Risk factors for serious infections in ANCA-associated vasculitis.

OBJECTIVES: Severe infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial. METHODS: Data on 197 patients recruited into the RAVE trial were analysed. Participants received either rituximab (RTX) or cyclophosphamide (CYC), followed by azathioprine (AZA). Clinical and laboratory data of patients with and without severe infections (≥grade 3, according to the Common Terminology Criteria for Adverse Events version 3.0) were compared. Risk factors for severe infections were investigated using Cox-regression models. RESULTS: Eighteen of 22 (82%) severe infections occurred within 6 months after trial entry, most commonly respiratory tract infections (15/22, 68%). At baseline, lower absolute numbers of CD19+ cells were observed in patients with severe infections either receiving RTX or CYC/AZA at baseline, while CD5+B and CD3+T cells did not differ between groups. In Cox-regression analysis, higher baseline serum immunoglobulin M levels were associated with the risk of severe infections, whereby a higher baseline total CD19+B cell number and prophylaxis against Pneumocystis jirovecii with trimethoprim-sulfamethoxazole (TMP/SMX) with decreased risk of severe infections. Use of TMP/SMX was associated with lower risk of severe infections in both groups, receiving either RTX or CYC/AZA. CONCLUSIONS: The use of low-dose TMP/SMX is associated with reduced risk of severe infections in patients with AAV treated with either RTX or CYC/AZA. Reduced B cell subpopulations at start of treatment might be a useful correlate of reduced immunocompetence.

A single arm phase II study of bone-targeted Sn-117 m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases.

BACKGROUND: Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain since 1956, however, so far radium-223 dichloride is the first and only Food and Drug Administration (FDA) approved targeted alpha therapy for metastatic castration-resistant prostate cancer (mCRPC) based on ALSYMPCA phase 3 study. While radium-223 does improve pain and overall survival outcomes, the improvement can come at the expense of side effects such as bone marrow toxicity. The development of new and better treatment with long-standing pain relief is clearly an unmet medical need. METHODS: The study is a non-randomized phase II study. The study population consists of 25 patients with CRPC who had progressed on any lines of prior therapies and whose serum testosterone level is less than 50 ng/dl and have metastatic lesions to at least two bone sites, with at least one site that has clinically meaningful pain at baseline (≥ 4 on an 11-point intensity scale). Eligible patients will be given two cycles of Sn-117 m-DTPA every 8 weeks or 56 days. Treatment will be administered by slow IV injection over 5-10 min. Retreatment after two cycles is allowed if patients meet the following retreatment criteria. The primary objective is to evaluate the efficacy of Sn-117 m-DTPA on sustained pain response in patients with CRPC metastatic to at least two bone sites and at least one with clinically meaningful pain at baseline (≥ 4 on an 11-point pain intensity scale). Sustained pain response is defined as: 1) achieving pain index ≤ 3 within a 12-week period and 2) maintaining pain index ≤ 3 over a 16-week period. The secondary objectives are: safety and tolerability, measurement of Sn-117 m-DTPA activity by gamma-camera dosimetry scans, therapeutic efficacy, time to the first symptomatic skeletal event, duration of pain response, changes in PSA and ALP levels, patient-reported outcomes and progression free survival and overall survival. DISCUSSION: Sn-117 m-DTPA is a unique bone-targeting theranostic radiopharmaceutical agent that selectively binds most heavily to bone metastases sites. This study will be the first prospective phase II trial to assess the pain efficacy and anti-tumor activity of Sn-117 m-DTPA in mCRPC with at least one clinically meaningful pain at baseline. TRIAL REGISTRATION: ClincialTrials.gov Identifier: NCT04616547.

Conebeam CT-guided 3D MLC-based spatially fractionated radiation therapy for bulky masses.

