Proton vs Hyperarc™ radiosurgery: A planning comparison.

For many patients, stereotactic radiosurgery (SRS) offers a minimally invasive, curative option when surgical techniques are not possible. To date, the literature supporting the efficacy and safety of SRS treatment techniques uses photon beams. However, with the number of proton therapy facilities exponentially growing and the favorable physical properties of proton beam radiation therapy, there is an opportunity to develop proton therapy techniques for SRS. The goal of this paper is to determine the ability of clinical proton treatment planning systems to model small field dosimetry accurately and to compare various planning metrics used to evaluate photon SRS to determine the optimum beam configurations and settings for proton SRS (PSRS) treatment plans. Once established, these plan settings were used to perform a planning comparison on a variety of different SRS cases and compare SRS metrics between the PSRS plans and HyperArc™ (VMAT) SRS plans.

Innovating immune tolerance induction for haemophilia.

INTRODUCTION: Haemophilia A is an X-linked bleeding disorder characterized by a deficiency of coagulation protein factor VIII (FVIII). A challenging complication of therapeutic FVIII infusions is the formation of neutralizing alloantibodies against the FVIII protein defined as inhibitors. The development of FVIII inhibitors drastically alters the quality of life of the patients and is associated with tremendous increases in morbidity as well as treatment costs. AIM: Current clinical immune tolerance induction protocols to reverse inhibitors are lengthy, costly and not effective in all patients. Prophylactic protocols to prevent inhibitor formation have not yet been developed in the clinical setting. However, there has been ample progress towards this goal in recent years in preclinical studies using animal models of haemophilia. METHODS: Here, we review the mechanisms that lead to inhibitor formation against FVIII and two promising new strategies for antigen-specific tolerance induction. RESULTS: CD4+ T cells play an important role in the FVIII-specific B cell response. Immune tolerance can be induced based on transplacental delivery of FVIII domains fused to Fc or on oral delivery of leaf cells from chloroplast transgenic crop plants. CONCLUSIONS: Recent literature suggests that prophylactic tolerance induction protocols for FVIII may be feasible in haemophilia A patients.

US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors.

INTRODUCTION: The development of anti-factor VIII (FVIII) antibodies (inhibitors) is the most serious treatment-related complication in patients with hemophilia A, rendering standard replacement therapy ineffective, heightening the risk for uncontrollable bleeding and morbidity, decreasing quality of life, and increasing healthcare costs. AIM: Formulate evidence-based guidelines for optimizing immune tolerance induction (ITI) in patients with hemophilia A and inhibitors. METHODS: Results from the International ITI study and other available evidence were used to develop guidelines for ITI. RESULTS: Predictors of ITI success were identified and recommendations made for ITI with regard to candidates, timing, product, regimen, monitoring, defining success, concurrent immunomodulation, duration of treatment, and bleed management before and during ITI. CONCLUSION: Evidence-based recommendations to guide treatment decisions may increase the likelihood of successful inhibitor eradication and the induction of FVIII tolerance in patients with hemophilia A who develop inhibitory antibodies.

Late immune tolerance induction in haemophilia A patients.

The incidence of inhibitor development in patients with severe haemophilia A is approximately 30%. Immune tolerance induction (ITI) is commonly utilized to eradicate these antibodies and is successful in 63-100% of cases. Potential predictors of a poor outcome in ITI include a high preinduction titre, high historical peak titre, older age at start of ITI and prolonged interval from diagnosis to start of ITI. The goal of this study was to characterize the outcomes of patients from our centre who have undergone late ITI, many of whom had poor prognostic features. Medical records of patients in our centre with severe/moderately severe haemophilia A (<2% FVIII activity) and history of inhibitor were reviewed. Data were abstracted from all patients who attempted late ITI. Nine patients underwent late ITI between January 1999 and December 2011. Within this cohort, 7 (78%) patients were black, 6 (67%) were <21 years old and 4 (44%) had a family history of inhibitor. Three patients had previously received ITI unsuccessfully. To date, 4 (44%) patients are tolerized (persistently negative inhibitor titre, FVIII recovery >66% and successfully treated with FVIII products ± FVIII t(½) of >6 h). Three patients are partially tolerized (have low responding inhibitor, variable FVIII recovery and successfully treated with FVIII products). Two patients are not tolerized. Some patients with haemophilia A and long-standing inhibitors may benefit from ITI.

