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Abstract Background Emerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor. Methods One hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes. Discussion SABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making. Trial registration Clinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).

Abstract 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.

Background: A relationship between the axillary-lateral thoracic vessel juncture (ALTJ) dose and lymphedema rate has been reported in patients with breast cancer. The purpose of this study was to validate this relationship and explore whether incorporation of the ALTJ dose-distribution parameters improves the prediction model’s accuracy. Methods: A total of 1,449 women with breast cancer who were treated with multimodal therapies from two institutions were analyzed. We categorized regional nodal irradiation (RNI) as limited RNI, which excluded level I/II, vs extensive RNI, which included level I/II. The ALTJ was delineated retrospectively, and dosimetric and clinical parameters were analyzed to determine the accuracy of predicting the development of lymphedema. Decision tree and random forest algorithms were used to construct the prediction models of the obtained dataset. We used Harrell’s C-index to assess discrimination. Results: The median follow-up time was 77.3 months, and the 5-year lymphedema rate was 6.8 %. According to the decision tree analysis, the lowest lymphedema rate (5-year, 1.2 %) was observed in patients with ≤ six removed lymph nodes and ≤ 66 % ALTJ V35Gy. The highest lymphedema rate was observed in patients with > 15 removed lymph nodes and an ALTJ maximum dose (Dmax) of > 53 Gy (5-year, 71.4 %). Patients with > 15 removed lymph nodes and an ALTJ Dmax ≤ 53 Gy had the second highest rate (5-year, 21.5 %). All other patients had relatively minor differences, with a rate of 9.5 % at 5 years. Random forest analysis revealed that the model’s C-index increased from 0.84 to 0.90 if dosimetric parameters were included instead of RNI (P

Abstract Background Individuals with psychiatric disorders (PD) have a high prevalence of tobacco use. Patients with PD also potentially receive substandard care in comparison to the general population. Previous research has shown that individuals with PD have a decreased risk of receiving a tobacco related (TR) cancer diagnosis. To further assess this trend, this study assesses the survival of patients with a TR cancer with or without a PD. Materials and methods Our study utilized multiple databases, with methods described elsewhere,6 to identify people in British Columbia that have been diagnosed with psychiatric disorders and appendicitis (our control group). From these groups, we selected individuals who also had a TR cancer. We subsequently extracted information pertaining to these patients from these databases. Results Thirty-nine thousand eight hundred forty-one patients with cancer were included in our study. Analyses of these patients were controlled for by age, gender, cancer type and diagnosis year. This analysis displayed shorter survival time among patients who were diagnosed with depression (HR = 1.16; p = 0.01; 95% CI: 1.04–1.29), schizophrenia (HR = 1.62; p

There are limited patient-reported outcome (PRO) data tracking changes in toxicity in patients actively undergoing radiotherapy. Between 2015–2019, acute toxicity was prospectively measured in 698 patients undergoing a 5-week course of pelvic radiotherapy for gynecologic cancers using a weekly PRO questionnaire. Our questionnaire was able detect a pattern of onset and resolution of acute gastrointestinal (GI) and genitourinary (GU) toxicity in 27 out of 32 questions. Logistic regression analysis showed that increasing GI and GU toxicity at week 2 could predict for severe toxicity at week 5. However, due to a low number of severe events, univariate results could not be productively added to a multivariate model. We observed a >70% response rate for all sections of the questionnaire, except for questions on sexual and vaginal health, which had a 13% average response rate. By demonstrating that PRO data can be used to track acute toxicity during radiotherapy, there is a need to further examine how this tool may be implemented in the clinic to provide complex, adaptive care, such as early side effect management, and modifying radiation delivery in real-time.

Despite the known importance and necessity of the standardized collection and use of patient-reported outcomes (PROs), there remain challenges to successful clinical implementation. Facilitated through a quality improvement initiative spearheaded by the Canadian Partnership for Quality Radiotherapy (CPQR), and now guided by the Canadian Association of Radiation Oncology (CARO)’s Quality and Standards Committee, patient representatives and early-adopter radiation treatment programs continue to champion the expansion of PROs initiatives across the country. The current review discusses the evolution of a pan-Canadian approach to PROs use, striving to fill in gaps between clinical practice and guideline recommendations through multi-centre and multidisciplinary collaboration.