For fast, safe, and effective management of large and bulky (≥8 cm) non-resectable tumors, we have developed a conebeam CT-guided three-dimensional (3D)-conformal MLC-based spatially fractionated radiation therapy (SFRT) treatment. Using an in-house MLC-fitting algorithm, Millennium 120 leaves were fitted to the gross tumor volume (GTV) generating 1-cm diameter holes at 2-cm center-to-center distance at isocenter. SFRT plans of 15 Gy were generated using four to six coplanar crossfire gantry angles 60° apart with a 90° collimator, differentially weighted with 6- or 10-MV beams. A dose was calculated using AcurosXB algorithm, generating sieve-like dose channels without post-processing the physician-drawn GTV contour within an hour of CT simulation allowing for the same day treatment. In total, 50 extracranial patients have been planned and treated using this method, comprising multiple treatment sites. This novel MLC-fitting algorithm provided excellent dose parameters with mean GTV (V7.5 Gy) and mean GTV doses of 53.2% and 7.9 Gy, respectively, for 15 Gy plans. Average peak-to-valley dose ratio was 3.2. Mean beam-on time was 3.32 min, and treatment time, including patient setup and CBCT to beam-off, was within 15 min. Average 3D couch correction from original skin-markers was <1.0 cm. 3D MLC-based SFRT plans enhanced target dose for bulky masses, including deep-seated large tumors while protecting skin and adjacent critical organs. Additionally, it provides the same day, safe, effective, and convenient treatment by eliminating the risk to therapists and patients from heavy gantry-mounted physical GRID-block-we recommend other centers to use this simple and clinically useful method. This rapid SFRT planning technique is easily adoptable in any radiation oncology clinic by eliminating the need for plan optimization and patient-specific quality assurance times while providing dosimetry information in the treatment planning system. This potentially allows for dose-escalation to deep-seated masses to debulk unresectable large tumors providing an option for neoadjuvant treatment. An outcome study of clinical trial is underway.

Clinical validation of novel lightning dose optimizer for gamma knife radiosurgery of irregular-shaped arteriovenous malformations and pituitary adenomas.

PURPOSE: To demonstrate the clinical feasibility of a novel treatment planning algorithm via lightning dose optimizer (LDO) on Leksell Gamma Knife (LGK) GammaPlan with significantly faster planning times for stereotactic radiosurgery (SRS) of the complex and difficult arteriovenous malformations (AVMs) and pituitary adenomas. METHODS AND MATERIALS: After completing the in-house end-to-end phantom testing and independent dose verification of the recently upgraded LDO algorithm on GammaPlan using the MD Anderson's IROC anthropomorphic SRS head phantom irradiation credentialing, 20 previously treated GK-SRS patients (10 AVM, average volume 3.61 cm3 and 10 pituitary adenomas, average volume 0.86 cm3 ) who underwent manual forward planning on GammaPlan were retrospectively replanned via LDO. These pathologies were included because of the need for adequate dose delivery with organs at risk in very close proximity. LDO finds the target curvature boundary by well-formulated linear programing objectives and inversely optimizes the GK-SRS plan by isocenter placement, optimization, and sequencing. For identical target coverage, the LDO and original manual plans were compared for target conformity, gradient index, dose to critical organs, and surrounding normal brain. Additionally, various treatment delivery parameters, including beam-on time were recorded. RESULTS: For both patient cohorts, LDO provided similar target coverage with better dose conformity, tighter radiosurgical dose distribution with a lower value of gradient indices (all p < 0.001), and lower dose to critical organs. For AVMs, there was a significant reduction of normal brain V10Gy , V12Gy , and V14Gy by 4.74, 3.67, and 2.67 cm3 (all p < 0.001). LDO had twice the number of shots (p < 0.001), and longer beam-on time (p = 0.012) by a factor of 1.44. For pituitary adenomas, LDO provided systematically lower values of V10Gy , V12Gy , and V14Gy by 1.08, 0.86, and 0.68 cm3 (all p < 0.001), and lower maximum dose to optic pathway by 0.7 Gy (p = 0.005), but had almost twice the numbers of shots (p < 0.001) and increased beam-on time (p = 0.005) by a factor of 1.2. However, for both patient groups, the average planning time for the LDO was <5 min, compared to the estimated 30-90 min of manual planning times. CONCLUSION: GK-SRS treatment on Leksell Perfexion GammaPlan using the LDO provided highly conformal target coverage with a steep dose gradient, spared critical organs, and significantly reduced normal brain dose for complex targets at the cost of slightly higher treatment times. LDO generated high-quality treatment plans and could significantly reduce planning time. If available, the LDO algorithm is suggested for validation and clinical use for complex and difficult GK cases.

