Integrated assessment of pollution status of MSW sites: a case study of Uyo, Ikot Ekpene and Oron, Akwa Ibom State, southern Nigeria.

One of the main causes of contaminated groundwater in emerging nations is improper trash disposal in urban areas, which affects the level of groundwater contamination caused by contaminants of municipal solid waste (MSW) origin within the three local government headquarters in Akwa Ibom State, southeastern Nigeria. The main thrust of this research survey is to assess the level of groundwater contaminations and their consequences. The research used statistical data generated from the Electrical Resistivity Survey (ERS) in combination with hydrogeochemical investigations. Analysis of variance of resistivity between Uyo, Ikot Ekpene and Oron was carried out. The test result indicated significant difference in contamination among the three cities. This was followed by a t-test between each pair of dump and control sites in the three cities. The test results showed significant difference between each control and dumpsite. The results showed that leachate layer conductivity is always higher than that of the layer above it. All water samples from boreholes close to the dumpsites were identified by hydrogeochemical analysis to exhibit pH (3.70-4.15) lower than the permissible limit of the WHO; few water samples exhibit increased electrical conductivity (EC), cadmium and total dissolved solids (TDS). Similarly, the bacteriological analyses indicated a high level of microbial load due to the waste dump. Formations found in boreholes close to the dumpsite have litho-correlations which depict intercalations of comparatively impermeable and porous materials. The findings reveal that leachate (contaminate) travels slowly downward, allowing for physical, chemical and biological processes to filter out impurities before they get to the aquifer. It is recommended that no new water supply wells should be placed in areas of abnormally low resistivity and physicochemical and bacteriological parameters, until the reasons for these values are properly assessed.

Clinical application of a template-guided automated planning routine.

PURPOSE: Determine the dosimetric quality and the planning time reduction when utilizing a template-based automated planning application. METHODS: A software application integrated through the treatment planning system application programing interface, QuickPlan, was developed to facilitate automated planning using configurable templates for contouring, knowledge-based planning structure matching, field design, and algorithm settings. Validations are performed at various levels of the planning procedure and assist in the evaluation of readiness of the CT image, structure set, and plan layout for automated planning. QuickPlan is evaluated dosimetrically against 22 hippocampal-avoidance whole brain radiotherapy patients. The required times to treatment plan generation are compared for the validations set as well as 10 prospective patients whose plans have been automated by QuickPlan. RESULTS: The generations of 22 automated treatment plans are compared against a manual replanning using an identical process, resulting in dosimetric differences of minor clinical significance. The target dose to 2% volume and homogeneity index result in significantly decreased values for automated plans, whereas other dose metric evaluations are nonsignificant. The time to generate the treatment plans is reduced for all automated plans with a median difference of 9' 50″ ± 4' 33″. CONCLUSIONS: Template-based automated planning allows for reduced treatment planning time with consistent optimization structure creation, treatment field creation, plan optimization, and dose calculation with similar dosimetric quality. This process has potential expansion to numerous disease sites.

Sports Gambling Intention Comparison Between Males and Females in the United States.

The focus of this research is to understand the sports gambling intentions of Gen Z (those born between 1997 and 2012) that can potentially lead to problematic gambling behavior. Rooted in the theory of planned behavior, the study delves into the roles of attitude, subjective norms, and perceived behavior control in shaping these intentions. A cross-sectional study of 513 Gen Z's in the United States was conducted. The partial least square structural equation modeling was used to analyze the relationship and compare the differences between males and females with multigroup analysis. The results indicate that attitude and perceived behavior control have a significant impact on this intention, while subjective norms do not exert substantial influence. Notably, gender differences are observed, with males showing a stronger association with perceived behavior control and females with attitude. The model effectively accounts for significant variations in sports gambling intention, highlighting a higher inclination among females as compared to males. This study provides a new perspective for analyzing disparities in sports gambling intention between genders and delves into the underlying motivations that can potentially contribute to the development of problematic gambling disorders. Given the significant societal impact and the adverse effects that gambling disorders have on those affected, it is imperative to conduct research aimed at understanding the reasons behind Gen Z's engagement in gambling. The findings can then be harnessed to inform the development of preventive programs aimed at curbing problematic gambling behaviors.

