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Background Breast cancer is the leading cause of global cancer incidence. In early-stage disease, standard treatment with breast-conserving surgery followed by whole breast irradiation (WBI) is associated with excellent outcomes. Multiple studies with extensive follow-up periods have demonstrated the comparative efficacy and toxicity outcomes of partial breast irradiation (PBI) in contrast to WBI. Various dose fractionation schedules for PBI have been recommended in clinical practice guidelines. In British Columbia (BC), a dose of 26 Gy in 5 fractions has been adopted. Early studies on single-fraction (SF) radiation for PBI have investigated its safety and effect on cosmetic outcomes, with promising initial results. In the context of the ongoing health care crisis, single-fraction PBI has the potential to reduce wait times and improve access to radiation. This study will therefore investigate a single-fraction PBI dose of 13 Gy. Methods This is a phase II randomized controlled trial, with a primary objective of testing the feasibility of randomizing participants to 1 vs. 5 fractions of PBI for early stage, node negative, breast cancer. The primary endpoint is the ability to accrue 60 participants at 4 of the 6 BC Cancer centres over a 2- year period and to randomize them to 1 vs. 5 fractions of radiotherapy for PBI. Its secondary endpoints are time from CT simulation to partial breast radiotherapy, local control rates, quality of life as measured by Prospective Outcomes and Support Initiative (POSI)-Breast, rates of provider-rated toxicities as measured by Common Terminology Criteria for Adverse Events (CTCAE), rates of participant-reported toxicities as measured by participant reported outcome version of CTCAE (PRO-CTCAE), overall survival, and progression-free survival. Discussion One of the trial’s objectives is testing the feasibility of randomizing participants to single vs. multiple fractions for PBI. If successful, it will lead to a phase III non-inferiority trial with the potential to inform breast cancer treatment guidelines. Ultimately, if found to be non-inferior, a single-fraction PBI can reduce wait times, facilitate access to radiation, and improve patient convenience, particularly for those in rural and remote communities who must travel long distances to receive high-quality cancer care. Trial registration Clinicaltrials.gov identifier: NCT06885671. Date of Registration: 14 March 2025.

As cancer survivors live longer, technologies improve, and reirradiation (reRT) becomes more common, standardised methods for the assessment and reporting of cumulative radiation doses are needed to allow treatment optimisation and integration with other medical specialties managing these complex patients. This consensus statement, developed by an international collaboration of radiation oncologists, physicists, and other experts in the Reirradiation Collaborative Group, proposes a framework for consistent evaluation, documentation, reporting, and clinical decision making in reRT. This paper outlines practical strategies for dose accumulation from multiple courses of radiation therapy with the use of both image registration-based and point dose-based methods, accounting for uncertainties in data availability, physiological organ recovery, and anatomical changes. The emphasis of the consensus statement is on institutional workflows, improved software tools, and better capture of longitudinal patient outcomes. We also highlight the need for improved biological models, data infrastructure, and cross-specialty collaboration. Ultimately, reRT is framed as a transformative challenge for oncology, demanding interdisciplinary innovation across science, clinical care, and health systems. Widespread adoption of these recommendations could accelerate progress toward improved outcomes for patients receiving reRT worldwide.

Background Oligometastases refer to a state of disease where cancer has spread beyond the primary site, but is not yet widely metastatic, often defined as 1–3 or 1–5 metastases in number. Stereotactic ablative radiotherapy (SABR) is an emerging radiotherapy technique to treat oligometastases that require further prospective population-based toxicity estimates. Methods This is a non-randomized phase II trial where all participants will receive experimental SABR treatment to all sites of newly diagnosed or progressing oligometastatic disease. We will accrue 200 patients to assess toxicity associated with this experimental treatment. The study was powered to give a 95% confidence on the risk of late grade 4 toxicity, anticipating a < 5% rate of grade 4 toxicity. Discussion SABR treatment of oligometastases is occurring off-trial at a high rate, without sufficient evidence of its efficacy or toxicity. This trial will provide necessary toxicity data in a population-based cohort, using standardized doses and organ at risk constraints, while we await data on efficacy from randomized phase III trials. Trial Registration Registered through clinicaltrials.gov NCT02933242 on October 14, 2016 prospectively before patient accrual.

Background Bone metastases in the lower spine and pelvis are effectively palliated with radiotherapy (RT), though this can come with side effects such as radiation induced nausea and vomiting (RINV). We hypothesize that high rates of RINV occur in part because of the widespread use of inexpensive simple unplanned palliative radiotherapy (SUPR), over more complex and resource intensive 3D conformal RT, such as volumetric modulated arc therapy (VMAT). Methods This is a randomized, multi-centre phase III trial of SUPR versus VMAT. We will accrue 250 patients to assess the difference in patient-reported RINV. This study is powered to detect a difference in quality of life between patients treated with VMAT vs. SUPR. Discussion This trial will determine if VMAT reduces early toxicity compared to SUPR and may provide justification for this more resource-intensive and costly form of RT. Trial registration Clinicaltrials.gov identifier: NCT03694015 . Date of registration: October 3, 2018.