The RelB-BLNK Axis Determines Cellular Response to a Novel Redox-Active Agent Betamethasone during Radiation Therapy in Prostate Cancer.

Aberrant levels of reactive oxygen species (ROS) are potential mechanisms that contribute to both cancer therapy efficacy and the side effects of cancer treatment. Upregulation of the non-canonical redox-sensitive NF-kB family member, RelB, confers radioresistance in prostate cancer (PCa). We screened FDA-approved compounds and identified betamethasone (BET) as a drug that increases hydrogen peroxide levels in vitro and protects non-PCa tissues/cells while also enhancing radiation killing of PCa tissues/cells, both in vitro and in vivo. Significantly, BET increases ROS levels and exerts different effects on RelB expression in normal cells and PCa cells. BET induces protein expression of RelB and RelB target genes, including the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), in normal cells, while it suppresses protein expression of RelB and MnSOD in LNCaP cells and PC3 cells. RNA sequencing analysis identifies B-cell linker protein (BLNK) as a novel RelB complementary partner that BET differentially regulates in normal cells and PCa cells. RelB and BLNK are upregulated and correlate with the aggressiveness of PCa in human samples. The RelB-BLNK axis translocates to the nuclear compartment to activate MnSOD protein expression. BET promotes the RelB-BLNK axis in normal cells but suppresses the RelB-BLNK axis in PCa cells. Targeted disruptions of RelB-BLNK expressions mitigate the radioprotective effect of BET on normal cells and the radiosensitizing effect of BET on PCa cells. Our study identified a novel RelB complementary partner and reveals a complex redox-mediated mechanism showing that the RelB-BLNK axis, at least in part, triggers differential responses to the redox-active agent BET by stimulating adaptive responses in normal cells but pushing PCa cells into oxidative stress overload.

SBRT treatment of abdominal and pelvic oligometastatic lymph nodes using ring-mounted Halcyon Linac.

PURPOSE/OBJECTIVES: This work seeks to evaluate the plan quality, treatment delivery efficiency, and accuracy of single-isocenter volumetric modulated arc therapy (VMAT) of abdominal/pelvic oligometastatic lymph nodes (LNs) stereotactic body radiation therapy (SBRT) on Halcyon Linac. MATERIALS AND METHODS: After completing the in-house multitarget end-to-end phantom testing and independent dose verification using MD Anderson's single-isocenter/multi-target (lung and spine target inserts) thorax phantom, eight patients with two to three abdominal/pelvic oligometastatic LNs underwent highly conformal single-isocenter VMAT-SBRT treatment using the Halcyon Linac 6MV flattening filter free (FFF) beam. Targets were identified using an Axumin PET/CT scan co-registered with planning CT images and a single-isocenter was placed between/among the targets. Doses between 25 and 36.25 Gy in 5 fractions were delivered. Patients were treated every other day. Plans were calculated in Eclipse with advanced AcurosXB algorithm for heterogeneity corrections. For comparison, Halcyon VMAT-SBRT plans were retrospectively generated for SBRT-dedicated TrueBeam with a 6MV-FFF beam using identical planning geometry and objectives. Target coverage, conformity index (CI), dose to 2 cm away from each target (D2cm) and dose to adjacent organs-at-risk (OAR) were evaluated. Additionally, various treatment delivery parameters including beam-on time were recorded. RESULTS: Phantom measurements showed acceptable spatial accuracy of conebeam CT-guided Halcyon SBRT treatments including compliance with MD Anderson's single-isocenter/multi-targets phantom credentialing results. For patients, the mean isocenter to tumor center distance was 3.4 ± 1.2 cm (range, 1.5-4.8 cm). The mean combined PTV was 18.9 ± 10.9 cc (range, 5.6-39.5 cc). There was no clinically significant difference in dose to LNs, CI, D2cm and maximal doses to OAR between single-isocenter Halcyon and Truebeam VMAT-SBRT plans, although, Halcyon plans provided preferably lower maximal dose to adjacent OAR. Additionally, total monitor units, beam-on time and overall treatment time was lower with Halcyon plans. Halcyon's portal dosimetry demonstrated a high pass rate of 98.1 ± 1.6% for clinical gamma passing criteria of 2%/2 mm. CONCLUSION: SBRT treatment of abdominal/pelvic oligometastatic LNs with single-isocenter VMAT on Halcyon was dosimetrically equivalent to TrueBeam. Faster treatment delivery to oligometastatic LNs via single-isocenter Halcyon VMAT can improve clinic workflow and patient compliance, potentially reducing intrafraction motion errors for well-suited patients. Clinical follow-up of these patients is ongoing.