The BC-brain questionnaire was developed by BC Cancer to detect health problems in patients with central nervous system (CNS) tumours in routine clinical care, treated with radiotherapy (RT), as part of the Prospective Outcomes and Support Initiative (POSI). This study aimed to present and validate the BC-brain questionnaire in patients with brain metastases (BrM) treated with RT. The BC-brain questionnaire was constructed with three subscales: mobility, thinking and CNS symptoms. Patients with BrM from five BC Cancer centres completed this questionnaire at first visit and subsequent follow-up appointments. A total of 365 patients finished the first and 105 finished the follow-up questionnaire. Summary scores of each subscale were calculated. Mobility, thinking and subtotal score showed good reliability with Cronbach’s α > 0.7. Multitrait scaling analysis showed good convergent and divergent validity. The correlations between subscales ranged from 0.262 to 0.456 for baseline and from 0.378 to 0.597 for follow-up. Patients on dexamethasone had worse performance. Patients with a KPS of 70. In general, this BC-brain questionnaire has good reliability and validity, and is proper to use as an option for a patient-reported outcome (PRO) instrument to measure the quality of life in BrM patients treated with RT.

BackgroundOligometastatic disease (OMD) represents an indolent cancer status characterized by slow tumor growth and limited metastatic potential. The use of local therapy in the management of the condition continues to rise. This study aimed to investigate the advantage of pretreatment tumor growth rate in addition to baseline disease burden in characterizing OMDs, generally defined by the presence of ≤ 5 metastatic lesions.MethodsThe study included patients with metastatic melanoma treated with pembrolizumab. Gross tumor volume of all metastases was contoured on imaging before (TP-1) and at the initiation of pembrolizumab (TP0). Pretreatment tumor growth rate was calculated by an exponential ordinary differential equation model using the sum of tumor volumes at TP-1 and TP0 and the time interval between TP-1. and TP0. Patients were divided into interquartile groups based on pretreatment growth rate. Overall survival, progression-free survival, and subsequent progression-free survival were the study outcomes.ResultsAt baseline, median cumulative volume and number of metastases were 28.4 cc (range, 0.4-1194.8 cc) and 7 (range, 1-73), respectively. The median interval between TP-1 and TP0 was -90 days and pretreatment tumor growth rate (×10-2 days-1) was median 4.71 (range -0.62 to 44.1). The slow-paced group (pretreatment tumor growth rate ≤ 7.6 ×10-2 days-1, the upper quartile) had a significantly higher overall survival rate, progression-free survival, and subsequent progression-free survival compared to those of the fast-paced group (pretreatment tumor growth rate > 7.6 ×10-2 days-1). Notably, these differences were prominent in the subgroup with >5 metastases.ConclusionPretreatment tumor growth rate is a novel prognostic metric associated with overall survival, progression-free survival, and subsequent progression-free survival among metastatic melanoma patients, especially patients with >5 metastases. Future prospective studies should validate the advantage of disease growth rate plus disease burden in better defining OMDs.

Background: Individuals with psychiatric disorders (PD) have a high prevalence of tobacco use. Therefore, we assessed the hazard of receiving a tobacco-related (TR) cancer diagnosis among individuals with PD. Methods: Several population-based provincial databases were used to identify individuals in BC diagnosed with depression, schizophrenia, bipolar disorder, anxiety disorders, or multiple PD between 1990 and 2013. A primary population proxy comparison group (appendicitis) was also identified and matched to the psychiatric cohort based on age at cohort entry, gender, year of cohort entry, and postal code. We linked individuals in the cohort and comparison groups with the BC Cancer Registry. Using a competing risks approach, we estimated the effect of having a PD on the risk of receiving a TR cancer diagnosis, in light of the competing risk of mortality. Results: In total, 165,289 patients were included. Individuals with depression (HR = 0.81; p < 0.01; 95% CI: 0.73–0.91), anxiety disorders (HR = 0.84; p = 0.02; 95% CI: 0.73–0.97), or multiple PD (HR = 0.74; p < 0.01; 95% CI: 0.66–0.83) had a statistically significant lower risk of a TR cancer diagnosis compared to the comparison group. Individuals with schizophrenia (HR = 0.86; p = 0.40; 95% CI: 0.62–1.21) or bipolar disorder (HR = 0.58; p = 0.12; 95% CI: 0.29–1.14), however, showed no evidence of a statistically significant difference from the comparison group. Interpretation: We found that individuals with depression, anxiety disorders, or multiple PD diagnoses had a significantly reduced risk of receiving a tobacco-related cancer diagnosis. These results were unexpected and could be explained by individuals with a PD having barriers to a cancer diagnosis rather than a true decreased incidence.

