The Rad51 paralog complex Rad55-Rad57 acts as a molecular chaperone during homologous recombination.

Homologous recombination (HR) is essential for maintenance of genome integrity. Rad51 paralogs fulfill a conserved but undefined role in HR, and their mutations are associated with increased cancer risk in humans. Here, we use single-molecule imaging to reveal that the Saccharomyces cerevisiae Rad51 paralog complex Rad55-Rad57 promotes assembly of Rad51 recombinase filament through transient interactions, providing evidence that it acts like a classical molecular chaperone. Srs2 is an ATP-dependent anti-recombinase that downregulates HR by actively dismantling Rad51 filaments. Contrary to the current model, we find that Rad55-Rad57 does not physically block the movement of Srs2. Instead, Rad55-Rad57 promotes rapid re-assembly of Rad51 filaments after their disruption by Srs2. Our findings support a model in which Rad51 is in flux between free and single-stranded DNA (ssDNA)-bound states, the rate of which is controlled dynamically though the opposing actions of Rad55-Rad57 and Srs2.

Dynamic Processing of Displacement Loops during Recombinational DNA Repair.

Displacement loops (D-loops) are pivotal intermediates of homologous recombination (HR), a universal DNA double strand break (DSB) repair pathway. We developed a versatile assay for the physical detection of D-loops in vivo, which enabled studying the kinetics of their formation and defining the activities controlling their metabolism. Nascent D-loops are detected within 2 h of DSB formation and extended in a delayed fashion in a genetic system designed to preclude downstream repair steps. The majority of nascent D-loops are disrupted by two pathways: one supported by the Srs2 helicase and the other by the Mph1 helicase and the Sgs1-Top3-Rmi1 helicase-topoisomerase complex. Both pathways operate without significant overlap and are delineated by the Rad54 paralog Rdh54 in an ATPase-independent fashion. This study uncovers a layer of quality control of HR relying on nascent D-loop dynamics.

Network Rewiring of Homologous Recombination Enzymes during Mitotic Proliferation and Meiosis.

Homologous recombination (HR) is essential for high-fidelity DNA repair during mitotic proliferation and meiosis. Yet, context-specific modifications must tailor the recombination machinery to avoid (mitosis) or enforce (meiosis) the formation of reciprocal exchanges-crossovers-between recombining chromosomes. To obtain molecular insight into how crossover control is achieved, we affinity purified 7 DNA-processing enzymes that channel HR intermediates into crossovers or noncrossovers from vegetative cells or cells undergoing meiosis. Using mass spectrometry, we provide a global characterization of their composition and reveal mitosis- and meiosis-specific modules in the interaction networks. Functional analyses of meiosis-specific interactors of MutLγ-Exo1 identified Rtk1, Caf120, and Chd1 as regulators of crossing-over. Chd1, which transiently associates with Exo1 at the prophase-to-metaphase I transition, enables the formation of MutLγ-dependent crossovers through its conserved ability to bind and displace nucleosomes. Thus, rewiring of the HR network, coupled to chromatin remodeling, promotes context-specific control of the recombination outcome.

Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids.

Fatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated fatty acids (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme active in cancer. Here, we studied how the dynamics between SFAs and UFAs regulated by SCD impacts ovarian cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman scattering (SRS) microscopy. Further, increased levels of SFAs resulting from SCD knockdown triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes. Disorganized ER membrane was visualized by electron microscopy and SRS imaging in ovarian cancer cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and apoptosis could be readily rescued by supplementation with UFAs and reequilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro translated into suppression of intraperitoneal tumor growth in ovarian cancer xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA-enriched diet initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the cancer cell fate under metabolic stress and point to treatment strategies targeting the lipid balance.

Rad54 and Rdh54 prevent Srs2-mediated disruption of Rad51 presynaptic filaments.

