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• Crc16 C

Bone-metastatic, castration-resistant prostate cancer (bmCRPC) represents a lethal stage of the most common noncutaneous cancer in men. The recent introduction of Radium-223 dichloride, a bone-seeking alpha particle (α)-emitting radiopharmaceutical, demonstrates statistically significant survival benefit and palliative effect for bmCRPC patients. Clinical results have established safety and efficacy, yet questions remain regarding pharmacodynamics and dosing for optimized patient benefit.We elucidated the biodistribution of (223)Ra as well as interaction with the bone and tumor compartments in skeletally mature mice (C57Bl/6 and CD-1, n = 3-6) and metastasis models (LNCaP and PC3, n = 4). Differences in uptake were evaluated by µCT and histological investigation. Novel techniques were leveraged on whole-mount undecalcified cryosections to determine microdistribution of Radium-223. All statistical tests were two-sided.(223)Ra uptake in the bones (30% injected activity per gram) at 24 hours was also accompanied by non-negligible remnant activity in the kidney (2.33% ± 0.36%), intestines (5.73% ± 2.04%), and spleen (10.5% ± 5.9%) Skeletal accumulation across strains did not correspond with bone volume or surface area but instead to local blood vessel density (P =.04). Microdistribution analysis by autoradiography and α camera revealed targeting of the ossifying surfaces adjacent to the epiphyseal growth plate.

In models of PCa metastasis, radioactivity does not localize directly within tumors but instead at the apposite bone surface. Osteoblastic and lytic lesions display similar intensity, which is comparable with uptake at sites of normal bone remodeling.Profiling the macro- and microdistribution of (223)Ra in healthy and diseased models has important implications to guide precision application of this emerging α-therapy approach for bmCRPC and other bone metastastic diseases.

Background: Bone-metastatic, castration-resistant prostate cancer (bmCRPC) represents a lethal stage of the most common noncutaneous cancer in men. The recent introduction of Radium-223 dichloride, a bone-seeking alpha particle (α)–emitting radiopharmaceutical, demonstrates statistically significant survival benefit and palliative effect for bmCRPC patients.

Clinical results have established safety and efficacy, yet questions remain regarding pharmacodynamics and dosing for optimized patient benefit. Qpst 3.1 download. Results: 223Ra uptake in the bones (30% injected activity per gram) at 24 hours was also accompanied by non-negligible remnant activity in the kidney (2.33% ± 0.36%), intestines (5.73% ± 2.04%), and spleen (10.5% ± 5.9%) Skeletal accumulation across strains did not correspond with bone volume or surface area but instead to local blood vessel density ( P =.04). Microdistribution analysis by autoradiography and α camera revealed targeting of the ossifying surfaces adjacent to the epiphyseal growth plate. In models of PCa metastasis, radioactivity does not localize directly within tumors but instead at the apposite bone surface. Osteoblastic and lytic lesions display similar intensity, which is comparable with uptake at sites of normal bone remodeling.

Prostate cancer (PCa) is the most commonly diagnosed cancer among men, with over a quarter of a million new cases in 2014 in the United States alone. Initially sensitive to endocrine therapy, the disease invariably overcomes these approaches and the fatal stage of the disease is characterized by strong tropism to the skeleton.

Crc16 C

PCa mortality is strongly influenced by bone metastasis and its associated skeletal-related events (SRE), decreased bone strength, malignant compression fracture, debilitating pain, and marrow failure as metastases displace the haematological compartment. Treatment of bone-metastatic, castrate-resistant prostate cancer (bmCRPC) may involve bisphosphonates, androgen receptor antagonists, biological, and radiopharmaceuticals. Bisphosphonates and the anti-RANKL antibody denosumab act on the bone microenvironment and reduce incidence of SRE. However, they neither prevent metastasis nor improve progression-free or overall survival (,).

Beta particle (β)–emitting Strontium-89 and Samarium-153 Lexidronam both target areas of bone turnover and are approved for bone pain palliation but likewise fail to extend survival. Recently, Radium-223 dichloride ( 223RaCl 2) demonstrated median survival extension in bmCRPC of 3.5 months vs placebo and gained approval for patients free of visceral disease. Through decay of the 11.4 day half-life 223Ra and its daughters a total of four alpha particles (α) are emitted, which are helium nuclei with high linear energy transfer (LET) properties. The weighted average energy of αs from the 223Ra decay chain is 5.78 MeV, and this dose is deposited with an average travel of merely 57 μm (,).

