Benchmarking Tests of Contemporary SRS Platforms: Have Technological Developments Resulted in Improved Treatment Plan Quality?

PURPOSE: Stereotactic radiosurgery treatment delivery can be performed with a range of devices, each of which have evolved over recent years. We sought to evaluate the differences in performance of contemporary stereotactic radiosurgery platforms and also to compare them with earlier platform iterations from a previous benchmarking study. METHODS AND MATERIALS: The following platforms were selected as "state of the art" in 2022: Gamma Knife Icon (GK), CyberKnife S7 (CK), Brainlab Elements (Elekta VersaHD and Varian TrueBeam), Varian Edge with HyperArc (HA), and Zap-X. Six benchmarking cases were used from a 2016 study. To reflect the evolution of increasing numbers of metastases treated per patient, a 14-target case was added. The 28 targets among the 7 patients ranged from 0.02 to 7.2 cc in volume. Participating centers were sent images and contours for each patient and asked to plan them to the best of their ability. Although some variation in local practice was allowed (eg, margins), groups were asked to prescribe a specified dose to each target and tolerance doses to organs at risk were agreed upon. Parameters compared included coverage, selectivity, Paddick conformity index, gradient index (GI), R50%, efficiency index, doses to organs at risk, and planning and treatment times. RESULTS: Mean coverage for all targets ranged from 98.2% (Brainlab/Elekta) to 99.7% (HA-6X). Paddick conformity index values ranged from 0.722 (Zap-X) to 0.894 (CK). GI ranged from a mean of 3.52 (GK), representing the steepest dose gradient, to 5.08 (HA-10X). The GI appeared to follow a trend with beam energy, with the lowest values from the lower energy platforms (GK, 1.25 MeV; Zap-X, 3 MV) and the highest value from the highest energy (HA-10X). Mean R50% values ranged from 4.48 (GK) to 5.98 (HA-10X). Treatment times were lowest for C-arm linear accelerators. CONCLUSIONS: Compared with earlier studies, newer equipment appears to deliver higher quality treatments. CyberKnife and linear accelerator platforms appear to give higher conformity whereas lower energy platforms yield a steeper dose gradient.

Determining Planning Priorities for SABR for Oligometastatic Disease: A Secondary Analysis of the SABR-COMET Phase II Randomized Trial.

PURPOSE: SABR may improve survival in patients with oligometastases, but for some lesions, safe delivery of SABR may require a reduction in delivered dose or target coverage. This study assessed the association between target coverage compromise and oncologic and survival outcomes. METHODS AND MATERIALS: Patients with a controlled primary malignancy and 1 to 5 oligometastases were randomized (1:2) between standard of care (SOC) treatment and SOC plus SABR. In patients receiving SABR, the target dose coverage was reduced to meet organ at risk (OAR) constraints, if necessary. The D99 value (minimum dose received by the hottest 99% of the planning target volume [PTV]) was used as a measure of PTV coverage for each treatment plan, and the relationship between the coverage compromise index (CCI, defined as D99/prescription dose) and patient outcomes was assessed. RESULTS: Sixty-two patients in the SABR arm had dosimetric information available and a total of 109 lesions were evaluated. The mean CCI per lesion was 0.96 (95% CI, 0.56-1.61). Of the 109 lesions evaluated, 29.4% (n = 32) required coverage compromise (CCI <0.9). Adrenal metastases required coverage compromise in 100% of analyzed lesions (n = 7). CCI was not significantly associated with lesional control, adverse events, overall survival (OS), or progression-free survival (PFS). CONCLUSIONS: Target compromise was required in a substantial minority of cases, but PTV coverage was not associated with OS, progression-free survival, or lesional control. This suggests that OAR constraints used for SABR treatments in the oligometastatic setting should continue to be prioritized during planning.

Treatment of multiple intracranial metastases in radiation oncology: a contemporary review of available technologies.

The use of stereotactic radiosurgery to treat multiple intracranial metastases, frequently concurrently, has become increasingly common. The ability to accurately and safely deliver stereotactic radiosurgery treatment to multiple intracranial metastases (MIM) relies heavily on the technology available for targeting, planning, and delivering the dose. A number of platforms are currently marketed for such applications, each with intrinsic capabilities and limitations. These can be broadly categorised as cobalt-based, linac-based, and robotic. This review describes the most common representative technologies for each type along with their advantages and current limitations as they pertain to the treatment of multiple intracranial metastases. Each technology was used to plan five clinical cases selected to represent the clinical breadth of multiple metastases cases. The reviewers discuss the different strengths and limitations attributed to each technology in the case of MIM as well as the impact of disease-specific characteristics (such as total number of intracranial metastases, their size and relative proximity) on plan and treatment quality.