Introduction: After palliative radiotherapy for bone metastases from NSCLC, up to 30% of patients may derive no symptomatic benefit, and there are a lack of biological predictors for this. The purpose was to investigate whether EGFR and ALK genetic rearrangements were associated with greater rates of pain response to palliative radiotherapy. Methods: Patients were identified from a prospectively collected patient-reported outcomes database for all patients with lung cancer treated with conventional palliative radiotherapy for bone metastases from 2013 to 2016 in the province of British Columbia. Patients were divided on the basis of mutational status into the following: EGFR and ALK wild type (WT), EGFR mutation present (EGFR+), or ALK mutation present (ALK+). Patient-reported outcomes of global pain severity were collected before and after radiotherapy and on an ordinal scale of 0 to 4, with 0 representing no bone pain and 4 representing the maximal possible bone pain. The primary outcome was the rate of partial pain response (any improvement in score), and the secondary outcome was the rate of complete pain response (final pain score of 0). Stepwise, multivariable logistic analysis was used to compare response rates between treatment courses for different mutational statuses. Results: The final cohort consisted of 388 treatment courses for 329 unique patients. For the WT, EGFR+, and ALK+ groups, there were 180, 63, and nine treatment courses, respectively. There were 92 patients with no ALK and EGFR testing. The most common treatment fractionations were 8 Gy in one fraction (188 of 388) and 20 Gy in five fractions (160 of 388), and use of multifraction radiotherapy did not differ between mutation status groups (p = 0.3). Partial pain response rates were as follows: WT 63%, EGFR+ 75%, and ALK+ 78%. On multivariable analysis, rates of partial response were higher for EGFR+ (OR = 5.4, p < 0.001) and for ALK+ (OR = 12.8, p = 0.008) in comparison to WT. Complete response rates were as follows: WT 20.5%, EGFR+ 35%, and ALK+ 67%. On multivariable analysis, complete response was not significantly increased in EGFR+ compared with WT (OR = 1.6, p = 0.127). ALK+ mutation status was associated with a higher rate of complete response compared with WT (OR = 5.2, p = 0.031). Conclusions: There was an association between EGFR+ and ALK+ tumors and increased rates of partial pain response to palliative radiotherapy.

Abstract Background A recent randomized phase II trial evaluated stereotactic ablative radiotherapy (SABR) in a group of patients with a small burden of oligometastatic disease (mostly with 1–3 metastatic lesions), and found that SABR was associated with a significant improvement in progression-free survival and a trend to an overall survival benefit, supporting progression to phase III randomized trials. Methods Two hundred and ninety-seven patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care [SOC] palliative-intent treatments), and the SABR arm (consisting of SOC treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (prostate, breast, or renal vs. all others), and disease-free interval (defined as time from diagnosis of primary tumor until first detection of the metastases being treated on this trial; divided as ≤2 vs. > 2 years). The primary endpoint is overall survival, and secondary endpoints include progression-free survival, cost effectiveness, time to development of new metastatic lesions, quality of life (QoL), and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. Discussion This study will provide an assessment of the impact of SABR on survival, QoL, and cost effectiveness to determine if long-term survival can be achieved for selected patients with 1–3 oligometastatic lesions. Trial registration Clinicaltrials.gov identifier: NCT03862911 . Date of registration: March 5, 2019,

ABSTRACT The ARTIC Network provides a common resource of PCR primer sequences and recommendations for amplifying SARS-CoV-2 genomes. The initial tiling strategy was developed with the reference genome Wuhan-01, and subsequent iterations have addressed areas of low amplification and sequence drop out. Recently, a new version (V4) was released, based on new variant genome sequences, in response to the realization that some V3 primers were located in regions with key mutations. Herein, we compare the performance of the ARTIC V3 and V4 primer sets with a matched set of 663 SARS-CoV-2 clinical samples sequenced with an Illumina NovaSeq 6000 instrument. We observe general improvements in sequencing depth and quality, and improved resolution of the SNP causing the D950N variation in the spike protein. Importantly, we also find nearly universal presence of spike protein substitution G142D in Delta-lineage samples. Due to the prior release and widespread use of the ARTIC V3 primers during the initial surge of the Delta variant, it is likely that the G142D amino acid substitution is substantially underrepresented among early Delta variant genomes deposited in public repositories. In addition to the improved performance of the ARTIC V4 primer set, this study also illustrates the importance of the primer scheme in downstream analyses. IMPORTANCE ARTIC Network primers are commonly used by laboratories worldwide to amplify and sequence SARS-CoV-2 present in clinical samples. As new variants have evolved and spread, it was found that the V3 primer set poorly amplified several key mutations. In this report, we compare the results of sequencing a matched set of samples with the V3 and V4 primer sets. We find that adoption of the ARTIC V4 primer set is critical for accurate sequencing of the SARS-CoV-2 spike region. The absence of metadata describing the primer scheme used will negatively impact the downstream use of publicly available SARS-Cov-2 sequencing reads and assembled genomes.