Srs2 is a superfamily 1 (SF1) helicase that participates in several pathways necessary for the repair of damaged DNA. Srs2 regulates formation of early homologous recombination (HR) intermediates by actively removing the recombinase Rad51 from single-stranded DNA (ssDNA). It is not known whether and how Srs2 itself is down-regulated to allow for timely HR progression. Rad54 and Rdh54 are two closely related superfamily 2 (SF2) motor proteins that promote the formation of Rad51-dependent recombination intermediates. Rad54 and Rdh54 bind tightly to Rad51-ssDNA and act downstream of Srs2, suggesting that they may affect the ability of Srs2 to dismantle Rad51 filaments. Here, we used DNA curtains to determine whether Rad54 and Rdh54 alter the ability of Srs2 to disrupt Rad51 filaments. We show that Rad54 and Rdh54 act synergistically to greatly restrict the antirecombinase activity of Srs2. Our findings suggest that Srs2 may be accorded only a limited time window to act and that Rad54 and Rdh54 fulfill a role of prorecombinogenic licensing factors.

Incidence and imaging characteristics of difficult to detect retrospectively identified brain metastases in patients receiving repeat courses of stereotactic radiosurgery.

PURPOSE: During stereotactic radiosurgery (SRS) planning for brain metastases (BM), brain MRIs are reviewed to select appropriate targets based on radiographic characteristics. Some BM are difficult to detect and/or definitively identify and may go untreated initially, only to become apparent on future imaging. We hypothesized that in patients receiving multiple courses of SRS, reviewing the initial planning MRI would reveal early evidence of lesions that developed into metastases requiring SRS. METHODS: Patients undergoing two or more courses of SRS to BM within 6 months between 2016 and 2018 were included in this single-institution, retrospective study. Brain MRIs from the initial course were reviewed for lesions at the same location as subsequently treated metastases; if present, this lesion was classified as a "retrospectively identified metastasis" or RIM. RIMs were subcategorized as meeting or not meeting diagnostic imaging criteria for BM (+ DC or -DC, respectively). RESULTS: Among 683 patients undergoing 923 SRS courses, 98 patients met inclusion criteria. There were 115 repeat courses of SRS, with 345 treated metastases in the subsequent course, 128 of which were associated with RIMs found in a prior MRI. 58% of RIMs were + DC. 17 (15%) of subsequent courses consisted solely of metastases associated with + DC RIMs. CONCLUSION: Radiographic evidence of brain metastases requiring future treatment was occasionally present on brain MRIs from prior SRS treatments. Most RIMs were + DC, and some subsequent SRS courses treated only + DC RIMs. These findings suggest enhanced BM detection might enable earlier treatment and reduce the need for additional SRS.

The role of spine stereotactic radiosurgery for patients with breast cancer metastases.

PURPOSE: Breast cancer that metastasizes to the spine is associated with low quality of life and poor survival. Radiosurgery has an increasing role in this patient population. This single-institution (2003-2023) study analyzes clinical outcomes and prognostic factors for patients who underwent spinal stereotactic radiosurgery (SSRS) for metastatic breast cancer. METHODS: Ninety patients (155 unique breast cancer spinal metastases) were treated with SSRS. The median age was 57 years (range: 35-88), and the median KPS was 80 (range: 40-100). Forty-two (27%) lesions were managed surgically prior to radiosurgery. At SSRS, 75 (48%) lesions impinged or compressed the spinal cord per the epidural spinal cord scale (ESCC). Seventy-nine (51%) lesions were categorized as potentially unstable or unstable by the Spinal Instability Neoplastic Score (SINS). RESULTS: The median follow-up was 15 months (range: 1-183). The median single-session tumor volume was 25.4 cc (range: 2-197), and the median single-fraction prescription dose was 17 Gy (range: 12-25). Seven (5%) lesions locally progressed. The 1-, 2-, and 5-year local control rates were 98%, 97%, and 92%, respectively. The median overall survival (OS) for the cohort was 32 months (range: 2-183). The 1-, 2-, and 5-year OS rates were 72%, 53%, and 30%, respectively. On univariate analysis, KPS ≥ 80 (p = 0.009, HR: 0.51, 95% CI: 0.31-0.84) was associated with improved OS. Patient-reported pain improved (68%), remained stable (29%), or worsened (3%) following radiosurgery. Fifteen (10%) radiation-induced toxicities were reported. CONCLUSIONS: Spinal radiosurgery is a safe and highly effective long-term treatment modality for metastases to the spine that originate from breast cancer.