The result is exquisitely cytotoxic radiation highly localized to the distribution of the radionuclide. Calibration 223RaCl 2 (Bayer HealthCare Pharmaceuticals, Leverkusen, Germany) was calibrated according to guidelines provided by the supplier in response to the Nuclear Regulator Commission. Briefly, the dial setting of the calibrator (CRC-127R, Capintec; Ramsey, New Jersey) was determined by selecting a value that was confirmed with the decay-corrected National Institute of Standards and Technology standard calibrated dose upon vialing. This empirically determined dial setting (#277) was used for all experiments. Animals received 150 µL of clinical-grade 223RaCl 2 citrate solution, diluted in sterile physiological saline, immediately before injection. Mouse Experimentation All mice were skeletally mature males (greater than 14 weeks of age).

CD-1 mice (Charles River Laboratories), B6.Cg C57Bl/6 mice (Jackson Laboratories; Bar Harbor, ME), and Nu/Nu mice (Harlan Laboratories; Indianapolis, IN) were placed on standard feed ad libitum. All mouse experimentation was in accordance with institutional animal welfare protocols at The Johns Hopkins University School of Medicine. PC3 and LNCaP-AR cells were inoculated intratibially in Nu/Nu mice, as described. Bone metastasis was monitored by bioluminescence and x-ray computed tomography (CT) using the IVIS SpectrumCT (Perkin Elmer; Waltham, MA). Mice were dosed with 223RaCl 2 (10 kBq, n = 4–6 per experimentation group) and killed at one, four, or 24 hours for prompt dissection. To determine remnant whole-body activity at these time points, anesthetized mice were placed in a dose calibrator (n = 5).

Tissue activity was assayed by gamma (γ) counting or was cryo-embedded (OCT, Sakura Fintec, Torrance, CA). For whole-body autoradiography samples, mice were killed at 24 hours (n = 3). No fixation or decalcification chemicals were applied to mouse tissues, which were either stored (-80° C) or flash-frozen in liquid nitrogen.

Γ-counting energy was set between 240 and 300 keV. The main photopeak detected at 270 keV was provided by 223Ra (269 keV; 13.6%) and 219Rn (271 keV; 9.9%) emissions (Wizard 2, Perkin Elmer). High-resolution µCT (HRµCT), histological and autoradiographic methods are described in the (available online).

Organ Distribution of Radium-223 Dichloride Previous studies in rodents have found minimal or undetectable uptake of 223Ra outside of the calcified tissues. This contrasts with the human planar imaging of therapeutic doses of the radiopharmaceutical, which demonstrated intense abdominal uptake.

To test the utility of mice as models, we examined the kinetic biodistribution of 223RaCl 2 in skeletally mature C57Bl/6 mice. Localization to the bone was rapid, with 1.85% ± 0.49%, 2.86% ± 0.49%, and 4.54% ± 0.65% injected activity (IA) in the tibia, femur, and vertebrae samples after one hour determined by γ-counting. Bone labeling at four and 24 hours was non-statistically significant from the initial reading, and this confirms previous reports that Radium-223 (and its short-lived daughters) do not redistribute in rodent or man (,). We therefore focused our interest on the acute distribution of the radionuclide. Adjusting for the mass of resected tissues for the readings, at 24 hours postadministration we measured 51.19% ± 11.53%, 46.68% ± 5.12%, and 30.78% ± 3.99% IA per gram (%IA/g) in the tibia, femur, and vertebrae, respectively. Dynamic organ-level distribution of Radium-223 evaluated in skeletally mature male CD-1 mice. Mice (n = 4–5 per group) were killed at one, four, and 24 hours postinjection, and organs evaluated for activity by γ counting.

A) The distribution. Uptake in the spleen, stomach, and intestinal organs and the expected renal clearance and early bladder passage (genitourinary package) were observed. These results underline the non-negligible levels of 223Ra outside of the bone and reveal that a statistically significant fraction (25% IA) of the agent rapidly transits to the small and large intestine to be excreted. 223Ra uptake in the bones (30% injected activity per gram) at 24 hours was also accompanied by non-negligible remnant activity in the kidney (2.33% ± 0.36%), intestines (5.73% ± 2.04%), and spleen (10.5% ± 5.9%). Whole-body clearance was monitored using a well counter. Combined renal and intestinal clearance resulted in retention of 81% ± 5% of the IA at one hour, which decreased at four hours to 76% ± 3% and fell further at 24 hours to only 46.5% ± 2%. These values resemble those determined in a phase I pharmacokinetic study in men with bmCRPC and validate the use of skeletally mature rodents as a model to study Radium-223 in men.