Neoadjuvant stereotactic radiosurgery for brain metastases: a new paradigm.

OBJECTIVE: For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor "seeding" away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases. METHODS: A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed. RESULTS: Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32-84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease. CONCLUSIONS: Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS.

Development of custom RF coils for use in a small animal platform for magnetic resonance-guided focused ultrasound hyperthermia compatible with a clinical MRI scanner.

Three different magnetic resonance imaging (MRI) coils were developed and assessed for use with an experimental platform designed to generate hyperthermia in mice using magnetic resonance-guided focused ultrasound (MRgFUS). An ergonomic animal treatment bed was integrated with MRI coils. Three different coil designs optimized for small targets were tested, and performance in targeting and conducting accurate temperature imaging was evaluated. Two transmit/receive surface coils of different diameters (4 and 7 cm) and a transmit-only/receive-only (TORO) coil were used. A software platform was developed to provide real-time targeting and temperature maps and to deliver controlled ultrasound exposure. MR thermometry was conducted on different targets, including fresh chicken breasts and mouse cadavers. Multiple experiments were performed in which tissues were targeted with high reproducibility. The TORO coil was the most resilient to temperature drift, resulting in an increase in the calculated temperature of 0.29 ± 0.12 °C, compared to 1.27 ± 0.13 °C and 0.47 ± 0.04 °C for the medium and small coils, respectively. Controlled closed-loop hyperthermia exposure was successfully performed with all three coils. Considering all assessments, the TORO coil exhibited the best overall performance for thermometry acquisition when accounting for stability, precision, temperature spread and resilience to temperature drift. B1 maps of the three coils confirmed that the TORO coil exhibited the most homogeneous B1 field, which explained the improved thermometry performance. The use of coils specifically designed for small targets within the proposed experimental platform allowed accurate thermometry during hyperthermia.

Effect of organic loading on the microbiota in a temperature-phased anaerobic digestion (TPAD) system co-digesting dairy manure and waste whey.

Temperature-phased anaerobic digestion (TPAD) has gained increasing attention because it provides the flexibility to operate digesters under conditions that enhance overall digester performance. However, research on impact of organic overloading rate (OLR) to microbiota of TPAD systems was limited. In this study, we investigated the composition and successions of the microbiota in both the thermophilic and the mesophilic digesters of a laboratory-scale TPAD system co-digesting dairy manure and waste whey before and during organic overloading. The thermophilic and the mesophilic digesters were operated at 50 and 35 °C, respectively, with a hydraulic retention time (HRT) of 10 days for each digester. High OLR (dairy manure with 5 % total solid and waste whey of ≥60.4 g chemical oxygen demand (COD)/l/day) resulted in decrease in pH and in biogas production and accumulation of volatile fatty acids (VFAs) in the thermophilic digester, while the mesophilic digester remained unchanged except a transient increase in biogas production. Both denaturant gradient gel electrophoresis (DGGE) and Illumina sequencing of 16S ribosomal RNA (rRNA) gene amplicons showed dramatic change in microbiota composition and profound successions of both bacterial and methanogenic communities. During the overloading, Thermotogae was replaced by Proteobacteria, while Methanobrevibacter and archaeon classified as WCHD3-02 grew in predominance at the expense of Methanoculleus in the thermophilic digester, whereas Methanosarcina dominated the methanogenic community, while Methanobacterium and Methanobrevibacter became less predominant in the mesophilic digester. Canonical correspondence analysis (CCA) revealed that digester temperature and pH were the most influential environmental factors that explained much of the variations of the microbiota in this TPAD system when it was overloaded.

Polycomb repressive complex 2 silences human cytomegalovirus transcription in quiescent infection models.

