Stereotactic Body Radiotherapy for Lung Oligo-metastases: Systematic Review and International Stereotactic Radiosurgery Society Practice Guidelines

PURPOSE A systematic review of treatment characteristics, outcomes, and treatment-related toxicities of stereotactic body radiation therapy (SBRT) for pulmonary oligometastases served as the basis for development of this International Stereotactic Radiosurgery Society (ISRS) practice guideline. METHODS In accordance with PRISMA guidelines, a systematic review was performed of retrospective series with ≥50 patients/lung metastases, prospective trials with ≥25 patients/lung metastases, analyses of specific high-risk situations, and all randomized trials published between 2012 and July 2022 in the MEDLINE or Embase database using the key words "lung oligometastases", "lung metastases", "pulmonary metastases", "pulmonary oligometastases", "stereotactic body radiation therapy (SBRT)" and "stereotactic ablative body radiotherapy (SBRT)". Weighted random effects models were used to calculate pooled outcomes estimates. RESULTS Of the 1884 articles screened, 35 analyses (27 retrospective-, 5 prospective, and 3 randomized trials) reporting on treatment of >3600 patients and >4650 metastases were included. The median local control was 90 % (Range: 57-100 %) at 1 year and 79 % (R: 70-96 %) at 5 years. Acute toxicity ≥3 was reported for 0.5 % and late toxicity ≥3 for 1.8 % of patients. A total of 21 practice recommendations covering the areas of staging & patient selection (n = 10), SBRT treatment (n = 10), and follow-up (n = 1) were developed, with agreements rates of 100 %, except for recommendation 13 (83 %). CONCLUSION SBRT represents an effective definitive local treatment modality combining high local control rates with low risk of radiation-induced toxicities

Stereotactic body radiotherapy for Ultra-Central lung Tumors: A systematic review and Meta-Analysis and International Stereotactic Radiosurgery Society practice guidelines

BACKGROUND Stereotactic body radiotherapy (SBRT) is an effective and safe modality for early-stage lung cancer and lung metastases. However, tumors in an ultra-central location pose unique safety considerations. We performed a systematic review and meta-analysis to summarize the current safety and efficacy data and provide practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS We performed a systematic review using PubMed and EMBASE databases of patients with ultra-central lung tumors treated with SBRT. Studies reporting local control (LC) and/or toxicity were included. Studies with <5 treated lesions, non-English language, re-irradiation, nodal tumors, or mixed outcomes in which ultra-central tumors could not be discerned were excluded. Random-effects meta-analysis was performed for studies reporting relevant endpoints. Meta-regression was conducted to determine the effect of various covariates on the primary outcomes. RESULTS 602 unique studies were identified of which 27 (one prospective observational, the remainder retrospective) were included, representing 1183 treated targets. All studies defined ultra-central as the planning target volume (PTV) overlapping the proximal bronchial tree (PBT). The most common dose fractionations were 50 Gy/5, 60 Gy/8, and 60 Gy/12 fractions. The pooled 1- and 2-year LC estimates were 92 % and 89 %, respectively. Meta-regression identified biological effective dose (BED10) as a significant predictor of 1-year LC. A total of 109 grade 3-4 toxicity events, with a pooled incidence of 6 %, were reported, most commonly pneumonitis. There were 73 treatment related deaths, with a pooled incidence of 4 %, with the most common being hemoptysis. Anticoagulation, interstitial lung disease, endobronchial tumor, and concomitant targeted therapies were observed risk factors for fatal toxicity events. CONCLUSION SBRT for ultra-central lung tumors results in acceptable rates of local control, albeit with risks of severe toxicity. Caution should be taken for appropriate patient selection, consideration of concomitant therapies, and radiotherapy plan design

Variable dose interplay effects across radiosurgical apparatus in treating multiple brain metastases

PURPOSE: Normal brain tissue doses have been shown to be strongly apparatus dependent for multi-target stereotactic radiosurgery. In this study, we investigated whether inter-target dose interplay effects across contemporary radiosurgical treatment platforms are responsible for such an observation. METHODS: For the study, subsets ([Formula: see text] and 12) of a total of 12 targets were planned at six institutions. Treatment platforms included the (1) Gamma Knife Perfexion (PFX), (2) CyberKnife, (3) Novalis linear accelerator equipped with a 3.0-mm multi-leaf collimator (MLC), and the (4) Varian Truebeam flattening-filter-free (FFF) linear accelerator also equipped with a 2.5 mm MLC. Identical dose–volume constraints for the targets and critical structures were applied for each apparatus. All treatment plans were developed at individual centers, and the results were centrally analyzed. RESULTS: We found that dose–volume constraints were satisfied by each apparatus with some differences noted in certain structures such as the lens. The peripheral normal brain tissue doses were lowest for the PFX and highest for TrueBeam FFF and CyberKnife treatment plans. Comparing the volumes of normal brain receiving 12 Gy, TrueBeam FFF, Novalis, and CyberKnife were 180–290 % higher than PFX. The mean volume of normal brain-per target receiving 4-Gy increased by approximately 3.0 cc per target for TrueBeam, 2.7 cc per target for CyberKnife, 2.0 cc per target for Novalis, and 0.82 cc per target for PFX. The beam-on time was shortest with the TrueBeam FFF (e.g., 6–9 min at a machine output rate of 1,200 MU/min) and longest for the PFX (e.g., 50–150 mins at a machine output rate of 350 cGy/min). CONCLUSION: The volumes of normal brain receiving 4 and 12 Gy were higher, and increased more swiftly per target, for Linac-based SRS platforms than for PFX. Treatment times were shortest with TrueBeam FFF