The methodological quality of systematic reviews regarding the Core Outcome Set (COS) development.

BACKGROUND: The Core Outcome Measures in Effectiveness Trials (COMET) working group proposed core outcome sets (COS) to address the heterogeneity in outcome measures in clinical studies. According to the recommendations of COMET, performing systematic reviews (SRs) usually was the first step for COS development. However, the SRs that serve as a basis for COS are not specifically appraised by organizations such as COMET regarding their quality. Here, we investigated the status of SRs related to development of COS and evaluated their methodological quality. METHODS: We conducted a search on PubMed to identify SRs related to COS development published from inception to May 2022. We qualitatively summarized the disease included in SR topics, and the studies included in the SRs. We evaluated the methodological quality of the SRs using AMSTAR 2.0 and compared the overall quality of SRs with and without protocols using the Mann-Whitney U test. RESULTS: We included 175 SRs from 23 different countries or regions, and they mainly focused on five diseases: musculoskeletal system or connective tissue disease (n = 19, 10.86%), injury, poisoning, or certain other consequences of external causes (n = 18, 10.29%), digestive system disease (n = 16, 9.14%), nervous system disease (n = 15, 8.57%), and genitourinary system disease (n = 15, 8.57%). Although 88.00% of SRs included randomized controlled trials (RCTs), only a few SRs (23.38%) employed appropriate tools to assess the risk of bias in RCTs. The assessment results on the basis of AMSTAR 2.0 indicated that most SRs (93.71%) were rated as ''critically low'' to ''low'' in terms of overall confidence. The overall confidence of SRs with protocols was significantly higher than that without protocols (P <.001). Compared to the SRs with protocols on Core Outcome Measures in Effectiveness Trials (COMET), SRs with protocols on PROSPERO were of better overall confidence (P = .017). CONCLUSION: The overall quality of published SRs regarding COS development was poor. Our findings emphasize the need for researchers to carefully select the disease topic and strictly adhere to the requirements of optimal methodology when conducting a SR for the establishment of a COS.

Nanoplastics Detected in Commercial Sea Salt.

People of all ages consume salt every day, but is it really just salt? Plastic nanoparticles [nanoplastics (NPs)] pose an increasing environmental threat and have begun to contaminate everyday salt in consumer goods. Herein, we developed a combined surface enhanced Raman scattering (SERS) and stimulated Raman scattering (SRS) approach that can realize the filtration, enrichment, and detection of NPs in commercial salt. The Au-loaded (50 nm) anodic alumina oxide substrate was used as the SERS substrate to explore the potential types of NP contaminants in salts. SRS was used to conduct imaging and quantify the presence of the NPs. SRS detection was successfully established through standard plastics, and NPs were identified through the match of the hydrocarbon group of the nanoparticles. Simultaneously, the NPs were quantified based on the high spatial resolution and rapid imaging of the SRS imaging platform. NPs in sea salts produced in Asia, Australasia, Europe, and the Atlantic were studied. We estimate that, depending on the location, an average person could be ingesting as many as 6 million NPs per year through the consumption of sea salt alone. The potential health hazards associated with NP ingestion should not be underestimated.

Stereotactic radiosurgery for intracranial cavernous malformations of the deep-seated locations: systematic review and meta-analysis.