Chromatin-based regulation of herpesviral transcriptional programs is increasingly appreciated as a mechanism for modulating infection outcomes. Transcriptionally permissive euchromatin predominates during lytic infection, whereas heterochromatin domains refractory to transcription are enriched at lytic genes during latency. Reversibly silenced facultative heterochromatin domains are often enriched for histone H3 trimethylated on lysine 27 (H3K27me3), a modification catalyzed by Polycomb repressive complex 2 (PRC2). The requirement for PRC2 in suppressing the human cytomegalovirus (HCMV) lytic transcriptional program during latency has not been thoroughly evaluated. Therefore, we disrupted PRC2 activity in the highly tractable THP1 and NT2D1 quiescent-infection models by treating cells with small-molecule inhibitors of PRC2 activity. Compared to control cells, disruption of PRC2 in HCMV-infected THP1 or NT2D1 cells resulted in significant increases in viral transcript levels and the detection of viral protein. Using chromatin immunoprecipitation, we demonstrated that enrichment of H3K27me3, deposited by PRC2, correlates inversely with lytic transcriptional output, suggesting that PRC2 catalytic activity at viral chromatin directly represses lytic transcription. Together, our data suggest that PRC2-mediated repression of viral transcription is a key step in the establishment and maintenance of HCMV latency.

Large Language Models to Help Appeal Denied Radiotherapy Services.

PURPOSE: Large language model (LLM) artificial intelligences may help physicians appeal insurer denials of prescribed medical services, a task that delays patient care and contributes to burnout. We evaluated LLM performance at this task for denials of radiotherapy services. METHODS: We evaluated generative pretrained transformer 3.5 (GPT-3.5; OpenAI, San Francisco, CA), GPT-4, GPT-4 with internet search functionality (GPT-4web), and GPT-3.5ft. The latter was developed by fine-tuning GPT-3.5 via an OpenAI application programming interface with 53 examples of appeal letters written by radiation oncologists. Twenty test prompts with simulated patient histories were programmatically presented to the LLMs, and output appeal letters were scored by three blinded radiation oncologists for language representation, clinical detail inclusion, clinical reasoning validity, literature citations, and overall readiness for insurer submission. RESULTS: Interobserver agreement between radiation oncologists' scores was moderate or better for all domains (Cohen's kappa coefficients: 0.41-0.91). GPT-3.5, GPT-4, and GPT-4web wrote letters that were on average linguistically clear, summarized provided clinical histories without confabulation, reasoned appropriately, and were scored useful to expedite the insurance appeal process. GPT-4 and GPT-4web letters demonstrated superior clinical reasoning and were readier for submission than GPT-3.5 letters (P < .001). Fine-tuning increased GPT-3.5ft confabulation and compromised performance compared with other LLMs across all domains (P < .001). All LLMs, including GPT-4web, were poor at supporting clinical assertions with existing, relevant, and appropriately cited primary literature. CONCLUSION: When prompted appropriately, three commercially available LLMs drafted letters that physicians deemed would expedite appealing insurer denials of radiotherapy services. LLMs may decrease this task's clerical workload on providers. However, LLM performance worsened when fine-tuned with a task-specific, small training data set.

A Pilot Study of Simulation-Free Hippocampal-Avoidance Whole Brain Radiation Therapy Using Diagnostic MRI-Based and Online Adaptive Planning.

PURPOSE: We aimed to demonstrate the clinical feasibility and safety of simulation-free hippocampal avoidance whole brain radiation therapy (HA-WBRT) in a pilot study (National Clinical Trial 05096286). METHODS AND MATERIALS: Ten HA-WBRT candidates were enrolled for treatment on a commercially available computed tomography (CT)-guided linear accelerator with online adaptive capabilities. Planning structures were contoured on patient-specific diagnostic magnetic resonance imaging (MRI), which were registered to a CT of similar head shape, obtained from an atlas-based database (AB-CT). These patient-specific diagnostic MRI and AB-CT data sets were used for preplan calculation, using NRG-CC001 constraints. At first fraction, AB-CTs were used as primary data sets and deformed to patient-specific cone beam CTs (CBCT) to give patient-matched density information. Brain, ventricle, and brain stem contours were matched through rigid translation and rotation to the corresponding anatomy on CBCT. Lens, optic nerve, and brain contours were manually edited based on CBCT visualization. Preplans were then reoptimized through online adaptation to create final, simulation-free plans, which were used if they met all objectives. Workflow tasks were timed. In addition, patients underwent CT-simulation to create immobilization devices and for prospective dosimetric comparison of simulation-free and simulation-based plans. RESULTS: Median time from MRI importation to completion of "preplan" was 1 weekday (range, 1-4). Median on-table workflow duration was 41 minutes (range, 34-70). NRG-CC001 constraints were achieved by 90% of the simulation-free plans. One patient's simulation-free plan failed a planning target volume coverage objective (89% instead of 90% coverage); this was deemed acceptable for first-fraction delivery, with an offline replan used for subsequent fractions. Both simulation-free and simulation CT-based plans otherwise met constraints, without clinically meaningful differences. CONCLUSIONS: Simulation-free HA-WBRT using online adaptive radiation therapy is feasible, safe, and results in dosimetrically comparable treatment plans to simulation CT-based workflows while providing convenience and time savings for patients.