Seizures in Patients With Metastatic Brain Tumors: Prevalence, Clinical Characteristics, and Features on EEG.

INTRODUCTION: Metastases to the brain (MB) occur in up to 30% of adults with cancer; of these, 15% to 35% may have seizures. We investigated clinical and pathologic associations with seizure and EEG findings in patients with MB, given the sparse literature in this area. METHODS: We performed a retrospective chart review of adults with pathologically confirmed MB treated at a large tertiary care center between April 8, 2006, and December 14, 2018. Primary outcomes were odds of "chart-documented seizure" (CDS) in the full sample and EEG-captured seizure or any epileptiform discharges among those monitored on EEG. RESULTS: We studied 187 patients with MB, of whom 55 (28.3%) were monitored on EEG. We found an overall CDS prevalence of 29.4% and an EEG-captured seizure of 18.9% among patients monitored on EEG. Of those monitored on EEG, 47.2% had epileptiform discharges. Adenocarcinoma pathology was associated with lower odds of CDS (odds ratio [OR] 0.50, 95% CI 0.26-0.96) and EEG-captured seizure (OR 0.09, 95% CI 0.01-0.87) versus other pathologies. When modeled separately, melanoma pathology was associated with CDS (OR 4.45, 95% CI 1.58-12.57) versus other pathologies. Hemorrhagic MB were associated with any epileptiform discharges (OR 5.50, 95% CI 1.65-18.37), regardless of pathology modeled. Increasing size of the largest dimension of the largest MB was associated with lower odds of CDS (OR 0.68, 95% CI 0.52-0.89 when adenocarcinoma modeled, OR 0.69, 95% CI 0.53-0.91 when melanoma modeled). CONCLUSIONS: Seizures and epileptiform discharges are common in patients with MB. Tumor size and pathology were significantly associated with CDS. Larger studies are needed for further analysis.

Rhodoxanthin synthase from honeysuckle; a membrane diiron enzyme catalyzes the multistep conversation of ß-carotene to rhodoxanthin.

Rhodoxanthin is a vibrant red carotenoid found across the plant kingdom and in certain birds and fish. It is a member of the atypical retro class of carotenoids, which contain an additional double bond and a concerted shift of the conjugated double bonds relative to the more widely occurring carotenoid pigments, and whose biosynthetic origins have long remained elusive. Here, we identify LHRS (Lonicera hydroxylase rhodoxanthin synthase), a variant ß-carotene hydroxylase (BCH)-type integral membrane diiron enzyme that mediates the conversion of ß-carotene into rhodoxanthin. We identify residues that are critical to rhodoxanthin formation by LHRS. Substitution of only three residues converts a typical BCH into a multifunctional enzyme that mediates a multistep pathway from ß-carotene to rhodoxanthin via a series of distinct oxidation steps in which the product of each step becomes the substrate for the next catalytic cycle. We propose a biosynthetic pathway from ß-carotene to rhodoxanthin.

Clinical characteristics, EEG findings and implications of status epilepticus in patients with brain metastases.

PURPOSE: To evaluate the clinical implications of status epilepticus in patients with metastases to the brain as well as associated demographic, clinical, EEG and radiographic features. METHODS: Retrospective chart review of 19 patients with metastases to the brain who subsequently developed status epilepticus. RESULTS: Of the patients who developed status epilepticus only 36.8% had a prior history of seizures since diagnosis of brain metastases. Status epilepticus most commonly occurred in the setting of a new structural injury to the brain such as new metastases, increase in size of metastases or hemorrhage. 57.9% of patients had either refractory or super-refractory status epilepticus. Focal non-convulsive status epilepticus was the most common subtype occurring in 42.1% of patients. 31.6% of patients died within 30 days of the onset of status epilepticus. CONCLUSION: Status epilepticus eventually resolved with treatment in all patients with brain metastases; however, it is associated with poor outcomes as nearly one-third was deceased within 30-days of onset. Nevertheless, no patients died during status epilepticus. Thus, status epilepticus may be indicative of an overall poor clinical status among patients with brain metastases.

Seizures in patents with primary central nervous system lymphoma: Prevalence and associated features.

