Evaluation of single-fraction high dose FLASH radiotherapy in a cohort of canine oral cancer patients

BackgroundFLASH radiotherapy (RT) is a novel method for delivering ionizing radiation, which has been shown in preclinical studies to have a normal tissue sparing effect and to maintain anticancer efficacy as compared to conventional RT. Treatment of head and neck tumors with conventional RT is commonly associated with severe toxicity, hence the normal tissue sparing effect of FLASH RT potentially makes it especially advantageous for treating oral tumors. In this work, the objective was to study the adverse effects of dogs with spontaneous oral tumors treated with FLASH RT.MethodsPrivately-owned dogs with macroscopic malignant tumors of the oral cavity were treated with a single fraction of ≥30Gy electron FLASH RT and subsequently followed for 12 months. A modified conventional linear accelerator was used to deliver the FLASH RT.ResultsEleven dogs were enrolled in this prospective study. High grade adverse effects were common, especially if bone was included in the treatment field. Four out of six dogs, who had bone in their treatment field and lived at least 5 months after RT, developed osteoradionecrosis at 3-12 months post treatment. The treatment was overall effective with 8/11 complete clinical responses and 3/11 partial responses.ConclusionThis study shows that single-fraction high dose FLASH RT was generally effective in this mixed group of malignant oral tumors, but the risk of osteoradionecrosis is a serious clinical concern. It is possible that the risk of osteonecrosis can be mitigated through fractionation and improved dose conformity, which needs to be addressed before moving forward with clinical trials in human cancer patients

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer : international expert consensus based on a modified Delphi process

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or>100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process.Peer reviewe

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer: international expert consensus based on a modified Delphi process

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or >100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process

Tetraazaperopyrenes: A new class of multifunctional chromophores

Tetra azaperopyrene and a range of derivatives have been synthesised and their photophysical and redox-chemical properties studied. The parent compound, 1,3,8,10-tetraazaperopyrene (1), was prepared by treating 4,9-diamino-3,10-perylenequinone diimine with triethyl orthoformate, whereas the 2,9-disubstituted derivatives of 1 were obtained after treatment with the corresponding carboxylic acid chloride or anhydride (2 mol equiv). The 1,3,8,10-tetraazaperopyrene core structure was established by X-ray diffraction of 2,9-bis(2-bromophenyl)-1,3,8,10- tetra azaperopyrene (6). The UV-visible absorption spectra of the compounds have a characteristic visible pi(*) <- pi absorption band at 440 nm (log epsilon(max),=4.80) with a strong vibrational progression (Delta v approximate to 1450 cm(-1)). Diprotonation of the nitrogen atoms induces a bathochromic shift of this band from 430-440 to 470-480 mm and all four nitrogen atoms are protonated when pure H2SO4 is used as the solvent. The first and second as well as the third and fourth protonations occur concomitantly, which implies that they have very similar pKa values and, consequently, similar proton affinities. A theoretical study of the proton affinities in the gas phase and in solution attributes this behaviour to the effects of polar solvents, which dampen the charge of a protonated site at the other end of the molecule and thus effectively decouple the two opposite pyrimidine units in the polycondensed aromatic compound. The photophysical data were modelled in a time-dependent DFT study of 1, 1H(2)(2+) and 1H(4)(4+) in both the gas phase and in a polar solvent. All the dyes show weak fluorescence in organic solvents, however, their protonated conjugate acids show dramatically increased fluorescence intensity. All of the dyes undergo two electrochemically reversible one-electron reductions with cyclovoltammetric half-wave potentials at E (red1) approximate to -0.9 V and E-red2 approximate to -1.3 V (vs. SCE), which are associated with characteristic spectral changes

Intracavitary Electron FLASH Radiotherapy in a Canine Cancer Patient With Oral Malignant Melanoma

PURPOSE/OBJECTIVE(S): Studies of electron FLASH radiotherapy (FLASH-RT) in companion animals are being conducted at several institutions. High energy electron beams are generally suitable for treatment of superficial cancers, but of limited use for deep-seated tumors. In this case report, the feasibility of intracavitary electron FLASH-RT is demonstrated.MATERIALS/METHODS: A canine cancer patient with a large oral malignant melanoma in the caudal part of the hard palate was palliatively treated with FLASH-RT at a modified clinical linear accelerator, using a cylindrical PMMA applicator (length 200 mm, inside diameter 50 mm). The patient had a poor prognosis, with an estimated survival of two weeks and no other available treatment options. A dose of 35 Gy was delivered to the depth of dose maximum in 26 pulses with a pulse dose rate of 4.5•105 Gy/s. The average dose rate was 280 Gy/s, corresponding to a total beam-on time of 125 months. One month after the treatment, the tumor was re-irradiated, using the same treatment parameters. The treatment head of the LINAC was fitted with a short electron applicator holder with a Cerrobend collimator at 65 cm from the source. The cylindrical PMMA applicator was aligned perpendicularly to the Cerrobend collimator using soft docking with a 1 cm gap. Prior to the treatments, the 2D dose distribution of the FLASH beam exiting the PMMA applicator was measured with radiographic film. In addition, the dosimetric effect of misalignment between the collimator and the electron applicator was studied based on intentional misalignments of 2.5°, 5°, 2.5 mm, and 5 mm.RESULTS: A partial response of the tumor and clinical improvement of the patient was observed two weeks after the first treatment. A hypopigmented area in the hard palate was observed, consistent with a grade 1 adverse event, but there were no signs of mucositis or reports of patient discomfort. However, due to the thickness of the tumor (> 3 cm), the posterior part only received a limited dose, and the tumor was still obstructing the airflow at one month post treatment. At this time, a second treatment was administered with limited normal tissue receiving full dose from both treatments. At one month post the second treatment, a partial response was achieved, and no evidence of side effects other than hypopigmentation was observed. The patient was euthanized 2.5 months after the initial therapy due to progressive disease involving the oropharynx. The dosimetric evaluation showed that a conformal dose distribution could be obtained by delivering the electron beam using a cylindrical PMMA applicator. Misalignments between the applicator and the collimator were shown to result in reduced dose homogeneity.CONCLUSION: This case report of a canine cancer patient, with a large oral malignant melanoma in the caudal part of the hard palate, has demonstrated the feasibility of intracavitary electron FLASH-RT. Two treatments of 35 Gy each, resulted in prolonged survival and increased quality-of-life