Medical radiation exposure in children with bleeding disorders: an institutional experience.

Patients with bleeding disorders may be exposed to ionizing radiation during medical care. We hypothesized that children with severe haemophilia may have higher radiation exposure than those with mild bleeding disorders (MBDs). To compare medical radiation exposure rates between children with severe haemophilia and MBDs. Charts of 35 pediatric patients with severe haemophilia were randomly selected from a database of active male patients followed in our bleeding disorders clinic from 2000 to 2010. Case patients were age and sex matched with two control patients with MBDs [Type 1 von Willebrand disease (VWD) or mild platelet function defect (PFD)]. By retrospective review, data on radiation exposure in millisieverts (mSv) was collected from radiological studies performed within Emory/CHOA. The rates of exposure between cohorts were compared using the Mann-Whitney Test. Case patients had a mean of 11.3 (median 8, IQR = 29) radiographic studies compared with 1.8 (median 1, IQR = 11) for controls (P < 0.001). The mean effective dose of radiation per patient per year of study was two mSv for case patients (median 0.4, IQR = 3) and 0.4 mSv for control patients (median 0.01, IQR = 0.3) (P < 0.001). Overall, 1.4% of controls and 31.4% of cases accumulated high to very high levels of exposure ( > 20 mSv). Case patients with severe hemophilia accumulated significantly more medical radiation exposure than controls. While the use of ionizing radiation is often necessary for management of these patients, avoidance of unnecessary exposure along with exploration of alternative imaging techniques and low dose protocols should be considered whenever possible.

Design and characterization of a prototype tertiary device for proton beam stereotactic radiosurgery.

Though potentially beneficial, proton beam stereotactic radiosurgery has not been adopted widely secondary to the technical challenge of safely delivering multiple focused beams of proton radiation. In this study, we describe the design and characterization of a proton beam stereotactic radiosurgery system that can be adopted by existing passive scattering systems. This system utilizes a helmet-like device in which patient-specific brass apertures required for final beam collimation are positioned on a scaffold that is separate from the treatment gantry. The proton snout is then fitted with a generic aperture to focus the primary proton beam onto the patient specific apertures that are in the helmet-like device. The patient-specific apertures can all be placed at the start of the treatment, thus treatment with multiple beams can be accomplished without the delay of switching the apertures. In this report we describe a prototype design of this collimation system and dosimetric testing to verify efficacy. Subsequently, we describe a custom 3D printing of a prototype device and report on overall localization accuracy using Winston-Lutz tests. Our results show that it is possible to develop an add-on device for proton beam radiosurgery that is safe and efficient and capable of wide adoption on existing proton delivery systems.

Dosimetric evaluation of a novel polymer gel dosimeter for proton therapy.

PURPOSE: The aim of this study is to evaluate the dosimetric performance of a newly developed proton-sensitive polymer gel formulation for proton therapy dosimetry. METHODS: Using passive scattered modulated and nonmodulated proton beams, the dose response of the gel was assessed. A next-generation optical CT scanner is used as the readout mechanism of the radiation-induced absorbance in the gel medium. Comparison of relative dose profiles in the gel to ion chamber profiles in water is performed. A simple and easily reproducible calibration protocol is established for routine gel batch calibrations. Relative stopping power ratio measurement of the gel medium was performed to ensure accurate water-equivalent depth dose scaling. Measured dose distributions in the gel were compared to treatment planning system for benchmark irradiations and quality of agreement is assessed using clinically relevant gamma index criteria. RESULTS: The dosimetric response of the gel was mapped up to 600 cGy using an electron-based calibration technique. Excellent dosimetric agreement is observed between ion chamber data and gel. The most notable result of this work is the fact that this gel has no observed dose quenching in the Bragg peak region. Quantitative dose distribution comparisons to treatment planning system calculations show that most (> 97%) of the gel dose maps pass the 3%/3 mm gamma criterion. CONCLUSIONS: This study shows that the new proton-sensitive gel dosimeter is capable of reproducing ion chamber dose data for modulated and nonmodulated Bragg peak beams with different clinical beam energies. The findings suggest that the gel dosimeter can be used as QA tool for millimeter range verification of proton beam deliveries in the dosimeter medium.

The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment.

Prothrombin (factor II) deficiency is a rare autosomal recessive coagulation disorder that occurs in approximately 1 in 1-2 million people. Prothrombin is activated to thrombin, which in turn proteolytically cleaves fibrinogen to fibrin and contributes to forming a stable fibrin clot. The haemostatic level of prothrombin is thought to be between 20 and 40%, and the half-life is approximately 3 days. There are more than 40 known mutations in prothrombin. Both hypoprothrombinemia and dysprothrombinemia have been described. Low prothrombin activity typically prolongs both the activated partial thromboplastin time and prothrombin time. Clinical manifestations are predominantly mucosal or surgical- or trauma-associated bleeding, but joint bleeding and intracranial haemorrhages have been reported. No purified prothrombin products are available for replacement therapy. Both fresh frozen plasma and prothrombin complex concentrates contain prothrombin and may be used for treatment.

Performance evaluation of an improved optical computed tomography polymer gel dosimeter system for 3D dose verification of static and dynamic phantom deliveries.

The performance of a next-generation optical computed tomography scanner (OCTOPUS-5X) is characterized in the context of three-dimensional gel dosimetry. Large-volume (2.2 L), muscle-equivalent, radiation-sensitive polymer gel dosimeters (BANG-3) were used. Improvements in scanner design leading to shorter acquisition times are discussed. The spatial resolution, detectable absorbance range, and reproducibility are assessed. An efficient method for calibrating gel dosimeters using the depth-dose relationship is applied, with photon- and electron-based deliveries yielding equivalent results. A procedure involving a preirradiation scan was used to reduce the edge artifacts in reconstructed images, thereby increasing the useful cross-sectional area of the dosimeter by nearly a factor of 2. Dose distributions derived from optical density measurements using the calibration coefficient show good agreement with the treatment planning system simulations and radiographic film measurements. The feasibility of use for motion (four-dimensional) dosimetry is demonstrated on an example comparing dose distributions from static and dynamic delivery of a single-field photon plan. The capability to visualize three-dimensional dose distributions is also illustrated.

Anti-C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model.

Essentials Inhibitor formation remains a challenging complication of hemophilia A care. The Bethesda assay is the primary method used for determining bleeding risk and management. Antibodies that block factor VIII binding to von Willebrand factor can increase FVIII clearance. Antibodies that increase clearance contribute to antibody pathogenicity. SUMMARY: Background The development of neutralizing anti-factor VIII (FVIII) antibodies remains a challenging complication of modern hemophilia A care. In vitro assays are the primary method used for quantifying inhibitor titers, predicting bleeding risk, and determining bleeding management. However, other mechanisms of inhibition are not accounted for in these assays, which may result in discrepancies between the inhibitor titer and clinical bleeding symptoms. Objectives To evaluate FVIII clearance in vivo as a potential mechanism for antibody pathogenicity and to determine whether increased FVIII dosing regimens correct the associated bleeding phenotype. Methods FVIII-/- or FVIII-/- /von Willebrand factor (VWF)-/- mice were infused with anti-FVIII mAbs directed against the FVIII C1, C2 or A2 domains, followed by infusion of FVIII. Blood loss via the tail snip bleeding model, FVIII activity and FVIII antigen levels were subsequently measured. Results Pathogenic anti-C1 mAbs that compete with VWF for FVIII binding increased the clearance of FVIII-mAb complexes in FVIII-/- mice but not in FVIII-/- /VWF-/- mice. Additionally, pathogenic anti-C2 mAbs that inhibit FVIII binding to VWF increased FVIII clearance in FVIII-/- mice. Anti-C1, anti-C2 and anti-A2 mAbs that do not inhibit VWF binding did not accelerate FVIII clearance. Infusion of increased doses of FVIII in the presence of anti-C1 mAbs partially corrected blood loss in FVIII-/- mice. Conclusions A subset of antibodies that inhibit VWF binding to FVIII increase the clearance of FVIII-mAb complexes, which contributes to antibody pathogenicity. This may explain differences in the bleeding phenotype observed despite factor replacement in some patients with hemophilia A and low-titer inhibitors.

Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.

UNLABELLED: ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. BACKGROUND: The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. OBJECTIVES: We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. METHODS: Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. RESULTS: All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. CONCLUSIONS: We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a defined genetic background.

Evaluation of a diode array for QA measurements on a helical tomotherapy unit.

A helical tomotherapy system is used in our clinic to deliver intensity-modulated radiation therapy (IMRT) treatments. Since this machine is designed to deliver IMRT treatments, the traditional field flatness requirements are no longer applicable. This allows the unit to operate without a field flatness filter and consequently the 400 mm wide fan beam is highly inhomogeneous in intensity. The shape of this beam profile is mapped during machine commissioning and for quality assurance purposes the shape of the beam profile needs to be monitored. The use of a commercial diode array for quality assurance measurements is investigated. Central axis beam profiles were acquired at different depths using solid water built-up material. These profiles were compared with ion chamber scans taken in a water tank to test the accuracy of the diode array measurements. The sensitivity of the diode array to variations in the beam profile was checked. Over a seven week period, beam profiles were repeatedly measured. The observed variations are compared with those observed with an on-board beam profile monitor. The diode measurements were in agreement with the ion chamber scans. In the high dose, low gradient region the average ratio between the diode and ion chamber readings was 1.000 +/- 0.005 (+/- 1 standard deviation). In the penumbra region the agreement was poorer but all diodes passed the distance to agreement (DTA) requirement of 2 mm. The trend in the beam profile variations that was measured with the diode array device was in agreement with the on-board monitor. While the calculated amount of variation differs between the devices, both were sensitive to subtle variations in the beam profile. The diode array is a valuable tool to quickly and accurately monitor the beam profile on a helical tomotherapy unit.

The use of megavoltage CT (MVCT) images for dose recomputations.

Megavoltage CT (MVCT) images of patients are acquired daily on a helical tomotherapy unit (TomoTherapy, Inc., Madison, WI). While these images are used primarily for patient alignment, they can also be used to recalculate the treatment plan for the patient anatomy of the day. The use of MVCT images for dose computations requires a reliable CT number to electron density calibration curve. In this work, we tested the stability of the MVCT numbers by determining the variation of this calibration with spatial arrangement of the phantom, time and MVCT acquisition parameters. The two calibration curves that represent the largest variations were applied to six clinical MVCT images for recalculations to test for dosimetric uncertainties. Among the six cases tested, the largest difference in any of the dosimetric endpoints was 3.1% but more typically the dosimetric endpoints varied by less than 2%. Using an average CT to electron density calibration and a thorax phantom, a series of end-to-end tests were run. Using a rigid phantom, recalculated dose volume histograms (DVHs) were compared with plan DVHs. Using a deformed phantom, recalculated point dose variations were compared with measurements. The MVCT field of view is limited and the image space outside this field of view can be filled in with information from the planning kVCT. This merging technique was tested for a rigid phantom. Finally, the influence of the MVCT slice thickness on the dose recalculation was investigated. The dosimetric differences observed in all phantom tests were within the range of dosimetric uncertainties observed due to variations in the calibration curve. The use of MVCT images allows the assessment of daily dose distributions with an accuracy that is similar to that of the initial kVCT dose calculation.

Expanding the ortholog approach for hemophilia treatment complicated by factor VIII inhibitors.