Purpose: Standard planning target volume (PTV) margins for lung stereotactic ablative radiation therapy (SABR) are 5 mm. High-dose-rate volumetric modulated arc therapy delivered using flattening filter-free (FFF) beams with modern immobilization systems may allow for PTV margin reduction. This study assesses whether PTV margins can be reduced from 5 to 3 mm. Methods: Target intrafractional motions derived from pretreatment and posttreatment cone beam computed tomography (CBCT) scans for 33 patients receiving lung SABR treated with 10XFFF energy and 5-mm PTV margins from 2016 to 2019 were used to calculate the required PTV margin. Deformable registration of the planning CT scan and internal gross tumor volume (IGTV) contour to posttreatment CBCT scans for 36 consecutive patients with 4 fraction schedules was completed to capture volume changes and intrafractional movement. Plans were replanned with 3-mm margins and recalculated on each deformed CT scan to assess deformed IGTV (d-IGTV) coverage and organ-at-risk doses. Results: Margin analysis showed PTV margins may be reduced to 3 mm. The mean d-IGTV coverage (percentage of the d-IGTV receiving ≥100% of the prescription dose [V100%] and the minimum dose covering 99.9% of the d-IGTV volume [D99.9%]) over 4 fractions for each patient was >95% with both margins. With 5-mm PTV margins, all 144 fractions had a d-IGTV V100% of >95% and a D99.9% >95%. With 3-mm PTV margins, the d-IGTV V100% was >95% in 99.3% of fractions (143 of 144) and the D99.9% was >95% in 98.6% of fractions (142 of 144). With 3-mm PTV margins, significant reductions in body V50%, body V80%, the volume of the lung receiving ≥20 Gy, and the mean lung dose and chest wall dose to 0.035 cm3 and 30 cm3 were observed (all P < .001). Using theoretical models, the normal tissue complication probability for radiation pneumonitis decreased by a mean of 0.8% (range, 0.1%-2.7%), and the mean 2-year tumor control probability was 96.1% and 95.2% with 5-mm and 3-mm PTV margins, respectively. Conclusion: With modern treatment and immobilization techniques in lung SABR, 3-mm PTV margins maintain acceptable IGTV coverage, modestly reduce toxicity to organs at risk, and maintain a calculated 2-year local control rate of >95%.

Abstract Background Recent advances in high-volume sequencing technology and mining of genomes from metagenomic samples call for rapid and reliable genome quality evaluation. The current release of the PATRIC database contains over 220,000 genomes, and current metagenomic technology supports assemblies of many draft-quality genomes from a single sample, most of which will be novel. Description We have added two quality assessment tools to the PATRIC annotation pipeline. EvalCon uses supervised machine learning to calculate an annotation consistency score. EvalG implements a variant of the CheckM algorithm to estimate contamination and completeness of an annotated genome.We report on the performance of these tools and the potential utility of the consistency score. Additionally, we provide contamination, completeness, and consistency measures for all genomes in PATRIC and in a recent set of metagenomic assemblies. Conclusion EvalG and EvalCon facilitate the rapid quality control and exploration of PATRIC-annotated draft genomes.

Abstract 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.

Abstract Background Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1–3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4–10 metastatic cancer lesions. Methods One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. Discussion This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4–10 oligometastatic lesions. Trial registration Clinicaltrials.gov identifier: NCT03721341. Date of registration: October 26, 2018.

A growing number of studies are using machine learning models to accurately predict antimicrobial resistance (AMR) phenotypes from bacterial sequence data. Although these studies are showing promise, the models are typically trained using features derived from comprehensive sets of AMR genes or whole genome sequences and may not be suitable for use when genomes are incomplete. In this study, we explore the possibility of predicting AMR phenotypes using incomplete genome sequence data. Models were built from small sets of randomly-selected core genes after removing the AMR genes. For Klebsiella pneumoniae, Mycobacterium tuberculosis, Salmonella enterica, and Staphylococcus aureus, we report that it is possible to classify susceptible and resistant phenotypes with average F1 scores ranging from 0.80-0.89 with as few as 100 conserved non-AMR genes, with very major error rates ranging from 0.11-0.23 and major error rates ranging from 0.10-0.20. Models built from core genes have predictive power in cases where the primary AMR mechanisms result from SNPs or horizontal gene transfer. By randomly sampling non-overlapping sets of core genes, we show that F1 scores and error rates are stable and have little variance between replicates. Although these small core gene models have lower accuracies and higher error rates than models built from the corresponding assembled genomes, the results suggest that sufficient variation exists in the core non-AMR genes of a species for predicting AMR phenotypes.