Prostate SBRT using O-Ring Halcyon Linac - Plan quality, delivery efficiency, and accuracy.

Cone beam CT-guided prostate stereotactic body radiotherapy (SBRT) treatment on the recently installed novel O-ring coplanar geometry Halcyon Linac with a single energy 6MV-flattening filter free (FFF) beam and volumetric modulated arc therapy (VMAT) is a fast, safe, and feasible treatment modality for early stage low- and intermediate-risk prostate cancer patients. Following the RTOG-0938 compliance criteria and utilizing two-full arc geometry, VMAT prostate SBRT plans were generated for ten consecutive patients using advanced Acuros-based algorithm for heterogeneity corrections with Halcyon couch insert. Halcyon VMAT plans with the stacked and staggered multileaf collimators (MLC) produced highly conformal SBRT dose distributions to the prostate, lower intermediate dose spillage and similar dose to adjacent organs-at-risks (OARs) compared to SBRT-dedicated Truebeam VMAT plans. Due to lower monitor units per fraction and less MLC modulation through the target, the Halcyon VMAT plan can deliver prostate SBRT fractions in and overall treatment time of less than 10 minutes (for 36.25 Gy in five fractions), significantly improving patient compliance and clinic workflow. Pretreatment quality assurance results were similar to Truebeam VMAT plans. We have implemented Halcyon Linac for prostate SBRT treatment in our institution. We recommend that others use Halcyon for prostate SBRT treatments to expand the access of curative hypofractionated treatments to other clinics only equipped with a Halcyon Linac. Clinical follow-up results for patients who underwent prostate SBRT treatment on our Halcyon Linac is underway.

Changes in Angioarchitecture After Stereotactic Radiosurgery for Dural Arteriovenous Fistula.

INTRODUCTION: Dural arteriovenous fistulae (DAVF) are intracranial vascular abnormalities encountered in neurosurgery practice. Treatment options are microsurgical disconnection, endovascular embolization and/or radiosurgery. Past studies have reported the efficacy, safety, and predictors of success of radiosurgery. In this study, we investigated the angioarchitecture of fistulae at the time of radiosurgery and how the anatomy changed in the time after treatment based on angiogram follow-ups. METHODS: A retrospective analysis was performed on patients with angiographic diagnosis of DAVF treated with Gamma Knife radiosurgery (GKRS) between 2013 and 2018. Data collection included demographics, symptoms, grading scores, vascular anatomy, radiation data, treatment strategy, angiographic results, and length of patient follow-up. RESULTS: Our study reports data on 10 patients with a total of 14 fistulae. On follow-up angiography, 8 (57%) had complete occlusion of the fistula with a median time to follow up of 19.5 months. The remaining 6 (43%) were deemed as near-complete occlusion of fistula with a median time to follow up of 12.0 months. Time from radiosurgery to angiogram revealing incomplete vs. angiogram revealing complete obliteration was significantly different (p=0.045). Nearly all AVFs had decreased feeders over time after treatment with only one AVF developing an additional feeder post-treatment. Arterial feeders, drainage site, sex, Borden type, lesion volume and treatment volume had no predictive value of obliteration outcome. CONCLUSIONS: This study provides data on the angioarchitecture of fistulae treated with GKRS and also serves as an extension of previous studies reporting the safety and efficacy of GKRS treatment for DAVF in a specific patient population.