A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma.

PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

Molecular investigation of the 7.2 kb RNA of murine cytomegalovirus.

BACKGROUND: HCMV encodes a stable 5 kb RNA of unknown function that is conserved across cytomegalovirus species. In vivo studies of the MCMV orthologue, a 7.2 kb RNA, demonstrated that viruses that do not express the RNA fail to establish efficient persistent replication in the salivary glands of mice. To gain further insight into the function and properties of this conserved locus, we characterized the MCMV intron in finer detail. METHODS: We performed multiple analyses to evaluate transcript expression kinetics, identify transcript termini and promoter elements. The half-lives of intron locus RNAs were quantified by measuring RNA levels following actinomycin D treatment in a qRT-PCR-based assay. We also constructed a series of recombinant viruses to evaluate protein coding potential in the locus and test the role of putative promoter elements. These recombinant viruses were tested in both in vitro and in vivo assays. RESULTS: We show that the 7.2 kb RNA is expressed with late kinetics during productive infection of mouse fibroblasts. The termini of the precursor RNA that is processed to produce the intron were identified and we demonstrate that the m106 open reading frame, which resides on the spliced mRNA derived from precursor processing, can be translated during infection. Mapping the 5' end of the primary transcript revealed minimal promoter elements located upstream that contribute to transcript expression. Analysis of recombinant viruses with deletions in the putative promoter elements, however, revealed these elements exert only minor effects on intron expression and viral persistence in vivo. Low transcriptional output by the putative promoter element(s) is compensated by the long half-life of the 7.2 kb RNA of approximately 28.8 hours. Detailed analysis of viral spread prior to the establishment of persistence also showed that the intron is not likely required for efficient spread to the salivary gland, but rather enhances persistent replication in this tissue site. CONCLUSIONS: This data provides a comprehensive transcriptional analysis of the MCMV 7.2 kb intron locus. Our studies indicate that the 7.2 kb RNA is an extremely long-lived RNA, a feature which is likely to be important in its role promoting viral persistence in the salivary gland.

Activity of the human immunodeficiency virus type 1 cell cycle-dependent internal ribosomal entry site is modulated by IRES trans-acting factors.

The 5' leader of the human immunodeficiency virus type 1 (HIV-1) genomic RNA harbors an internal ribosome entry site (IRES) that is functional during the G2/M phase of the cell cycle. Here we show that translation initiation mediated by the HIV-1 IRES requires the participation of trans-acting cellular factors other than the canonical translational machinery. We used 'standard' chemical and enzymatic probes and an 'RNA SHAPE' analysis to model the structure of the HIV-1 5' leader and we show, by means of a footprinting assay, that G2/M extracts provide protections to regions previously identified as crucial for HIV-1 IRES activity. We also assessed the impact of mutations on IRES function. Strikingly, mutations did not significantly affect IRES activity suggesting that the requirement for pre-formed stable secondary or tertiary structure within the HIV-1 IRES may not be as strict as has been described for other viral IRESes. Finally, we used a proteomic approach to identify cellular proteins within the G2/M extracts that interact with the HIV-1 5' leader. Together, data show that HIV-1 IRES-mediated translation initiation is modulated by cellular proteins.