Background and purpose: Planning complex radiotherapy treatments can be inefficient, with large variation in plan quality. In this study we evaluated plan quality and planning efficiency using real-time interactive planning (RTIP) for head and neck (HN) volumetric modulated arc therapy (VMAT). Materials and methods: RTIP allows manipulation of dose volume histograms (DVHs) in real-time to assess achievable planning target volume (PTV) coverage and organ at risk (OAR) sparing. For 20 HN patients previously treated with VMAT, RTIP was used to minimize OAR dose while maintaining PTV coverage. RTIP DVHs were used to guide VMAT optimization. Dosimetric differences between RTIP-assisted plans and original clinical plans were assessed. Five blinded radiation oncologists indicated their preference for each PTV, OAR and overall plan. To assess efficiency, ten patients were planned de novo by experienced and novice planners and a RTIP user. Results: The average planning time with RTIP was

Abstract 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

Ontogenetic sequencing of suture fractal dimensions from a single ammonite specimen was not previously accessible without extreme measures. The necessity for destruction of the full conch due to whorl overlap or, alternatively, the prohibitively expensive or inaccessible imaging equipment for use by paleontologists has led to this rich source of data remaining elusive. Tracings of ontogenetic sequences of sutures have rarely been published since the middle of the last century. These studies only focused on the outermost whorl of a given specimen or composited several specimens. Oftentimes, they focused only on the umbilical and juvenile stages of shell growth. Complete or multi-whorled ontogenetic sequences, including those of subadult and mature specimens, are especially uncommon. Using methods published in 2021 to address the accessibility problem in sutural ontogenies, our paper represents the first comparisons of the fractal trajectories of ammonoids and includes several significant Jurassic ammonite families. We found that ammonite sutures did not steadily increase in complexity, as was previously suggested. Instead, juvenile ammonoids were more likely to exhibit ups and downs in their fractal ontogeny. We also found that pathologies must be considered as extremely common phenomena for ammonoids. Finally, we explored the ways that the unsteady ontogenetic trends of fractal complexity in ammonoids offer insights into the formation mechanism of ammonoid septa.

The remarkable advance in sequencing technology and the rising interest in medical and environmental microbiology, biotechnology, and synthetic biology resulted in a deluge of published microbial genomes. Yet, genome annotation, comparison, and modeling remain a major bottleneck to the translation of sequence information into biological knowledge, hence computational analysis tools are continuously being developed for rapid genome annotation and interpretation. Among the earliest, most comprehensive resources for prokaryotic genome analysis, the SEED project, initiated in 2003 as an integration of genomic data and analysis tools, now contains >5,000 complete genomes, a constantly updated set of curated annotations embodied in a large and growing collection of encoded subsystems, a derived set of protein families, and hundreds of genome-scale metabolic models. Until recently, however, maintaining current copies of the SEED code and data at remote locations has been a pressing issue. To allow high-performance remote access to the SEED database, we developed the SEED Servers (http://www.theseed.org/servers): four network-based servers intended to expose the data in the underlying relational database, support basic annotation services, offer programmatic access to the capabilities of the RAST annotation server, and provide access to a growing collection of metabolic models that support flux balance analysis. The SEED servers offer open access to regularly updated data, the ability to annotate prokaryotic genomes, the ability to create metabolic reconstructions and detailed models of metabolism, and access to hundreds of existing metabolic models. This work offers and supports a framework upon which other groups can build independent research efforts. Large integrations of genomic data represent one of the major intellectual resources driving research in biology, and programmatic access to the SEED data will provide significant utility to a broad collection of potential users.

Viruses are the most common biological entities in the marine environment. There has not been a global survey of these viruses, and consequently, it is not known what types of viruses are in Earth's oceans or how they are distributed. Metagenomic analyses of 184 viral assemblages collected over a decade and representing 68 sites in four major oceanic regions showed that most of the viral sequences were not similar to those in the current databases. There was a distinct "marine-ness" quality to the viral assemblages. Global diversity was very high, presumably several hundred thousand of species, and regional richness varied on a North-South latitudinal gradient. The marine regions had different assemblages of viruses. Cyanophages and a newly discovered clade of single-stranded DNA phages dominated the Sargasso Sea sample, whereas prophage-like sequences were most common in the Arctic. However most viral species were found to be widespread. With a majority of shared species between oceanic regions, most of the differences between viral assemblages seemed to be explained by variation in the occurrence of the most common viral species and not by exclusion of different viral genomes. These results support the idea that viruses are widely dispersed and that local environmental conditions enrich for certain viral types through selective pressure.