A double-blind, placebo-controlled, phase II, randomized study of lovastatin therapy in the treatment of mildly active rheumatoid arthritis.

OBJECTIVES: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. METHODS: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. RESULTS: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. CONCLUSION: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.

Bilateral Radiation Optic Neuropathy Following Concurrent Chemotherapy and Radiation in Glioblastoma.

Radiation optic neuropathy (RON) is an iatrogenic complication that causes severe, irreversible vision loss within months to years following radiation to lesions close to the visual pathway. The authors describe a case of RON in glioblastoma after radio-sensitisation with temozolomide with sequential involvement of both optic nerves. This case provides a timeline for clinical and imaging findings with RON and specifically resolution of nerve enhancement. The authors also highlight the potential of an increase in incidence of RON in glioblastoma with advances in survival seen with greater use of second-line chemotherapy and even re-radiation.

Allosteric modulation of proteinase 3 activity by anti-neutrophil cytoplasmic antibodies in granulomatosis with polyangiitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) with proteinase 3 (PR3) specificity are a useful laboratory biomarker for the diagnosis of Granulomatosis with Polyangiitis (GPA) and are believed to be implicated in the pathogenesis. It has been repeatedly suggested that disease activity of GPA is more closely related to the appearance and rise of PR3-inhibiting ANCA than to an increase of total ANCA. Previous studies on a limited number of patient samples, however, have yielded inconclusive results. To overcome the previous methodological limitations, we established a new ultrasensitive method to quantify the inhibitory capacity of PR3-ANCA using small volumes of plasma from patients with GPA. A large collection of longitudinally-collected samples from the Wegener Granulomatosis Etanercept Trial (WGET) became available to us to determine the functional effects of ANCA on PR3 in comparison to clinical disease manifestations. In these patient samples we not only detected PR3-ANCA with inhibitory capacity, but also PR3-ANCA with enhancing effects on PR3 activity. However no correlation of these activity-modulating PR3-ANCA with disease activity at either the time of enrollment or over the course of disease was found. Only patients with pulmonary involvement, especially patients with nodule formation in the respiratory tract, showed a slight, but not significant, decrease of inhibitory capacity. Epitope mapping of the activity-modulating PR3-ANCA revealed a binding on the active site surface of PR3. Yet these ANCA were able to bind to PR3 with an occupied active site cleft, indicating an allosteric mechanism of inhibition. The recently described signal ratio between the MCPR3-3 and MCPR3-2 capture ELISA was consistent with the binding of activity-modulating ANCA to the active site surface. Evidence for a shared epitope between activity-modulating PR3-ANCA and MCPR3-7, however, was very limited, suggesting that a majority of PR3-ANCA species do not inhibit PR3 by the same mechanism as previously reported for MCPR3-7.

Implications of polychronous neuronal groups for the continuity of mind.

Is conceptual space continuous? The answer to this question depends on how concepts are represented in the brain. Vector space representations, which ground conceptual states in the instantaneous firing rates of neurons, have successfully captured cognitive dynamics in a broad range of domains. There is a growing body of evidence, however, that conceptual information is encoded in spatiotemporal patterns of neural spikes, sometimes called polychronous neuronal groups (PNGs). The use of PNGs to represent conceptual states, rather than employing a continuous vector space, introduces new challenges, including issues of temporally extended representations, meaning through symbol grounding, compositionality, and representational similarity. In this article, we explore how PNGs support discontinuous transitions between concepts. While the continuous dynamics of vector space approaches require such transitions to activate intermediate and blended concepts, PNGs offer the means to change the activation of concepts discretely, introducing a form of conceptual dynamics unavailable to vector space models.

Development and Quality Assurance of Multileaf Collimator (MLC) Auto-Feathering Junctions for Multi-Isocenter Supine Volumetric Modulated Arc Therapy (VMAT) Craniospinal Axis Irradiation on Halcyon.

