Results of the ACCEL trial: Dosimetry in accelerated partial breast irradiation.

PURPOSE: To report the achieved dosimetry in the ACCEL trial and compare the results to reported dosimetry from the major accelerated partial breast irradiation (APBI) phase III trials. METHODS: The ACCEL trial was a single arm, phase II, prospective cohort study. A five-field, inverse-planned, IMRT strategy was employed using a class solution technique to increase planning consistency including high dose conformity and low normal tissue dose to the ipsilateral breast. RESULTS: Between 2016 and 2019, 283 patients were treated with 27 Gy in five fractions in consecutive days. The average PTV conformity index was 1.1. For the ipsilateral breast, the median (range) volume receiving 95% and 50% of the prescription dose was 9.7% (3.2-22.4) and 30.3% (11.1-54.6), respectively. Compared to major APBI phase III trial constraints, this reduction in irradiated volume at the 95% and 50% isodose levels represents a reduction of 209 cm3 and 265 cm3, respectively. CONCLUSION: The IMRT planning strategy employed in the ACCEL trial demonstrated consistent and superior dosimetry by comparison to conventionally used 3D CRT techniques. Future APBI trials should update dosimetric constraints.

One-Year Cosmesis and Fibrosis From ACCEL: Accelerated Partial Breast Irradiation (APBI) Using 27 Gy in 5 Daily Fractions.

PURPOSE: To report 1-year cosmesis and toxicity outcomes of a prospective, phase II trial of accelerated partial breast irradiation using intensity-modulated radiation therapy (RT) to deliver 27 Gy in 5 daily fractions. METHODS AND MATERIALS: Node-negative breast cancer patients after breast conserving surgery with clear excision margins, with physician-assessed excellent or good baseline cosmesis were invited to participate in a prospective clinical trial to receive 27 Gy in 5 daily fractions to the expanded primary site. Clinical photographs and European Organisation for Research and Treatment of Cancer cosmetic score were collected at baseline prior to RT and 1-year after radiation therapy. A protocol-specified, interim analysis was scheduled when 50 patients had completed 1-year follow-up. A panel of 6 physicians provided a consensus global cosmetic score (termed panel-assessed score) based on clinical photographs at baseline and 1-year. Fibrosis and telangiectasia were prospectively assessed by clinical research staff at clinic visits. RESULTS: At the interim analysis, 55 patients had baseline and 1-year post-RT images available. Most patients had either an improvement (53%) or no change (40%) in cosmesis from baseline to 1-year. Among 49 patients with excellent or good panel-assessed score at baseline, only 2 (4%) patients had a fair score at 1-year post-RT, indicating cosmetic deterioration. No patients had evidence of telangiectasia or grade 2 or higher fibrosis. There were no recurrences. CONCLUSIONS: APBI using 27 Gy in 5 daily fractions achieved acceptable 1-year cosmesis and no grade 2 fibrosis. A preplanned stopping rule of 5% grade 2+ fibrosis was not observed. The trial will continue to the planned target accrual of 274 patients.

Interferon response factors 3 and 7 protect against Chikungunya virus hemorrhagic fever and shock.

Chikungunya virus (CHIKV) infections can produce severe disease and mortality. Here we show that CHIKV infection of adult mice deficient in interferon response factors 3 and 7 (IRF3/7(-/-)) is lethal. Mortality was associated with undetectable levels of alpha/beta interferon (IFN-α/ß) in serum, ∼50- and ∼10-fold increases in levels of IFN-γ and tumor necrosis factor (TNF), respectively, increased virus replication, edema, vasculitis, hemorrhage, fever followed by hypothermia, oliguria, thrombocytopenia, and raised hematocrits. These features are consistent with hemorrhagic shock and were also evident in infected IFN-α/ß receptor-deficient mice. In situ hybridization suggested CHIKV infection of endothelium, fibroblasts, skeletal muscle, mononuclear cells, chondrocytes, and keratinocytes in IRF3/7(-/-) mice; all but the latter two stained positive in wild-type mice. Vaccination protected IRF3/7(-/-) mice, suggesting that defective antibody responses were not responsible for mortality. IPS-1- and TRIF-dependent pathways were primarily responsible for IFN-α/ß induction, with IRF7 being upregulated >100-fold in infected wild-type mice. These studies suggest that inadequate IFN-α/ß responses following virus infection can be sufficient to induce hemorrhagic fever and shock, a finding with implications for understanding severe CHIKV disease and dengue hemorrhagic fever/dengue shock syndrome.

Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3).

PURPOSE: Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G(1) phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT. METHODS AND MATERIALS: A total of 216 patients were randomized to morning (8-10 AM) vs. afternoon (4-6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system. RESULTS: Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66-70 Gy in 33-35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025). CONCLUSION: In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving >/=66 Gy and in patients who smoked during therapy.

The Development of Simple Daily Jaw Exercises for Patients Receiving Radical Head and Neck Radiotherapy.

INTRODUCTION: Patients who receive radical radiotherapy to the head and neck may suffer from the late side effect of trismus due to radiation of the jaw. Trismus is progressive once it starts, and can be debilitating due to difficulty eating and inability to perform proper dental hygiene. Although radiotherapy to the temporomandibular joint can restrict mouth opening, the pterygoid muscles-which are responsible for lateral and protrusive motions of the jaw-are more sensitive to radiation. Therefore, damage to these muscles will also limit mouth opening. METHOD: A series of simple jaw exercises was designed to help patients maintain jaw mobility and reduce the effect of trismus. In the study, one group of patients used the exercises and the other did not. To assess whether trismus was occurring, dental gap measurements (measurements taken with a ruler from upper incisor to lower incisor, or gum-to-gum) were taken at the start of radiotherapy treatment and again at scheduled follow-up appointments. RESULTS: There was an overall statistically significant difference between the dental gap measurements of the jaw exercise and the no-jaw exercise group (P = .01, assuming the statistical significance level is .05). Patients who performed the jaw exercises were able to open their mouths wider than the patients who did not do them. Although there appeared to be a difference in decreasing dental gap across time between the two groups in the study, the Wald test did not find this to be statistically significant (P = .1). The use of chemotherapy was not statistically significant; that is, chemotherapy could not be linked with trismus in this study (P = .6171). CONCLUSION: The results of this study demonstrate that jaw exercises can be a useful aid to help prevent side effects of trismus due to radiotherapy treatment. Although it is not possible to accurately quantify the effect in this study due to the use of a compensator technique, this intervention was easy to implement and simple for patients to undertake. The jaw exercises continue to be used in the Cancer Centre for the Southern Interior, and a recent revision to the jaw exercises was made with the collaboration of the dental department.

A novel Cys1638Tyr NC1 domain substitution in alpha5(IV) collagen causes Alport syndrome with late onset renal failure without hearing loss or eye abnormalities.

BACKGROUND: Mutations in the type IV collagen gene, COL4A5, are associated with Alport syndrome, characterized by ultrastructural abnormalities of the glomerular basement membrane (GBM), with or without progressive loss of renal function, characteristic ophthalmic signs and/or high tone sensorineural deafness. More than 300 sequence variants in type IV collagen have been identified, including alterations in the non-collagenous NC1 domain. METHODS: We performed linkage analysis and sequencing to identify the mutation in a New Zealand family with Alport glomerulonephritis and late onset renal failure without hearing loss or eye abnormalities. RESULTS: We report a novel c.4913G>A (p.Cys1638Tyr) alteration in the NC1 domain of COL4A5, identified in a moderately large family, eight of whom were confirmed by renal biopsy to have renal abnormalities. Only three of eight mutant male members of the pedigree progressed to end-stage renal failure. The remaining five mutant males exhibit either chronic renal disease at age 36, 46 and 72, or as yet show no renal disease at ages 39 and 39. Extra-renal manifestations such as sensorineural deafness or ocular changes were absent from all family members carrying the mutation. CONCLUSION: This variant is the first reported to affect the tenth of 12 cysteine residues in the NC1 domain. We conclude that the cysteine to tyrosine substitution in the NC1 domain of the alpha5(IV) collagen chain in this family leads to a mild form of Alport syndrome, including absence of extra-renal features.