In silico trial of simulation-free hippocampal-avoidance whole brain adaptive radiotherapy.

Background and Purpose: Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) can be a time-consuming process compared to conventional whole brain techniques, thus potentially limiting widespread utilization. Therefore, we evaluated the in silico clinical feasibility, via dose-volume metrics and timing, by leveraging a computed tomography (CT)-based commercial adaptive radiotherapy (ART) platform and workflow in order to create and deliver patient-specific, simulation-free HA-WBRT. Materials and methods: Ten patients previously treated for central nervous system cancers with cone-beam computed tomography (CBCT) imaging were included in this study. The CBCT was the adaptive image-of-the-day to simulate first fraction on-board imaging. Initial contours defined on the MRI were rigidly matched to the CBCT. Online ART was used to create treatment plans at first fraction. Dose-volume metrics of these simulation-free plans were compared to standard-workflow HA-WBRT plans on each patient CT simulation dataset. Timing data for the adaptive planning sessions were recorded. Results: For all ten patients, simulation-free HA-WBRT plans were successfully created utilizing the online ART workflow and met all constraints. The median hippocampi D100% was 7.8 Gy (6.6-8.8 Gy) in the adaptive plan vs 8.1 Gy (7.7-8.4 Gy) in the standard workflow plan. All plans required adaptation at first fraction due to both a failing hippocampal constraint (6/10 adaptive fractions) and sub-optimal target coverage (6/10 adaptive fractions). Median time for the adaptive session was 45.2 min (34.0-53.8 min). Conclusions: Simulation-free HA-WBRT, with commercially available systems, was clinically feasible via plan-quality metrics and timing, in silico.

Simulation-Free Radiation Therapy: An Emerging Form of Treatment Planning to Expedite Plan Generation for Patients Receiving Palliative Radiation Therapy.

Purpose: Herein we report the clinical and dosimetric experience for patients with metastases treated with palliative simulation-free radiation therapy (SFRT) at a single institution. Methods and Materials: SFRT was performed at a single institution. Multiple fractionation regimens were used. Diagnostic imaging was used for treatment planning. Patient characteristics as well as planning and treatment time points were collected. A matched cohort of patients with conventional computed tomography simulation radiation therapy (CTRT) was acquired to evaluate for differences in planning and treatment time. SFRT dosimetry was evaluated to determine the fidelity of SFRT. Descriptive statistics were calculated on all variables and statistical significance was evaluated using the Wilcoxon signed rank test and t test methods. Results: Thirty sessions of SFRT were performed and matched with 30 sessions of CTRT. Seventy percent of SFRT and 63% of CTRT treatments were single fraction. The median time to plan generation was 0.88 days (0.19-1.47) for SFRT and 1.90 days (0.39-5.23) for CTRT (P = .02). The total treatment time was 41 minutes (28-64) for SFRT and 30 minutes (21-45) for CTRT (P = .02). In the SFRT courses, the maximum and mean deviations in the actual delivered dose from the approved plans for the maximum dose were 4.1% and 0.07%, respectively. All deliveries were within a 5% threshold and deemed clinically acceptable. Conclusions: Palliative SFRT is an emerging technique that allowed for a statistically significant lower time to plan generation and was dosimetrically acceptable. This benefit must be weighed against increased total treatment time for patients receiving SFRT compared with CTRT, and appropriate patient selection is critical.

A pilot phase Ib study to evaluate tadalafil to overcome immunosuppression during chemoradiotherapy for IDH-wild-type glioblastoma.