OBJECTIVE: To determine the outcomes of stereotactic radiosurgery (SRS) for deep-seated (brainstem, basal ganglia, thalamus, cerebellar peduncle) intracranial cavernous malformations (ICMs). METHODS: A systematic review and meta-analysis was performed according to PRISMA and MOOSE guidelines. The main outcomes were comparing pre- and post-SRS hemorrhage rates, using the pooled risk ratios (RR) as the measure of effect. Additionally, the study assessed lesion volume changes and radiation-injury incidence. RESULTS: Data of 850 patients across 14 studies were included in the meta-analysis. The pooled RR of all deep-seated ICMs show a decrease in hemorrhage rate after SRS compared to pre-SRS over the total follow-up period (RR =0.13), initial 2 years (RR =0.22), and after 2 years (RR =0.07). For 9 studies that reported hemorrhage rate of the brainstem only, the pooled RR shows a decrease of hemorrhage rate after SRS compared to pre-SRS over the total follow-up period (RR =0.13), initial 2 years (RR =0.19), and after 2 years (RR =0.07). Volumetric regression was achieved in 44.25% and stability in 56.1%. The pooled incidence of symptomatic and permanent radiation injury was 9% (95% CI, 7-11) and 3% (95% CI, 0-1.9%), respectively. CONCLUSION: SRS appears effective in reducing hemorrhage rates for deep-seated ICMs. The risk of symptomatic radiation injury is low. Given the high risk of surgical morbidity, SRS is a reasonable treatment option for patients with deep-seated ICMs with at least one prior hemorrhage.

A comparison between Boston brace and European braces in the treatment of adolescent idiopathic scoliosis (AIS) patients: a systematic review based on the standardised Scoliosis Research Society (SRS) inclusion criteria for brace treatment.

PURPOSE: To compare the Boston brace and European braces using a standardised Scoliosis Research Society (SRS) inclusion criteria for brace treatment as well as consensus recommendations for treatment outcome. METHODS: This was a systematic review that was carried out using MeSH terminology in our search protocol in PubMed, Cochrane Library, Scopus, Clinicaltrials.gov and Web of Science database between 1976 and 29th of Jan 2023. All studies that were included in this review had applied fully/partially the SRS inclusion criteria for brace wear. Outcome measures were divided into primary and secondary outcome measures. RESULTS: 3830 literatures were found in which 176 literatures were deemed relevant to the study once duplicates were removed and titles and abstracts were screened. Of these literatures, only 15 had fulfilled the eligibility criteria and were included in the study. 8 of the studies were Level IV studies, 5 were Level III studies and 2 studies were Level I studies (1 prospective randomised controlled trial (RCT) and 1 Quasi-RCT). The percentage of patients who avoided surgery for European braces ranged from 88 to 100%, whereas for Boston brace ranged from 70 to 94%. When treatment success was assessed based on the final Cobb angle > 45°, approximately 15% of patients treated with European braces had treatment failure. In contrast, 20-63% of patients treated with Boston brace had curves > 45° at skeletal maturity. The BrAIST study used a cut-off point of 50° to define failure of treatment and the rate of treatment failure was 28%. Curve correction was not achieved in most patients (24-51% of patients) who were treated with the Chêneau brace and its derivatives. However, none of the patients treated with Boston brace achieved curve correction. CONCLUSION: Boston brace and European braces were effective in the prevention of surgery. In addition, curve stabilisation was achieved in most studies. Limitation in current literature included lack of studies providing high level of evidence and lack of standardisation in terms of compliance to brace as well as multidisciplinary management of brace wear.

Surgical treatment of Roussouly type 1 with realigning Roussouly spinal shape and improving SRS-Schwab modifier: effect on minimal clinically important difference.