Background Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. Methods This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. Discussion This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. Trial registration Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Radiation therapy, or radiotherapy, is a commonly prescribed treatment for cancer, where ionizing radiation is used to disrupt the process of cellular reproduction in tumours. One form of radiotherapy is external beam radiation therapy, where beams of radiation are focused onto the patient from an external source. Unfortunately, for deep seated tumours, delivering a tumourcidal dose may result in excessive exposure of the normal tissue, and the patient may suffer complications. One strategy for safely escalating the tumour dose is conformal radiotherapy, where specially shaped beams deliver radiation from multiple angles around the patient. Intensity modulated radiation therapy (IMRT) takes this further, by also varying the fluence within each shaped beam. Very precise three-dimensional regions of high dose can be delivered by using computers to optimize the IMRT fluence patterns. This process is called 'inverse planning'. Tomotherapy is a special form of IMRT where a treatment is delivered by revolving a fan beam around a patient lying on a dynamic couch. The Medical Physics group at the Cancer Centre of Southeastern Ontario has been assessing the feasibility of using a Cobalt-60 (Co-60) radiation source for tomotherapy. The goal of this thesis is the development of an inverse planning method suitable for our experimental system, so that simulations of clinically relevant treatments can be performed. (Abstract shortened by UMI.)

Fabry disease is caused by a deficiency of α-galactosidase A (GLA) leading to the lysosomal accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids. Fabry patients experience significant damage to the heart, kidney, and blood vessels that can be fatal. Here we apply directed evolution to generate more stable GLA variants as potential next generation treatments for Fabry disease. GLAv05 and GLAv09 were identified after screening more than 12,000 GLA variants through 8 rounds of directed evolution. Both GLAv05 and GLAv09 exhibit increased stability at both lysosomal and blood pH, stability to serum, and elevated enzyme activity in treated Fabry fibroblasts (19-fold) and GLA –/– podocytes (10-fold). GLAv05 and GLAv09 show improved pharmacokinetics in mouse and non-human primates. In a Fabry mouse model, the optimized variants showed prolonged half-lives in serum and relevant tissues, and a decrease of accumulated Gb3 in heart and kidney. To explore the possibility of diminishing the immunogenic potential of rhGLA, amino acid residues in sequences predicted to bind MHC II were targeted in late rounds of GLAv09 directed evolution. An MHC II-associated peptide proteomics assay confirmed a reduction in displayed peptides for GLAv09. Collectively, our findings highlight the promise of using directed evolution to generate enzyme variants for more effective treatment of lysosomal storage diseases.

Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real‐world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia‐Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow‐up time of 29.5 months (interquartile range 13.3–54.3 months) were included in the analysis – 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in‐situ hybridisation status, receive first‐line myeloma treatment with immunomodulatory drugs or anti‐CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow‐up (adjusted hazard ratio 0.72, 95% CI 0.46–1.14, p = 0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources.

Background: Endovascular therapy for lower-limb arterial disease is widely performed today. A vast array of sheaths, catheters, wires, balloon types, stents, and tools such as atherectomy, thrombectomy, and lithotripsy devices are now available to achieve the best outcomes in terms of vessel patency and ultimately limb salvage. The use of atherectomy devices, however, has raised some controversies in terms of outcome efficacy, cost effectiveness, and safety profile in various series and studies. Objectively, the types and disease pattern in these studies are also greatly heterogeneous. Methods: Here, we reported three cases which exemplify how these atherectomy devices have served as a valuable tool, especially for patients with complex and heavily calcified lesions. Results: The three cases highlighted scenarios where atherectomy displayed good outcomes, each involving the use of atherectomy devices to treat highly calcified vessels. Conclusions: Despite the concerns with atherectomy devices, we believe that with proper selection, patients will benefit most from their ability to achieve the best outcomes of both vessel patency and limb salvage.

We employ several unsupervised machine learning techniques, including autoencoders, random trees embedding, and t-distributed stochastic neighboring ensemble (t-SNE), to reduce the dimensionality of, and therefore classify, raw (auxiliary) spin configurations generated, through Monte Carlo simulations of small clusters, for the Ising and Fermi-Hubbard models at finite temperatures. Results from a convolutional autoencoder for the three-dimensional Ising model can be shown to produce the magnetization and the susceptibility as a function of temperature with a high degree of accuracy. Quantum fluctuations distort this picture and prevent us from making such connections between the output of the autoencoder and physical observables for the Hubbard model. However, we are able to define an indicator based on the output of the t-SNE algorithm that shows a near perfect agreement with the antiferromagnetic structure factor of the model in two and three spatial dimensions in the weak-coupling regime. t-SNE also predicts a transition to the canted antiferromagnetic phase for the three-dimensional model when a strong magnetic field is present. We show that these techniques cannot be expected to work away from half filling when the \"sign problem\" in quantum Monte Carlo simulations is present.