Currently, there is a lack of methods and tools that efficiently evaluate the auto-feathering junctions created by multileaf collimator (MLCs) for supine volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) plans. We have investigated the feasibility of stitching together multi-isocenter fluence maps to then analyze the feathered junctions for patient-specific quality assurance (QA). Furthermore, we investigated the capability of Halcyon for the treatment of CSI patients. Three patients, who previously underwent VMAT CSI treatment on TrueBeam (6-MV flattening filter-free (FFF)) for 36 Gy in 20 fractions were replanned for Halcyon. A multi-isocenter approach with only translational superior-inferior shifts was used for both platforms. Each isocenter consists of two full arcs with anterior avoidance sectors, ±5° collimator rotations between arcs, and 5-8 cm of overlapping MLC auto-feathering junctions. All plans were QA'd via electronic portal imaging device (EPID) portal dosimetry and analyzed with a gamma criteria of 3%/3 mm. A variety of plan quality metrics were analyzed to evaluate dose distributions to the target, doses to organs at risk (OARs), and integral dose to the patient. A MATLAB script was developed to stitch the calculated and measured fluence maps in order to perform patient-specific QA for the composite fluence. The Halcyon plans provided highly conformal and homogenous dose distributions to the entire CSI target, superior to the clinical TrueBeam plans, while sparing critical organs with significantly lower values of V10Gy and V18Gy by up to 2% and 2.5%, respectively. Qualitative depictions of vertical dose profiles from the stitched DICOM of the entire CSI target for both planned and delivered fluence maps demonstrated equivalency, with slightly lower average pass rates with Halcyon (97%) compared to TrueBeam (99.9%). This approach to stitch multiple measured versus calculated EPID fluence maps has shown to be a feasible and accurate method and will be helpful for comprehensive VMAT CSI QA on both platforms. Further implementation of this script will be used in examining dosimetric impacts of daily patient positioning errors at MLC auto-feathering junctions.

Weighted mean difference statistics for paired data in the presence of missing values.

Missing data is a common issue in many biomedical studies. Under a paired design, some subjects may have missing values in either one or both of the conditions due to loss of follow-up, insufficient biological samples, etc. Such partially paired data complicate statistical comparison of the distribution of the variable of interest between the two conditions. In this article, we propose a general class of test statistics based on the difference in weighted sample means without imposing any distributional or model assumption. An optimal weight is derived from this class of tests. Simulation studies show that our proposed test with the optimal weight performs well and outperforms existing methods in practical situations. Two cancer biomarker studies are provided for illustration.

A Phase I Dose Escalation and Expansion Study of Epidiolex (Cannabidiol) in Patients with Biochemically Recurrent Prostate Cancer.

PURPOSE: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. EXPERIMENTAL DESIGN: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. RESULTS: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). CONCLUSION: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

Patient-specific dose correction for prostate postimplant evaluation with flexible timing of postimplant imaging.

PURPOSE: The dosimetric effect of edema on prostate implants have long been realized, but large uncertainties still exist in the estimation of dose actually received by the prostate. This study attempted to develop a new method to accurately estimate dose delivered to the prostate accounting for the variation of prostate volume and seed distribution, edema half-lives, and times for postimplant evaluation. METHODS AND MATERIALS: A series of prostate seed implants for Cs-131, Pd-103, and I-125 with various prostate volumes were simulated in a water phantom using the TG-43 algorithm on the Varian Eclipse treatment planning system. Dose analysis was performed to derive a quantitative relationship between the prostate peripheral dose and the prostate radius with the variation of prostate volume and seed distribution. Using this relationship to calculate dynamically, the total dose accumulated in the prostate (DT ) accounting for the variation of prostate volume and seed distribution and edema half-lives. Moreover, the total dose can be estimated statically based on the prostate volume that can be determined in a computerized tomography (CT) image taken at a time after implantation. The statically estimated total dose (DCT ) was compared with DT to determine optimal imaging times as well as dose correction factors for other imaging times. RESULTS: An inverse power law was established between the prostate peripheral dose and prostate radius. The value of the power was 1.3 for Cs-131 and I-125, and 1.5 for Pd-103, respectively. DT was derived dynamically using the inverse power law. Given the edema half-lives, TE , of 4, 9.3, and 25 days and the volume expansion of 1.1 and 2.0 times of the prostate without edema, the optimal times for postimplant imaging were: 7, 9, and 16 days for TE  = 4 days; 10, 14, and 28 days for TE  = 9.3 days; and 12, 19, 45 days TE  = 25 days, for Cs-131, Pd-103, and I-125, respectively. DCT calculated using the prostate volume determined on the optimal days agreed with DT to 0.0%-1.8% and within 0.3% for most cases. For various prostate volumes, edema half-lives, and nonoptimal times, DCT was able to achieve a 1% accuracy. CONCLUSION: The postimplant dose calculation based on the proposed inverse power law for prostate seed implants with edema has improved the accuracy of postimplant dosimetry with accurate and patient-specific dose corrections accounting for prostate size, edema half-life, and postimplant imaging times. Optimal times for postimplant imaging have been accurately determined, and the high accuracy of postimplant dose calculation can be achieved for both optimal imaging times and nonoptimal imaging times.