PURPOSE: To evaluate outcomes of choosing different Roussouly shapes and improving in Schwab modifiers for surgical Roussouly type 1 patients. METHODS: Baseline (BL) and 2-year (2Y) clinical data of adult spinal deformity (ASD) patients presenting with Roussouly type 1 sagittal spinal alignment were isolated in the single-center spine database. Patients were grouped into Roussouly type 1, 2 and 3 with anteverted pelvis (3a) postoperatively. Schwab modifiers at BL and 2Y were categorized as follows: no deformity (0), moderate deformity (+), and severe deformity (++) for pelvic tilt (PT), sagittal vertical axis (SVA), and pelvic incidence and lumbar lordosis mismatch (PI-LL). Improvement in SRS-Schwab was defined as a decrease in the severity of any modifier at 2Y. RESULTS: A total of 96 patients (69.9 years, 72.9% female, 25.2 kg/m2) were included. At 2Y, there were 34 type 1 backs, 60 type 2 backs and only 2 type 3a. Type 1 and type 2 did not differ in rates of reaching 2Y minimal clinically important difference (MCID) for health-related quality of life (HRQOL) scores (all P > 0.05). Two patients who presented with type 3a had poor HRQOL scores. Analysis of Schwab modifiers showed that 41.7% of patients improved in SVA, 45.8% in PI-LL, and 36.5% in PT. At 2Y, patients who improved in SRS-Schwab PT and SVA had lower Oswestry disability index (ODI) scores and significantly more of them reached MCID for ODI (all P < 0.001). Patients who improved in SRS-Schwab SVA and PI-LL had more changes of VAS Back and Short Form-36 (SF-36) outcomes questionnaire physical component summary (SF-36 PCS), and significantly more reached MCID (all P < 0.001). By 2Y, type 2 patients who improved in SRS-Schwab grades reached MCID for VAS back and ODI at the highest rate (P = 0.003, P = 0.001, respectively), and type 1 patients who improved in SRS-Schwab grades reached MCID for SF-36 PCS at the highest rate (P < 0.001). CONCLUSION: For ASD patients classified as Roussouly type 1, postoperative improvement in SRS-Schwab grades reflected superior patient-reported outcomes while type 1 and type 2 did not differ in clinical outcomes at 2Y. However, development of type 3a should be avoided at the risk of poor functional outcomes. Utilizing both classification systems in surgical decision-making can optimize postoperative outcomes.

The Srs2 helicase dampens DNA damage checkpoint by recycling RPA from chromatin.

The DNA damage checkpoint induces many cellular changes to cope with genotoxic stress. However, persistent checkpoint signaling can be detrimental to growth partly due to blockage of cell cycle resumption. Checkpoint dampening is essential to counter such harmful effects, but its mechanisms remain to be understood. Here, we show that the DNA helicase Srs2 removes a key checkpoint sensor complex, RPA, from chromatin to down-regulate checkpoint signaling in budding yeast. The Srs2 and RPA antagonism is supported by their numerous suppressive genetic interactions. Importantly, moderate reduction of RPA binding to single-strand DNA (ssDNA) rescues hypercheckpoint signaling caused by the loss of Srs2 or its helicase activity. This rescue correlates with a reduction in the accumulated RPA and the associated checkpoint kinase on chromatin in srs2 mutants. Moreover, our data suggest that Srs2 regulation of RPA is separable from its roles in recombinational repair and critically contributes to genotoxin resistance. We conclude that dampening checkpoint by Srs2-mediated RPA recycling from chromatin aids cellular survival of genotoxic stress and has potential implications in other types of DNA transactions.

Assessment of stereotactic high-resolution detectors for stereotactic body radiotherapy: comparative analysis between myQA® SRS and Gafchromic EBT-XD films.

The study aimed to evaluate dosimetry systems used for stereotactic body radiotherapy (SBRT), specifically 2D array dosimetry and film dosimetry systems, for exploring their characteristics and clinical suitability. For this, high-resolution myQA SRS detectors and Gafchromic EBT-XD films were employed. Film analysis included net optical density (OD) values depending on energy, dose rate, scanner orientation, scanning side, and post-exposure growth. For myQA SRS, signal values were evaluated in terms of dose rate (400-1400 MU/min) and angular dependence (0-180° at 30° intervals) along with couch angles of 0°, 45°, and 90°. Pre-treatment verification included 32 SBRT patients for whom myQA SRS results were compared with those obtained with Gafchromic EBT-XD films. Analysis revealed less than 1% deviation in net OD for energy and dose rate dependence. Scanner orientation caused 2.5% net OD variation, with minimal differences between film front and back scan orientations (variance < 1.0%). A rapid OD rise occurred within six hours post-exposure, followed by gradual increase. The myQA SRS detector showed - 3.7% dose rate dependence (400 MU/min), while the angular dependence at 90° was - 26.7%. A correction factor effectively reduced these differences to < 1%. For myQA SRS, gamma passing rates were-93.6% (2%/1 mm), while those for EBT-XD films were-92.8%. Improved rates were observed with 3%/1 mm: for myQA SRS-97.9%, and for EBT-XD film-98.16%. In contrast, for 2%/2 mm with 10% threshold, for myQA SRS-97.7% and for EBT-XD film-98.97% were obtained. It is concluded that both myQA SRS detectors and EBT-XD films are suitable for SBRT pre-treatment verification, ensuring accuracy and reliability. However, myQA SRS detectors are preferred over EBT-XD film due to the fact that they offer real-time measurements and user-friendly features.