Stereotactic body radiotherapy for hepatocellular carcinoma: meta-analysis and International Stereotactic Radiosurgery Society practice guidelines

PURPOSE This systematic review and meta-analysis reports on outcomes and hepatic toxicity rates following stereotactic body radiotherapy (SBRT) for liver confined hepatocellular carcinoma (HCC), and presents consensus guidelines regarding appropriate patient management. METHODS AND MATERIALS Using the Preferred Reporting Items for Systemic Review and Meta-analyses guidelines, a systematic review was performed from articles reporting outcomes at ≥5 years published prior to October 2022 from the Embase, MEDLINE, Cochrane, and Scopus databases using the key words terms ("Stereotactic body radiotherapy" OR "SBRT" OR "SABR" OR "Stereotactic ablative radiotherapy") AND ("Hepatocellular carcinoma" OR "HCC"). An aggregated data (AD) meta-analysis was conducted to assess overall survival (OS) and local control (LC) using weighted random effects models. In addition, an individual patient data (IPD) analysis incorporating data from 6 institutions was conducted as its own subgroup analyses. RESULTS Seventeen observational studies, comprising 1889 HCC patients treated with ≤9 SBRT fractions, between 2003 and 2019, were included in the AD meta-analysis. The 3- and 5- year OS rates after SBRT were 57% (95% confidence interval [CI], 47-66%) and 40% (95% CI, 29-51%). The 3- and 5- year LC rates after SBRT were 84% (95% CI, 77-90%) and 82% (95% CI, 74-88%), respectively. Tumor size was the only prognostic factor for LC. Tumor size and region were significantly associated with OS. Five-year LC and OS rates of 79% (95% CI, 0.74-0.84) and 25% (95% CI, 0.20-0.30), respectively, were observed in the IPD analyses. Factors prognostic for improved OS were tumor size <3 cm, eastern region, Child-Pugh score ≤B7, and the Barcelona Clinic Liver Cancer stage of 0 and A. The incidence of severe hepatic toxicity varied according to the criteria applied. CONCLUSIONS SBRT is an effective treatment modality for HCC patients with mature follow up. Clinical practice guidelines were developed on behalf of the XXXX

The 5-Choice Continuous Performance Test: Evidence for a Translational Test of Vigilance for Mice

Attentional dysfunction is related to functional disability in patients with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease. Indeed, sustained attention/vigilance is among the leading targets for new medications designed to improve cognition in schizophrenia. Although vigilance is assessed frequently using the continuous performance test (CPT) in humans, few tests specifically assess vigilance in rodents.We describe the 5-choice CPT (5C-CPT), an elaboration of the 5-choice serial reaction (5CSR) task that includes non-signal trials, thus mimicking task parameters of human CPTs that use signal and non-signal events to assess vigilance. The performances of C57BL/6J and DBA/2J mice were assessed in the 5C-CPT to determine whether this task could differentiate between strains. C57BL/6J mice were also trained in the 5CSR task and a simple reaction-time (RT) task involving only one choice (1CRT task). We hypothesized that: 1) C57BL/6J performance would be superior to DBA/2J mice in the 5C-CPT as measured by the sensitivity index measure from signal detection theory; 2) a vigilance decrement would be observed in both strains; and 3) RTs would increase across tasks with increased attentional load (1CRT task<5CSR task<5C-CPT).C57BL/6J mice exhibited superior SI levels compared to DBA/2J mice, but with no difference in accuracy. A vigilance decrement was observed in both strains, which was more pronounced in DBA/2J mice and unaffected by response bias. Finally, we observed increased RTs with increased attentional load, such that 1CRT task<5CSR task<5C-CPT, consistent with human performance in simple RT, choice RT, and CPT tasks. Thus we have demonstrated construct validity for the 5C-CPT as a measure of vigilance that is analogous to human CPT studies

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes