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Balancing ALARA with the requirement for effective target localization requires that imaging dose be managed based on the consideration of weighing risks and benefits to the patient.

Purpose:In the absence of a collimation system the lateral penumbra of spot scanning (SS) dose distributions delivered by low energy proton beams is highly dependent on the spot size. For current commercial equipment, spot size increases with decreasing proton energy thereby reducing the benefit of the SS technique. This paper presents a dynamic collimation system (DCS) for sharpening the lateral penumbra of proton therapy dose distributions delivered by SS. Methods: The collimation system presented here exploits the property that a proton pencil beam used for SS requires collimation only when it is near the target edge, enabling the use of trimmers that are in motion at times when the pencil beam is away from the target edge. The device consists of two pairs of parallel nickel trimmer blades of 2 cm thickness and dimensions of 2 cm × 18 cm in the beam's eye view. The two pairs of trimmer blades are rotated 90• relative to each other to form a rectangular shape. Each trimmer blade is capable of rapid motion in the direction perpendicular to the central beam axis by means of a linear motor, with maximum velocity and acceleration of 2.5 m/s and 19.6 m/s 2 , respectively. The blades travel on curved tracks to match the divergence of the proton source. An algorithm for selecting blade positions is developed to minimize the dose delivered outside of the target, and treatment plans are created both with and without the DCS. Results: The snout of the DCS has outer dimensions of 22.6 × 22.6 cm 2 and is capable of delivering a minimum treatment field size of 15 × 15 cm 2 . Using currently available components, the constructed system would weigh less than 20 kg. For irregularly shaped fields, the use of the DCS reduces the mean dose outside of a 2D target of 46.6 cm 2 by approximately 40% as compared to an identical plan without collimation. The use of the DCS increased treatment time by 1-3 s per energy layer. Conclusions:The spread of the lateral penumbra of low-energy SS proton treatments may be greatly reduced with the use of this system at the cost of only a small penalty in delivery time.

307 Introduction. Chronic GVHD (cGVHD) poses a significant risk for hematopoietic stem cell transplantation (HSCT) patients. Preclinical development of new therapies has been hindered by the dearth of models with pathological findings that simulate the development of human cGVHD. Although the exact causes of cGVHD in HSCT patients are unknown, higher alloantibody levels and the organ systems in which alloantibodies are deposited have not been well-represented in preclinical models. The present studies extend our recent publication on a mouse model of cGVHD and bronchiolitis obliterans (BO), which has been deemed pathognomonic of cGVHD diagnosis in patients according to the NIH consensus criteria. Further, we have elucidated the role that alloantibody deposition plays in cGVHD pathogenesis and have developed a new interventional approach that is highly effective in preventing BO and cGVHD manifestations. Methods/Results. B10.BR (H2k) recipients received myeloablative conditioning with Cytoxan and high dose radiation followed by allogeneic C57BL/6 (H2b) bone marrow (BM) and a low (sublethal) dose of T cells to induce a chronic anti-host immune response. Survival was ≥90% at 2 months in all studies and mice did not lose significant weight or have clinical manifestations of acute GVHD. On day 60 after HSCT, pulmonary function was measured in anesthesized mice by whole body plethysmography using the Flexivent mechanical ventilator. Mice with cGVHD and BO had decreased compliance and increased airway resistance along with histological features of BO, characterized by airway blockade, peri-bronchiolar fibroproliferation and bronchiole obliteration. Tissue manifestations of cGVHD occurred in a wide-spectrum of target organs, including the tongue. Fibrosis was demonstrated in the lung and liver, associated with CD4+ T-cells and B220+ B-cell infiltration and alloantibody deposition. Whereas serum IgM and IgG isotype levels did not differ in cGVHD compared with BM controls, alloantibody deposition (primarily IgG2c, IgG2b) could be found in the lung and liver. Recipients given μMT B cell deficient BM did not develop BO and had reduced cGVHD, implicating donor BM-derived B cell alloantibody production in cGVHD pathogenesis. To distinguish between alloantibody deposition and reduced B cell APC function, we utilized (m+s)IgMxJhD BALB/c donors, capable of generating membrane bound IgM antibody and secreting IgM but secreting ≥100-fold less antigen-specific IgG than similarly immunized controls. Recipients of (m+s)IgMxJhD BM and wildtype splenocytes had significantly reduced BO, indicating that the lack of IgG alloantibody secretion by donor BM-derived B-cells precluded BO. Germinal center (GC) formation is necessary for Ig class switching. cGVHD was associated with robust GC formation, in striking contrast to BM only or non-HSCT controls. Lymphotoxin-beta (LTβ), produced by T- and B- cells and LTβR signaling is required for GC formation. Thus, we sought to determine whether disruption of LTβR signaling by infusion of the known blocking reagent, mouse LTβR-Ig fusion protein, would reduce cGVHD pathology. Mice treated with LTβR-Ig showed disrupted GCs, reduced alloantibody deposition and no BO as assessed by pulmonary function tests. Conclusions. Our studies have identified a requirement for donor B cells and alloantibody deposition in cGVHD pathogenesis. Importantly, these studies have discovered LTβR-Ig as a potential clinical interventional strategy for prevention and therapy of cGVHD. Disclosures: Ranger: Biogen Idec: Employment. Browning:Biogen Idec: Employment.

No abstract

For the case considered, the proposed(153)Gd-based I-RSBT system has the potential to lower the urethral dose relative to HDR-BT by 29%-44% if the clinician allows a urethral dose gradient volume of 0-5 mm around the urethra to receive a dose below the prescription. A multisource approach is necessary in order to deliver the proposed (153)Gd-based I-RSBT technique in reasonable treatment times.

The ability of the DCS to provide collimation to each energy layer yielded better conformity in comparison to fixed aperture plans.

For treating peripheral brain lesions--where proton therapy would be expected to have the greatest depth-dose advantage over photon therapy--the lateral penumbra strongly impacts the SS plan quality relative to photon techniques: proton beamlet sigma at patient surface must be small (<7.1 mm for three-beam single-field optimized SS plans) in order to achieve comparable or smaller brain necrosis NTCP relative to photon radiosurgery techniques. Achieving such small in-air sigma values at low energy (<70 MeV) is a major technological challenge in commercially available proton therapy systems.