To verify γ counts, whole-body autoradiography visually confirmed soft-tissue and skeletal uptake. Standard tissue processing for histochemistry and evaluation (including fixation and decalcification) would remove 223Ra or alter the radionuclide distribution. Thus, mice were killed and flash frozen at 24 hours postinjection, prior to unfixed and undecalcifed sectioning. Macrographs, autoradiography, and overlay are shown for representative sections (, D-F). Direct imaging corroborates γ counts with prominent 223Ra labeling of the skeleton, spleen, stomach, and kidneys.

Radium-223 Uptake and Bone Microstructure Autoradiography and γ counting revealed non-negligible soft-tissue uptake. C57Bl/6 mice are known to be osteopenic relative to other strains , and it is conceivable that use of this low-bone model may bias 223Ra results towards lower bone uptake and greater intestinal accumulation. To interrogate the role of bone phenotype on uptake, we evaluated distribution in a second common strain. Skeletally mature, age-matched, male C57Bl/6 and CD-1 mice were dosed with 223RaCl 2, and distribution was evaluated.

Uptake was not statistically significant between the strains for any of the soft tissues (, A and B). The minimum statistical test value across the soft tissues was the small intestine (%IA/g, P =.39). However, greater labeling in the C57Bl/6 strain was noted in the skeleton, in total counts, when compared with CD-1 uptake. These differences were statistically significant for the femur ( P. Strain-dependent differences in Radium-223 uptake and bone microarchitecture.

A) The distribution of the radionuclide was compared in age- and sex-matched C57Bl/6 and CD-1 (n = 5) as percent injected activity%IA ± SD. B) The greater overall uptake. This greater uptake in smaller bone tissue was unexpected. We suspected that mouse strain–dependent features of bone microarchitecture might explain the difference in 223Ra distribution.

To ask this question, we undertook detailed HRµCT of the trabecular and cortical regions of the femur and tibia (femur schematic). The bone volume of the CD-1 was greater than that of the C57Bl/6 in the trabecular and cortical regions of the femur (, D and F).

Quantitative analysis confirmed that the CD-1 strain exhibits greater total tissue volume (5.31±0.95mm 3 vs 3.56±0.20mm 3; P =.02) and occupying bone volume (1.081±0.18mm 3 vs 0.781±0.11mm 3; P =.04) in the cancellous bone than C57Bl/6. However, there was no difference in the density or thickness of trabecular structures ( P =.21). Consequently, bone as a percent of the total tissue volume (BV/TV) was not statistically significantly different, at approximately 20% ( P =.35).

Similar results were determined from quantitative analysis in the cortical region. The amount of total tissue in the CD-1 was statistically significantly greater than the C57Bl/6 (2.33±0.137mm 2 compared with 1.73±0.077mm 2; P =.02) while the cortical area fraction, or bone-to-tissue area ratio, does not vary statistically significantly, at nearly 45% ( P =.09). Therefore, the paradoxically greater uptake in smaller bones could not be explained by a bone tissue area balance at the micron scale; CD-1 mice have statistically significantly more total bone and bone surface area yet lower 223Ra uptake. Vascular Dependence of Uptake 223RaCl 2 was rapidly cleared from the blood (, A and B), and we next tested the hypothesis that discrepant skeletal uptake could be attributed to differences in vascular delivery. We determined the vascular density by CD-31 staining.

The number of vessels in the trabecular compartment was computed by counting the number of CD31-positive vessels in 40 high-powered fields in the tibia and femur. The C57Bl/6 samples had a greater vascular density of CD31-positive vessels than that of CD-1. There was an approximately 28% ± 8% increase in the number of blood vessels per mm 2 across age- and sex-matched mice from the two strains ( P =.04). No statistically significant difference was found in the marrow cavity (data not shown). These results suggest that a dominant characteristic for the magnitude of 223Ra uptake at bone sites is blood vessel density dependent rather than the quantity of exposed bone surface area or bone volume. Radium-223 and Bone Metastasis Models of Prostate Cancer Using an intratibial inoculation model of metastasis, we evaluated the acute microdistribution of 223Ra with osteoblastic (LNCaP) and osteolytic (PC3) PCa lines.

En bloc macrophotographs and cryosections were exposed and developed histochemically (hematoxylin and eosin, Safranin-O) for tissue morphology identification. Representative autoradiograms demonstrate that 223Ra does not localize directly to the tumor (indicated by arrow), regardless of type. Instead, activity accumulates at the apposite bone surface surrounding the lesion, as well as again at the active bone modeling/remodeling sites. The 223Ra deposition in healthy bone sites is likewise equivalent to the levels in bone surrounding the tumors.