Background: Myeloid-derived suppressor cells (MDSCs) are critical regulators of immunosuppression and radioresistance in glioblastoma (GBM). The primary objective of this pilot phase Ib study was to validate the on-target effect of tadalafil on inhibiting MDSCs in peripheral blood and its safety when combined with chemoradiotherapy in GBM patients. Methods: Patients with newly diagnosed IDH-wild-type GBM received radiation therapy (RT) and temozolomide (TMZ) combined with oral tadalafil for 2 months. A historical cohort of 12 GBM patients treated with RT and TMZ was used as the comparison group. The ratio of MDSCs, T cells, and cytokines at week 6 of RT compared to baseline were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Tadalafil was well tolerated with no dose-limiting toxicity among 16 evaluable patients. The tadalafil cohort had a significantly lower ratio of circulating MDSCs than the control: granulocytic-MDSCs (mean 0.78 versus 3.21, respectively, P = 0.01) and monocytic-MDSCs (1.02 versus 1.96, respectively, P = 0.006). Tadalafil increased the CD8 ratio compared to the control (1.99 versus 0.70, respectively, P < 0.001), especially the PD-1-CD8 T cells expressing Ki-67, CD38, HLA-DR, CD28, and granzyme B. Proinflammatory cytokine IL-1ß was also significantly increased after tadalafil compared to the control. The tadalafil cohort did not have significantly different PFS and OS than the historical control. Conclusions: Concurrent tadalafil is well tolerated during chemoradiotherapy for GBM. Tadalafil is associated with a reduction of peripheral MDSCs after chemoradiotherapy and increased CD8 T-cell proliferation and activation.

Stereotactic Radiosurgery vs Conventional Radiotherapy for Localized Vertebral Metastases of the Spine: Phase 3 Results of NRG Oncology/RTOG 0631 Randomized Clinical Trial.

Importance: Spine metastasis can be treated with high-dose radiation therapy with advanced delivery technology for long-term tumor and pain control. Objective: To assess whether patient-reported pain relief was improved with stereotactic radiosurgery (SRS) as compared with conventional external beam radiotherapy (cEBRT) for patients with 1 to 3 sites of vertebral metastases. Design, Setting, and Participants: In this randomized clinical trial, patients with 1 to 3 vertebral metastases were randomized 2:1 to the SRS or cEBRT groups. This NRG 0631 phase 3 study was performed as multi-institutional enrollment within NRG Oncology. Eligibility criteria included the following: (1) solitary vertebral metastasis, (2) 2 contiguous vertebral levels involved, or (3) maximum of 3 separate sites. Each site may involve up to 2 contiguous vertebral bodies. A total of 353 patients enrolled in the trial, and 339 patients were analyzed. This analysis includes data extracted on March 9, 2020. Interventions: Patients randomized to the SRS group were treated with a single dose of 16 or 18 Gy (to convert to rad, multiply by 100) given to the involved vertebral level(s) only, not including any additional spine levels. Patients assigned to cEBRT were treated with 8 Gy given to the involved vertebra plus 1 additional vertebra above and below. Main Outcomes and Measures: The primary end point was patient-reported pain response defined as at least a 3-point improvement on the Numerical Rating Pain Scale (NRPS) without worsening in pain at the secondary site(s) or the use of pain medication. Secondary end points included treatment-related toxic effects, quality of life, and long-term effects on vertebral bone and spinal cord. Results: A total of 339 patients (mean [SD] age of SRS group vs cEBRT group, respectively, 61.9 [13.1] years vs 63.7 [11.9] years; 114 [54.5%] male in SRS group vs 70 [53.8%] male in cEBRT group) were analyzed. The baseline mean (SD) pain score at the index vertebra was 6.06 (2.61) in the SRS group and 5.88 (2.41) in the cEBRT group. The primary end point of pain response at 3 months favored cEBRT (41.3% for SRS vs 60.5% for cEBRT; difference, -19 percentage points; 95% CI, -32.9 to -5.5; 1-sided P = .99; 2-sided P = .01). Zubrod score (a measure of performance status ranging from 0 to 4, with 0 being fully functional and asymptomatic, and 4 being bedridden) was the significant factor influencing pain response. There were no differences in the proportion of acute or late adverse effects. Vertebral compression fracture at 24 months was 19.5% with SRS and 21.6% with cEBRT (P = .59). There were no spinal cord complications reported at 24 months. Conclusions and Relevance: In this randomized clinical trial, superiority of SRS for the primary end point of patient-reported pain response at 3 months was not found, and there were no spinal cord complications at 2 years after SRS. This finding may inform further investigation of using spine radiosurgery in the setting of oligometastases, where durability of cancer control is essential. Trial Registration: ClinicalTrials.gov Identifier: NCT00922974.