OBJECTIVE: Primary central nervous system (CNS) lymphoma (PCNSL) is a rare, aggressive, yet highly chemosensitive form of non-Hodgkin lymphoma which is associated with significant morbidity. Very little is known about the long-term risk for and features of seizures associated with this condition. METHODS: We performed a retrospective and longitudinal analysis of 36 patients with pathologically and radiographically confirmed primary CNS lymphoma to evaluate the incidence, prevalence and features associated with seizures. Demographic, radiographic, histological and electroencephalographic (EEG) data were included as part of the study. RESULTS: One-third of patients with primary CNS lymphoma had clinical seizures of which two-thirds occurred at time of initial presentation, while the remainder developed during a mean follow-up time of 1.49 years. The incidence rate of first seizure in PCNSL was 224.4 per 1000 persons, per year. There was a trend towards association with seizures in patients with cortical lesions relative to patients with subcortical lesions. EEG revealed epileptiform discharges in 44.4% of patients with both PCNSL and clinical seizures which suggests that it is a useful diagnostically in a substantial proportion of patients. CONCLUSIONS: A significant percentage of patients with primary CNS lymphoma develop comorbid seizures during their disease course. Increased awareness and collaboration between neuro-oncologists and epileptologists may enhance and improve care for these patients.

Three-year review of gene sequencing analyses of pulmonary non-small cell lung cancers obtained by fine-needle aspiration or surgical biopsy: mutation and failure rates.

INTRODUCTION: Mutational analysis is becoming the standard of diagnostic workup. Sufficient amounts of and quality tumor tissue can be challenging when faced with a small biopsy or biopsy by fine-needle aspiration (FNA). MATERIALS AND METHODS: We reviewed the failures of FNA and surgical biopsy to yield sequencing data and causes thereof over a 3-year period. We executed a search of the laboratory information system for requests to perform our targeted 50-gene assay by massively parallel sequencing on surgical biopsies and FNAs and compared the results. RESULTS: Three failure causes were assigned: insufficient tissue as defined by the pathologist, failure to meet quality control indicating library preparation or sequencing failure, and failure of pre-qualifying step for DNA integrity. A total of 327 of 354 cases were successfully sequenced (92%), including 151 FNA cases and 203 biopsies, with 16 (10.6%) and 11 (5.4%) failures, respectively. The Fisher's exact test two-tailed P-value equals 0.050381, making the difference between FNA and biopsy not statistically significant. Insufficient tissue, quality control failure, and DNA integrity were identified as the cause of the failure in 10 (62%), 3 (19%), and 3 (19%) FNA biopsies, and in 5 (45.5%), 1 (9%), and 5 (45.5%) surgical biopsies. The most common cause of failure of FNA was insufficient tissue. For surgical biopsies, DNA integrity and insufficient tissue were equally as likely to be implicated. Both FNA and surgical biopsy have a low failure rate overall without statistical significance between them. CONCLUSIONS: Although surgical biopsy is considered the gold standard, these findings support FNA as an equal modality.

Meeting the information needs of lower income cancer survivors: results of a randomized control trial evaluating the american cancer society's "I can cope".

The American Cancer Society is a leader in the development of cancer survivorship resources. One resource of the American Cancer Society is the I Can Cope program, an educational program for cancer survivors and their families. Evaluations of this program indicate that cancer patients highly rate its objectives. Yet, there are gaps in the understanding of the full impact of the program on diverse cancer survivors. In this study, the authors used a randomized trial to evaluate the program. Participants included 140 low-income survivors (79% Black; 38% breast cancer) from community hospitals who were randomized to 4 sessions of I Can Cope (learning about cancer; understanding cancer treatments; relieving cancer pain; and keeping well in mind and body) or 4 sessions of a wellness intervention (humor, meditation, relaxation, and music therapy). The authors' primary outcome was "met information needs." After controlling for covariates, their analysis indicated that I Can Cope was no more effective than the wellness intervention in addressing survivor information needs relative to the learning objectives. Participants provided high overall ratings for both interventions. Self-efficacy for obtaining advice about cancer, age, education, and income were associated with information needs. Educational programs tailored to levels of self-efficacy and patient demographics may be needed.

Recruitment of low income, predominantly minority cancer survivors to a randomized trial of the I Can Cope cancer education program.