Feasibility Study of Stereotactic Radiosurgery Treatment of Glomus Jugulare Tumors via HyperArc VMAT.

This study aims to report on the clinical validation and feasibility of utilizing a novel fully automated treatment planning and delivery system, HyperArc VMAT stereotactic radiosurgery (SRS) for glomus jugulare tumors (GJT). Independent dose verification of the HyperArc module via the MD Anderson's SRS head phantom irradiation and credentialing results showed compliance with the SRS treatment requirements per IROC MD Anderson's standard. Following the Alliance clinical trial, AAPM, RTOG protocols, and QUANTEC requirements, utilizing selected three-partial arc geometry of HyperArc module on TrueBeam Linac with 6MV-FFF beam, GJT SRS plans were generated for nine previously treated Gamma Knife (GK) radiosurgery patients using advanced Acuros-based algorithm to account for tissue inhomogeneity corrections and frameless immobilization with Q-fix mask and Encompass device insert. HyperArc VMAT produced highly conformal SRS dose distributions to GJT, a steep dose gradient around the GJT, and spared adjacent critical organs including the spinal cord (< 3.0 Gy). Due to faster patient setup and less MLC modulation through the target (average beam-on time, 6.2 minutes), the HyperArc VMAT plan can deliver a single high-dose of 18 Gy to the GJT in less than 15 minutes overall treatment time, significantly improving patient comfort and clinic workflow. Pretreatment portal dosimetry quality assurance results and independent dose verification via Monte Carlo-based physics second check met our clinical SRS protocol's requirements for treatment. Due to the highly conformal dose distribution, rapid dose fall-off, excellent sparing of adjacent critical organs, and highly precise and accurate treatment, clinical implementation of frameless HyperArc VMAT for GJT patients who may not have access to nor tolerate frame-based GK SRS treatment are underway.

A Redox-active Mn Porphyrin, MnTnBuOE-2-PyP5+, Synergizes with Carboplatin in Treatment of Chemoresistant Ovarian Cell Line.

We have employed a redox-active MnP (MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (H2O2) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX-001), a redox-active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in H2O2 levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP-based redox-active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients' chemotherapy outcomes, which develop resistance to platinum-based drugs.

Evaluating the clinical acceptability of deep learning contours of prostate and organs-at-risk in an automated prostate treatment planning process.