RapidPlan hippocampal sparing whole brain model version 2-how far can we reduce the dose?

Whole-brain radiotherapy has been the standard palliative treatment for patients with brain metastases due to its effectiveness, availability, and ease of administration. Recent clinical trials have shown that limiting radiation dose to the hippocampus is associated with decreased cognitive toxicity. In this study, we updated an existing Knowledge Based Planning model to further reduce dose to the hippocampus and improve other dosimetric plan quality characteristics. Forty-two clinical cases were contoured according to guidelines. A new dosimetric scorecard was created as an objective measure for plan quality. The new Hippocampal Sparing Whole Brain Version 2 (HSWBv2) model adopted a complex recursive training process and was validated with five additional cases. HSWBv2 treatment plans were generated on the Varian HalcyonTM and TrueBeamTM systems and compared against plans generated from the existing (HSWBv1) model released in 2016. On the HalcyonTM platform, 42 cases were re-planned. Hippocampal D100% from HSWBv2 and HSWBv1 models had an average dose of 5.75 Gy and 6.46 Gy, respectively (p < 0.001). HSWBv2 model also achieved a hippocampal Dmean of 7.49 Gy, vs 8.10 Gy in HSWBv1 model (p < 0.001). Hippocampal D0.03CC from HSWBv2 model was 9.86 Gy, in contrast to 10.57 Gy in HSWBv1 (p < 0.001). For PTV_3000, D98% and D2% from HSWBv2 model were 28.27 Gy and 31.81 Gy, respectively, compared to 28.08 Gy (p = 0.020) and 32.66 Gy from HSWBv1 (p < 0.001). Among several other dosimetric quality improvements, there was a significant reduction in PTV_3000 V105% from 35.35% (HSWBv1) to 6.44% (HSWBv2) (p < 0.001). On 5 additional validation cases, dosimetric improvements were also observed on TrueBeamTM. In comparison to published data, the HSWBv2 model achieved higher quality hippocampal avoidance whole brain radiation therapy treatment plans through further reductions in hippocampal dose while improving target coverage and dose conformity/homogeneity. HSWBv2 model is shared publicly.

Association of Pretreatment Hippocampal Volume With Neurocognitive Function in Patients Treated With Hippocampal Avoidance Whole Brain Radiation Therapy for Brain Metastases: Secondary Analysis of NRG Oncology/RTOG 0933.

Purpose: Hippocampal volume (HV) is an established predicting factor for neurocognitive function (NCF) in neurodegenerative disease. Whether the same phenomenon exists with hippocampal-avoidant whole brain radiation therapy is not known; therefore, we assessed the association of baseline HV with NCF among patients enrolled on RTOG 0933. Methods and Materials: Hippocampal volume and total brain volume were calculated from the radiation therapy plan. Hippocampal volume was correlated with baseline and 4-month NCF scores (Hopkins Verbal Learning Test-Revised [HVLT-R] Total Recall [TR], Immediate Recognition, and Delayed Recall [DR]) using Pearson correlation. Deterioration in NCF was defined per the primary endpoint of RTOG 0933(mean 4-month relative decline in HVLT-R DR). Comparisons between patients with deteriorated and nondeteriorated NCF were made using the Wilcoxon test. Results: Forty-two patients were evaluable. The median age was 56.5 years (range, 28-83 years), and 81% had a class II recursive partitioning analysis. The median total, right, and left HVs were 5.4 cm3 (range, 1.9-7.4 cm3), 2.8 cm3 (range, 0.9-4.0 cm3), and 2.7 cm3 (range, 1.0-3.7 cm3), respectively. The median total brain volume was 1343 cm3 (range, 1120.5-1738.8 cm3). For all measures of corrected HV, increasing HV was associated with higher baseline HVLT-R TR and DR scores (ρ: range, 0.35-0.40; P-value range, .009-.024) and 4-month TR and DR scores (ρ: range, 0.29-0.40; P-value range, .009-.04), with the exception of right HV and 4-month DR scores (ρ: 0.29; P = .059). There was no significant association between HV and NCF change between baseline and 4 months. Fourteen patients (33.3%) developed NCF deterioration per the primary endpoint of RTOG 0933. There was no significant difference in HV between patients with deteriorated and nondeteriorated NCF, although in all instances, patients with deteriorated NCF had numerically lower HV. Conclusions: Larger HV was positively associated with improved performance on baseline and 4-month HVLT-R TR and DR scores in patients with brain metastases undergoing hippocampal-avoidant whole brain radiation therapy but was not associated with a change in NCF.