Effect of florfenicol on Piscirickettsia salmonis biofilm formed in materials used in salmonid nets, nylon and high-density polyethylene.

Piscirickettsiosis is the most prevalent bacterial disease affecting seawater salmon in Chilean salmon industry. Antibiotic therapy is the first alternative to counteract infections caused by Piscirickettsia salmonis. The presence of bacterial biofilms on materials commonly used in salmon farming may be critical for understanding the bacterial persistence in the environment. In the present study, the CDC Biofilm Reactor® was used to investigate the effect of sub- and over-MIC of florfenicol on both the pre-formed biofilm and the biofilm formation by P. salmonis under the antibiotic stimuli on Nylon and high-density polyethylene (HDPE) surfaces. This study demonstrated that FLO, at sub- and over-MIC doses, decreases biofilm-embedded live bacteria in the P. salmonis isolates evaluated. However, it was shown that in the P. salmonis Ps007 strain the presence of sub-MIC of FLO reduced its biofilm formation on HDPE surfaces; however, biofilm persists on Nylon surfaces. These results demonstrated that P. salmonis isolates behave differently against FLO and also, depending on the surface materials. Therefore, it remains a challenge to find an effective strategy to control the biofilm formation of P. salmonis, and certainly other marine pathogens that affect the sustainability of the Chilean salmon industry.

Long-term treatment outcomes and natural course of low-grade intracranial dural arteriovenous fistulas.

OBJECTIVE: In contrast to high-grade dural arteriovenous fistula (dAVF), low-grade dAVF is mainly associated with tinnitus and carries a low risk of morbidity and mortality. It remains unclear whether the benefits of active interventions outweigh the associated risk of complications in low-grade dAVF. METHODS: The authors conducted a retrospective single-center study that included all consecutive patients diagnosed with an intracranial low-grade dAVF (Cognard type I and IIa) during 2012-2022 with DSA. The authors analyzed symptom relief, symptomatic angiographic cure, treatment-related complications, risk for intracerebral hemorrhage (ICH), and mortality. All patients were followed up until the end of 2022. RESULTS: A total of 81 patients were diagnosed with a low-grade dAVF. Of these, 48 patients (59%) underwent treatment (all primary endovascular treatments), and 33 patients (41%) did not undergo treatment. Nine patients (19%) underwent retreatments. Angiographic follow-up was performed after median (IQR) 7.7 (6.1-24.1) months by means of DSA (mean 15.0, median 6.4 months, range 4.5-83.4 months) or MRA (mean 29.3, median 24.7 months, range 5.9-62.1 months). Symptom control was achieved in 98% of treated patients after final treatment. On final angiographic follow-up, 73% of patients had a completely occluded dAVF. There were 2 treatment-related complications resulting in 1 transient (2%) and 1 permanent (2%) neurological complication. One patient showed recurrence and progression of a completely occluded low-grade dAVF to an asymptomatic high-grade dAVF. No cases of ICH- or dAVF-related mortality were found in either treated patients (median [IQR] follow-up 5.1 [2.0-6.8] years) or untreated patients (median [IQR] follow-up 5.7 [3.2-9.0] years). CONCLUSIONS: Treatment of low-grade dAVF provides a high rate of symptom relief with small risks for complications with neurological sequela. The risks of ICH and mortality in patients with untreated low-grade dAVF are minimal. Symptoms may not reveal high-grade recurrence, and radiological follow-up may be warranted in selected patients with treated low-grade dAVF. An optimal radiographic follow-up regimen should be developed by a future prospective multicenter registry.