BACKGROUND: The formation of neutralizing antibodies (inhibitors) directed against human coagulation factor VIII (hFVIII) is a life-threatening pathogenic response that occurs in 20-30% of severe congenital hemophilia A patients and 0.00015% of the remaining population (i.e. acquired hemophilia A). Interspecies amino acid sequence disparity among FVIII orthologs represents a promising strategy to mask FVIII from existing inhibitors while retaining procoagulant function. Evidence for the effectiveness of this approach exists in clinical data obtained for porcine FVIII (pFVIII) products, which have demonstrated efficacy in the setting of congenital and acquired hemophilia. OBJECTIVES: In the current study, recombinant (r) ovine FVIII (oFVIII) was evaluated for antigenicity and procoagulant activity in the context of human patient-derived and murine model-generated FVIII inhibitors. METHODS: The antigenicity of roFVIII was assessed using (i) inhibitor patient plasma samples, (ii) murine anti-FVIII MAbs, (iii) immunized murine hemophilia A plasmas and (iv) an in vivo model of acquired hemophilia A. RESULTS: Overall, roFVIII demonstrated reduced reactivity to, and inhibition by, anti-hFVIII immunoglobulin in patient plasmas. Additionally, several hFVIII epitopes were predicted and empirically shown not to exist within roFVIII. In a murine hemophilia A model designed to mimic clinical inhibitor formation, it was demonstrated that inhibitor titers to roFVIII were significantly reduced when compared with the orthologous immunogens, rhFVIII or rpFVIII. Furthermore, in a murine model of acquired hemophilia A, roFVIII administration conferred protection from bleeding following tail transection. CONCLUSION: These data support the investigation of FVIII orthologs as treatment modalities in both the congenital and acquired FVIII inhibitor settings.

Subarachnoid and intracerebral hemorrhage: natural history, prognosis, and precursive factors in the Framingham Study.

No uniformly accepted hypothesis explains the genesis and rupture of intracranial aneurysms. We followed 5,184 men and women prospectively for 26 years; 36 cases of aneurysmal subarachnoid hemorrhage (SAH) accounted for 62% of all intracranial hemorrhages. Blood pressure before SAH was higher in these patients than in controls. Definite hypertension (greater than or equal to 160 mm Hg and/or greater than or equal to 95 mm Hg) at entry to the study or at closest exam before SAH was more frequent than in controls. Cigarette smoking, particularly heavy smoking, was also more frequent among cases.

Calculation of cranial nerve complication probability for acoustic neuroma radiosurgery.

PURPOSE: Estimations of complications from stereotactic radiosurgery usually rely simply on dose-volume or dose-diameter isoeffect curves. Due to the sparse clinical data available, these curves have typically not considered the target location in the brain, target histology, or treatment plan conformality as parameters in the calculation. In this study, a predictive model was generated to estimate the probability of cranial neuropathies as a result of acoustic schwannoma radiosurgery. METHODS AND MATERIALS: The dose-volume histogram reduction scheme was used to calculate the normal tissue complication probability (NTCP) from brainstem dose-volume histograms. The model's fitting parameters were optimized to provide the best fit to the observed complication data for acoustic neuroma patients treated with stereotactic radiosurgery at the University of Florida. The calculation was then applied to the remainder of the patients in the database. RESULTS: The best fit to our clinical data was obtained using n = 0.04, m = 0.15, and alpha/beta = 2.1 Gy(-1). Although the fitting parameter m is relatively consistent with ranges found in the literature, both the volume parameter, n, and alpha/beta are much smaller than the values quoted in the literature. The fit to our clinical data indicates that brainstem, or possibly a specific portion of the brainstem, is more radiosensitive than the parameters in the literature indicate, and that there is very little volume effect; in other words, irradiation of a small fraction of the brainstem yields NTCPs that are nearly as high as those calculated for entire volume irradiation. These new fitting parameters are specific to acoustic neuroma radiosurgery, and the small volume effect that we observe may be an artifact of the fixed relationship of acoustic tumors to specific regions of the brainstem. Applying the model to our patient database, we calculate an average NTCP of 7.2% for patients who had no cranial nerve complications, and the average NTCP for was 66% for patients who sustained a cranial neuropathy. For the entire patient population, the actual percentage of patients suffering either facial or trigeminal neuropathy was 14.7%, whereas the calculated average NTCP was 14.8%. DISCUSSION: NTCP calculations using brainstem dose-volume histograms can be used to estimate the rate of cranial neuropathies from acoustic neuroma radiosurgery. More clinical data and further study will lead to refinement of the model with time.