysterious process in Alzheimer's disease development. Molecular dynamics simulations were performed to investigate the self-assembly of three full-length amyloid peptides in the zwitterionic dipalmitoylphosphatidylcholine and cholesterol mixed lipid bilayer. During the 1000 ns simulation, the residues 1-27 were found to interact preferentially with the lipid-aqueous interface region, while residues 28-42 show an inclination to remain inside the bilayer hydrophobic tail region. The interaction between peptides and lipids has facilitated the association of Aß peptides. However, the interaction between cholesterol and peptides is inversely correlated with the extent of the peptide-peptide interactions. Our simulation has uncovered the formation of a short segment of parallel ß-sheet between two peptide chains. In another chain, the N- and C-termini came close to each other. All the structural transitions indicate that our simulation has caught a glimpse of the complicated peptide oligomerization process. The full understanding of the underlying mechanism still requires further experimental and theoretical studies.

Effect of wetness level on the suitability of wet gauze as a substitute for Superflab as a bolus material for use with 6 mv photons.

Despite the availability of commercial tissue equivalent bolus material, wet gauze has an application in radiation therapy to provide superior conformance to irregular contours. Wet gauze bolus has the potential to reduce air gaps between the bolus and surface, which could decrease surface dose if sufficiently large to disrupt electronic equilibrium. Wet gauze bolus is often fabricated and wetness judged qualitatively. We assessed the effect of specific gauze wetness levels, quantified in terms of physical density, at various field sizes with respect to their effectiveness as bolus material compared with Superflab. For large fields, > 7 x 7 cm2 in this study, wet gauze sponges with a physical density of 1.02 g/cm3 performed essentially identical to Superflab; at a smaller field size the wet gauze was slightly less effective, likely due to the heterogeneity of the gauze-water matrix. Gauze that was wetter, with a physical density of 1.2 g/cm3, or less wet, with a physical density of 0.75 g/cm3 was not as effective either due to enhanced photon absorption in the wetter sponges, or less effective establishment of electronic equilibrium in the less wet sponges. The presence of an air gap under Superflab led to reduced surface dose, especially for small fields and large air gaps. Thus, if Superflab use leads to poor contact with the skin, wet gauze having a physical density of 1.02 g/cm3 can be used as a substitute. Judging the water content of wet gauze subjectively is not acceptable as over- or under wetness can lead to decreased effectiveness of the bolus material.

Spherical vesicles distorted by a grafted latex bead: an exact solution.

We present an exact solution to the problem of the global shape description of a spherical vesicle distorted by a grafted latex bead. This solution is derived by treating the nonlinearity in bending elasticity through the (topological) Bogomol'nyi decomposition technique and elastic compatibility. We recover the "hat-model" approximation in the limit of a small latex bead and find that the region antipodal to the grafted latex bead flattens. We also derive the appropriate shape equation using the variational principle and relevant constraints.