Further, alkaline phosphatase enzyme stain (ALP) colocalized osteoblastic activity and 223Ra uptake at both the malignant and joint site (, available online). Discussion Metastatic invasion of the skeleton in PCa results in pain, risk of fracture, and bone marrow failure. 223RaCl 2 provides selective and effective treatment of bmCRPC lesions. Currently administered based upon body weight—independent of disease characteristics—there is an urgent need to develop personalized treatment plans. Rodent models have provided considerable value in development of bmCRPC drug candidates (,). However, there is scant literature evaluating 223RaCl 2 in preclinical models of PCa, with notable exceptions.

Our investigation focused on understanding the pharmacodynamics of 223Ra and the development of tools to enable its detailed study at multiple scales. Whole-body 223Ra distribution was determined and compared with bone features including HRμCT and vasculature morphology. The skeletally mature mice (age 14 weeks) used in this work possess normalized bone growth and resorption rates. The epiphyseal plates of mice do not fuse, and 223Ra accumulation was noted at sites of bone activity—whether adjacent to the growth plate or surrounding implanted intraosseous xenografts. Along with expected skeletal accumulation, non-negligible uptake in the spleen, intestines, and kidney was quantified and imaged and corresponded with the gastrointestinal accumulation seen in men using planar γ-scintigraphy (,). Clinical effects of uptake at these sites are associated with reported adverse gastrointestinal events, often leading to cessation of treatment. Acknowledging differences between mouse and human bone properties, these results provide support for the use of skeletally mature mouse models as surrogates to evaluate the impact of Radium-223.

Statistically significantly greater 223Ra%IA ( P. The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

The authors would like to thank Dr. Theodore DeWeese (Department of Radiation Oncology, JHU) and Dr. Tom Clemens (Department of Orthopedics, JHU) for discussion. We are indebted to the Microscopy Facility of the JHU SOM, in particular Barbara Smith and Dr. Scot Kuo for their technical assistance. The authors declare no conflicts.

RFH has previously served as a consultant for Algeta ASA, purchased by Bayer HealthCare Pharmaceuticals, Inc. (Whippany, NJ), which manufactures and distributes Xofigo.

Thanks, I already have all that stuff. I am talking more like spare arms, hub carriers, side links and so on. At what tire diameter size should I start to use the optional ride height shims?

I noticed the shop is out of these shims and wondering if they are needed for 4041 mm front diameter? Hey Ed, The arms and all that are pretty bomb-proof, the only part that I've managed to break is the front steering knuckles, and even they are pretty stern. I would recommend you pick up the front roll center spacers, the front brace, and buy or fashion a thrust bearing for the diff, and that's about it. Maybe a bumper as the kit doesn't come with one stock. As for the ride height adjusters, you will be at about 4mm of ride height without any and a 41mm tire, so I guess it depends on your local rules. You can live without them, and if you have a bag of normal spacers or washers you can lift the sub-frame off the chassis to adjust ride height, and there is no need for kit-specific ones. Ps, what desertrat just explained is a SERIOUS PITA to do on a racenight.

Definitely plan to get the plastic ride heigh spacers. Even if its just one set. The rollcenter ones are optional if anything. I dont see them used on any of the stock cars. More of a mod thing. What most of us do is commit to the 1mm shims under the sub frame and when the tires get too small, too bad.

Though if you stick to 0.5mm ish droop, you should be able to run your tires to almost nothing with the 1mm underbrace shims. Ive heard that the slapmaster thrust kit doesnt fit the WC axle, but i had an alteredgo converted to wc when new so i dunno from first hand experience. Tommorrow ill get a second wc that will have the new axle, so ill prob mess around to see how i can make it work. Prob as simple as using the stock thrust bushing instead of the slapmaster one.

But we will see. Ive heard that the slapmaster thrust kit doesnt fit the WC axle, but i had an alteredgo converted to wc when new so i dunno from first hand experience. Tommorrow ill get a second wc that will have the new axle, so ill prob mess around to see how i can make it work. Prob as simple as using the stock thrust bushing instead of the slapmaster one.

But we will see. The latest WC axle is also used on the WTF F1 car. The threaded portion has been shortened to fit in the right side hub of the F1. So, the Slapmaster thrust system for the differential does not fit. This is what I was told by a racer at the local track.

He runs this car and wins most of the mod races (just local racers): 1. Xti WC kit 2. Black art Lola body 3.

Set of pinions from 52-57 4. They apparently sell nice wire for 1/12 scale, so he recommended picking up that. He also recommended picking up a 7000 1s lipo from the site because he said they were really good now, but others have recommended other batteries. A spare set of ball bearings.

We race on carpet with spec tires so he recommended the WGT Stripe tires as a good fit, but that is specific to our track. He also said that the Wc built straight out of the box would be competitive so he didn't mention any upgrades. Anyway, take that for what it i worth Marc What pitch pinions?