Is two-staged gamma knife surgery a reasonable management option for very large cerebellar metastases? A case series of three patients.

OBJECTIVE: Two-staged gamma knife surgery (GKS) is a method that may extend the upper tumor volume limit for using GKS in the management of brain metastases. However, the safety of treating very large posterior fossa lesions with this technique has not been well demonstrated. Therefore, we analyzed our experience in treating cerebellar metastases larger than 12 cm3 with two-staged GKS. METHODS: Four consecutive patients harboring 12 to 30 cm3 cerebellar metastases scheduled two-staged GKS were included in the study, and all but one patient completed the treatment. The treatment doses were 10-13 Gy. All patients were followed with regular MR imaging and clinical assessments, and the tumor volumes were measured on all treatment and follow-up images. RESULTS: Tumor progression was not demonstrated in any of the patients. Tumor volumes decreased by, on average, more than half between the two stages. The median survival was 22 months, and no patient died due to intracranial tumor progression. Peritumoral edema at the first GKS resolved in all patients, replaced by asymptomatic mild T2 changes in two of them not requiring any treatment. No radiation-induced complication has developed thus far. CONCLUSION: Staged GKS seems to be a feasible management option for very large cerebellar metastases.

Evaluating stereotactic accuracy with patient-specific MRI distortion corrections for frame-based radiosurgery.

PURPOSE: This study examines how MRI distortions affect frame-based SRS treatments and assesses the need for clinical distortion corrections. METHODS: The study included 18 patients with 80 total brain targets treated using frame-based radiosurgery. Distortion within patients' MRIs were corrected using Cranial Distortion Correction (CDC) software, which utilizes the patient's CT to alter planning MRIs to reduce inherent intra-cranial distortion. Distortion was evaluated by comparing the original planning target volumes (PTVORIG) to targets contoured on corrected MRIs (PTVCORR). To provide an internal control, targets were also re-contoured on uncorrected (PTVRECON) MRIs. Additional analysis was done to assess if 1 mm expansions to PTVORIG targets would compensate for patient-specific distortions. Changes in target volumes, DICE and JACCARD similarity coefficients, minimum PTV dose (Dmin), dose to 95% of the PTV (D95%), and normal tissue receiving 12 Gy (V12Gy), 10 Gy (V10Gy), and 5 Gy (V5Gy) were calculated and evaluated. Student's t-tests were used to determine if changes in PTVCORR were significantly different than intra-contouring variability quantified by PTVRECON. RESULTS: PTVRECON and PTVCORR relative changes in volume were 6.19% ± 10.95% and 1.48% ± 32.92%. PTVRECON and PTVCORR similarity coefficients were 0.90 ± 0.08 and 0.73 ± 0.16 for DICE and 0.82 ± 0.12 and 0.60 ± 0.18 for JACCARD. PTVRECON and PTVCORR changes in Dmin were -0.88% ± 8.77% and -12.9 ± 17.3%. PTVRECON and PTVCORR changes in D95% were -0.34% ± 5.89 and -8.68% ± 13.21%. The 1 mm expanded PTVORIG targets did not entirely cover 14 of the 80 PTVCORR targets. Normal tissue changes (V12Gy, V10Gy, V5Gy) calculated with PTVRECON were (-0.09% ± 7.39%, -0.38% ± 5.67%, -0.08% ± 2.04%) and PTVCORR were (-2.14% ± 7.34%, -1.42% ± 5.45%, -0.61% ± 1.93%). Except for V10Gy, all PTVCORR changes were significantly different (p < 0.05) than PTVRECON. CONCLUSION: MRIs used for SRS target delineation exhibit notable geometric distortions that may compromise optimal dosimetric accuracy. A uniform 1 mm expansion may result in geometric misses; however, the CDC algorithm provides a feasible solution for rectifying distortions, thereby enhancing treatment precision.

Single isocenter HyperArc treatment of multiple intracranial metastases: Targeting accuracy.