This report describes recruitment of minority cancer survivors for a randomized trial of I Can Cope, a support program of the American Cancer Society. Survivor Education and Evaluation (SURE), was designed to recruit patients, age 19 and older, with a primary cancer diagnosis. Recruitment was primarily carried out in a public hospital in Birmingham, Alabama. Of 373 patients approached, 226 were eligible for the study, 175 consented, and 140 were randomized during the 20-month recruitment period. Only 43 declined participation. This resulted in a 61.9% recruitment yield. The mean age of participants was 54.2 years (SD=10.9), 92 (65.7%) were female, and 111 (79.3%) were African American. Twenty-three different cancers were represented including breast (37.1%), colorectal (12.1%), hematologic (12.9%), and lung (7.1%). Over half (63%) had been diagnosed within 12 months. The experience of the SURE project provides evidence for optimism in recruiting racial minorities to cancer research studies.

The dynamics of homologous pairing during mating type interconversion in budding yeast.

Cells repair most double-strand breaks (DSBs) that arise during replication or by environmental insults through homologous recombination, a high-fidelity process critical for maintenance of genomic integrity. However, neither the detailed mechanism of homologous recombination nor the specific roles of critical components of the recombination machinery-such as Bloom and Werner syndrome proteins-have been resolved. We have taken a novel approach to examining the mechanism of homologous recombination by tracking both a DSB and the template from which it is repaired during the repair process in individual yeast cells. The two loci were labeled with arrays of DNA binding sites and visualized in live cells expressing green fluorescent protein-DNA binding protein chimeras. Following induction of an endonuclease that introduces a DSB next to one of the marked loci, live cells were imaged repeatedly to determine the relative positions of the DSB and the template locus. We found a significant increase in persistent associations between donor and recipient loci following formation of the DSB, demonstrating DSB-induced pairing between donor and template. However, such associations were transient and occurred repeatedly in every cell, a result not predicted from previous studies on populations of cells. Moreover, these associations were absent in sgs1 or srs2 mutants, yeast homologs of the Bloom and Werner syndrome genes, but were enhanced in a rad54 mutant, whose protein product promotes efficient strand exchange in vitro. Our results indicate that a DSB makes multiple and reversible contacts with a template during the repair process, suggesting that repair could involve interactions with multiple templates, potentially creating novel combinations of sequences at the repair site. Our results further suggest that both Sgs1 and Srs2 are required for efficient completion of recombination and that Rad54 may serve to dissociate such interactions. Finally, these results demonstrate that mechanistic insights into recombination not accessible from studies of populations of cells emerge from observations of individual cells.

The Saccharomyces cerevisiae recombination enhancer biases recombination during interchromosomal mating-type switching but not in interchromosomal homologous recombination.

Haploid Saccharomyces can change mating type through HO-endonuclease cleavage of an expressor locus, MAT, followed by gene conversion using one of two repository loci, HML or HMR, as donor. The mating type of a cell dictates which repository locus is used as donor, with a cells using HML and alpha cells using HMR. This preference is established in part by RE, a locus on the left arm of chromosome III that activates the surrounding region, including HML, for recombination in a cells, an activity suppressed by alpha 2 protein in alpha cells. We have examined the ability of RE to stimulate different forms of interchromosomal recombination. We found that RE exerted an effect on interchromosomal mating-type switching and on intrachromosomal homologous recombination but not on interchromosomal homologous recombination. Also, even in the absence of RE, MAT alpha still influenced donor preference in interchromosomal mating-type switching, supporting a role of alpha 2 in donor preference independent of RE. These results suggest a model in which RE affects competition between productive and nonproductive recombination outcomes. In interchromosome gene conversion, RE enhances both productive and nonproductive pathways, whereas in intrachromosomal gene conversion and mating-type switching, RE enhances only the productive pathway.

Directional bias during mating type switching in Saccharomyces is independent of chromosomal architecture.

Haploid Saccharomyces cells have the remarkable potential to change mating type as often as every generation, a process accomplished by an intrachromosomal gene conversion between an expressor locus MAT and one of two repositories of mating type information, HML or HMR. The particular locus selected as donor is dictated by the mating type of the cell, a bias that ensures productive mating type interconversion. Here we use green fluorescent protein tagging of the expressor and donor loci on chromosome III to show that this preference for donor locus does not result from a predetermined organization of chromosome III: HML and MAT as well as HMR and MAT remain separated in cells of both mating types. In fact, cells in which the inappropriate donor locus is artificially tethered to MAT still predominantly select the correct donor. We find, though, that initiation of switching leads to a rapid association of the correct donor locus with MAT. Thus, in mating type switching in Saccharomyces, donor preference is imposed at commitment to recombination rather than at physical contact of interacting DNA strands.