BACKGROUND: Radiation treatment is considered an effective and the most common treatment option for prostate cancer. The treatment planning process requires accurate and precise segmentation of the prostate and organs at risk (OARs), which is laborious and time-consuming when contoured manually. Artificial intelligence (AI)-based auto-segmentation has the potential to significantly accelerate the radiation therapy treatment planning process; however, the accuracy of auto-segmentation needs to be validated before its full clinical adoption. PURPOSE: A commercial AI-based contouring model was trained to provide segmentation of the prostate and surrounding OARs. The segmented structures were input to a commercial auto-planning module for automated prostate treatment planning. This study comprehensively evaluates the performance of this contouring model in the automated prostate treatment planning process. METHODS AND MATERIALS: A 3D U-Net-based model (INTContour, Carina AI) was trained and validated on 84 computed tomography (CT) scans and tested on an additional 23 CT scans from patients treated in our local institution. Prostate and OARs contours generated by the AI model (AI contour) were geometrically evaluated against reference contours. The prostate contours were further evaluated against AI, reference, and two additional observer contours for comparison using inter-observer variation (IOV) and 3D boundaries discrepancy analyses. A blinded evaluation was introduced to assess subjectively the clinical acceptability of the AI contours. Finally, treatment plans were created from an automated prostate planning workflow using the AI contours and were evaluated for their clinical acceptability following the Radiation Therapy Oncology Group-0815 protocol. RESULTS: The AI contours demonstrated good geometric accuracy on OARs and prostate contours, with average Dice similarity coefficients (DSC) for bladder, rectum, femoral heads, seminal vesicles, and penile bulb of 0.93, 0.85, 0.96, 0.72, and 0.53, respectively. The DSC, 95% directed Hausdorff distance (HD95), and mean surface distance for the prostate were 0.83 ± 0.05, 6.07 ± 1.87 mm, and 2.07 ± 0.73 mm, respectively. No significant differences were found when comparing with IOV. In the double-blinded evaluation, 95.7% of the AI contours were scored as either "perfect" (34.8%) or "acceptable" (60.9%), while only one case (4.3%) was scored as "unacceptable with minor changes required." In total, 69.6% of the AI contours were considered equal to or better than the reference contours by an independent radiation oncologist. Automated treatment plans created from the AI contours produced similar and clinically acceptable dosimetric distributions as those from plans created from reference contours. CONCLUSIONS: The investigated AI-based commercial model for prostate segmentation demonstrated good performance in clinical practice. Using this model, the implementation of an automated prostate treatment planning process is clinically feasible.

Hydrogen Peroxide Promotes the Production of Radiation-Derived EVs Containing Mitochondrial Proteins.

In spite of extensive successes, cancer recurrence after radiation treatment (RT) remains one of the significant challenges in the cure of localized prostate cancer (PCa). This study focuses on elucidating a novel adaptive response to RT that could contribute to cancer recurrence. Here, we used PC3 cell line, an adenocarcinoma from a bone metastasis and radio-resistant clone 695 cell line, which survived after total radiation dose of 66 Gy (2 Gy × 33) and subsequently regrew in nude mice after exposure to fractionated radiation at 10 Gy (2 Gy × 5). Clone 695 cells not only showed an increase in surviving fraction post-radiation but also an increase in hydrogen peroxide (H2O2) production when compared to PC3 cells. At the single cell level, confocal microscope images coupled with IMARIS rendering software demonstrate an increase in mitochondrial mass and membrane potential in clone 695 cells. Utilizing the Seahorse XF96 instrument to investigate mitochondrial respiration, clone 695 cells demonstrated a higher basal Oxygen Consumption Rate (OCR), ATP-linked OCR, and proton leak compared to PC3 cells. The elevation of mitochondrial function in clone 695 cells is accompanied by an increase in mitochondrial H2O2 production. These data suggest that H2O2 could reprogram PCa's mitochondrial homeostasis, which allows the cancer to survive and regrow after RT. Upon exposure to RT, in addition to ROS production, we found that RT induces the release of extracellular vesicles (EVs) from PC3 cells (p < 0.05). Importantly, adding H2O2 to PC3 cells promotes EVs production in a dose-dependent manner and pre-treatment with polyethylene glycol-Catalase mitigates H2O2-mediated EV production. Both RT-derived EVs and H2O2-derived EVs carried higher levels of mitochondrial antioxidant proteins including, Peroxiredoxin 3, Glutathione Peroxidase 4 as well as mitochondrial-associated oxidative phosphorylation proteins. Significantly, adding isolated functional mitochondria 24 h prior to RT shows a significant increase in surviving fractions of PC3 cells (p < 0.05). Together, our findings reveal that H2O2 promotes the production of EVs carrying mitochondrial proteins and that functional mitochondria enhance cancer survival after RT.