PURPOSE/OBJECTIVES: (A) To examine the alignment accuracy of CBCT guidance for brain metastases with off centered isocenters, (B) to test dose delivery and targeting accuracy for single isocenter treatments with multiple brain metastases. We report the results of the end-to-end test for Truebeam stereotactic radiosurgery (SRS). MATERIALS/METHODS: An anthropomorphic CT head phantom was drilled with five MOSFET inserts and two PTW Pinpoint chamber inserts. The phantom was simulated, planned, and delivered. For the purpose of comparing the accuracy of alignment, CBCTs were acquired with the isocenter centered and offset superiorly 8 cm, inferiorly 8 cm, anteriorly 7 cm, posteriorly 7 cm, and right 5 cm. There were six degrees of freedom corrections applied to the plans, as well as intentional rotational and translational errors for dose comparisons. Dose accuracy checks were performed with MOSFET and PTW Pinpoint chamber, and targeting accuracy was assessed with GafChromic films. RESULT: (A) Compared to centered CBCT, off-centered CBCT scan showed some alignment errors, with a maximum difference of 0.6-degree pitch and 0.9 mm translation when the phantom was placed 8 cm inferior off center. (B) For the single isocenter plan, measured doses of the five MOSFET were 95%-100% of the planned dose, whereas the multiple isocenter plans were 96%-100%. With intentional setup errors of 1-degree pitch, doses were 97.1%-100.4% compared to the perfect setup. The same was found for the two pinpoint chamber readings with 1-degree rotation and 1 mm translation. (C) Targeting accuracy for targets at the isocenter is 0.67 mm, within the machine specification of 0.75 mm. Targeting accuracy for isocenters 6-12 cm away from the target is in the range 0.67-1.18 mm. CONCLUSION: (A) Single isocenter HyperArc treatments for multiple brain metastases are feasible and targeting accuracy is clinically acceptable. (B) The vertex in a cranial scan is very important for proper alignment.

Is it still necessary to perform measured based pre-treatment patient-specific QA for SRS HyperArc treatments?

PURPOSE: The Mobius3D system was validated as a modern secondary check dosimetry system. In particular, our objective has been to assess the suitability of the M3D as pre-treatment patient-specific Quality Assurance (QA) tool for Stereotactic Radiosurgery (SRS) HyperArc (HA) treatments. We aimed to determine whether Mobius3D could safely replace the measurements-based patient-specific QA for this type of treatment. METHODS: 30 SRS HA treatment plans for brain were selected. The dose distributions, calculated by Mobius and our routinely used algorithm (AcurosXB v.15.6), were compared using gamma analysis index and DVH parameters based on the patient's CT dataset. All 30 plans were then delivered across the ionization chamber in a homogeneous phantom and the measured dose was compared with both M3D and TPS calculated one. The plans were delivered and verified in terms of PSQA using the electronic portal imaging device (EPID) with Portal Dosimetry (PD) and myQA SRS (IBA Dosimetry) detector. Plans that achieved a global gamma passing rate (GPR) ≥ 97% based on 2%/2 mm criteria, with both Mobius3D and the conventional methods were evaluated acceptable. Finally, we assessed the capability of the M3D system to detect errors related to the position of the Multi-Leaf Collimator (MLC) in comparison to the analyzed measurement-based systems. RESULTS: No relevant differences were observed in the comparison between the dose calculated on the CT-dataset by M3D and the TPS. Observed discrepancies are imputable to different used algorithms, but no discrepancies related to goodness of plans have been found. Average differences between calculated (M3D and TPS) vs measured dose with ionization chamber were 2.5% (from 0.41% to 3.2%) and 1.81% (from 0.66% to 2.65%), for M3D and TPS, respectively. All plans passed with a gamma passing rate > 97% using conventional PSQA methods with a gamma criterion of 2% dose difference and 2 mm distance-to-agreement. The average gamma passing rate for the M3D system was determined to be 99.4% (from 97.3% to 100%). Results from this study also demonstrated Mobius has better error detectability than conventional measurement-based systems. CONCLUSION: Our study shows Mobius3D could be a suitable alternative to conventional measured based QA methods for SRS HyperArc treatments.