Evaluation of interim MRI changes during limited-field radiation therapy for glioblastoma and implications for treatment planning.

BACKGROUND AND PURPOSE: Consensus for defining gross tumor volume (GTV) and clinical target volume (CTV) for limited-field radiation therapy (LFRT) of GBM are not well established. We leveraged a department MRI simulator to image patients before and during LFRT to address these questions. MATERIALS AND METHODS: Supratentorial GBM patients receiving LFRT (46 Gy + boost to 60 Gy) underwent baseline MRI (MRI1) and interim MRI during RT (MRI2). GTV1 was defined as T1 enhancement + surgical cavity on MRI1 without routine inclusion of T2 abnormality (unless tumor did not enhance). The initial CTV margin was 15 mm from GTV1, and the boost CTV margin was 5-7 mm. The GTV1 characteristics were categorized into three groups: identical T1 and T2 abnormality (Group A), T1 only with larger T2 abnormality not included (Group B), and T2 abnormality when tumor lacked enhancement (Group C). GTV2 was contoured on MRI2 and compared with GTV1 plus 5-15 mm expansions. RESULTS: Among 120 patients treated from 2014-2019, 29 patients (24%) underwent replanning based on MRI2. On MRI2, 84% of GTV2 were covered by GTV1 + 5 mm, 93% by GTV1 + 7 mm, and 98% by GTV1 + 15 mm. On MRI1, 43% of GTV1 could be categorized into Group A, 39% Group B, and 18% Group C. Group B's patterns of failure, local control, or progression-free survival were similar to Group A/C. CONCLUSIONS: Initial CTV margin of 15 mm followed by a boost CTV margin of 7 mm is a reasonable approach for LFRT of GBM. Omitting routine inclusion of T2 abnormality from GTV delineation may not jeopardize disease control.

Dosimetric predictors of symptomatic radiation necrosis after five-fraction radiosurgery for brain metastases.

BACKGROUND: To identify factors predictive of developing symptomatic radiation necrosis (sRN) among patients with either intact or resected brain metastases undergoing five-fraction stereotactic radiosurgery (5fSRS). METHODS: Multi-institutional retrospective review of 117 brain metastases from 83 patients treated with 5fSRS. The cumulative incidence of sRN and predictors of sRN were calculated using Gray's competing risks and Cox regression. RESULTS: The median dose of 5fSRS was 30 Gy (range: 25-40), and 21 lesions (18%) had prior SRS. After a median follow-up of 10.3 months (range: 3-52), the cumulative sRN incidence was 15%, with a median time to sRN of 6.9 months (range: 1.8-31.7). sRN incidence was significantly higher among the lesions treated with prior SRS: hazard ratio (HR): 7.48 [95% confidence interval: 2.57-21.8]. Among lesions without prior SRS, higher volume of uninvolved brain receiving 25 Gy (BrainV25; HR: 1.07 [1.02-1.12]) and 30 Gy (BrainV30; HR: 1.07 [1.01-1.33]) were the most significant factors associated with sRN. Similar results were also observed among the patients with prior SRS. For lesions without prior SRS, BrainV25 > 16 cm3 (HR: 11.7 [1.47-93.3]) and BrainV30 > 10 cm3 (HR: 7.08 [1.52-33.0]) were associated with significantly higher risk of sRN. At two years, the sRN incidence was 21% if violating either dosimetric threshold and 2% if violating neither (p = .007). CONCLUSION: BrainV25 and BrainV30 are significant dosimetric predictors of sRN of brain metastases treated with 5fSRS. In the absence of prior SRS, maintaining BrainV25Gy < 16 cm3 and BrainV30Gy < 10 cm3 may minimize sRN risk.