Interleukin-21 enhances rituximab activity in a cynomolgus monkey model of B cell depletion and in mouse B cell lymphoma models.

Rituximab, a monoclonal antibody targeting CD20 on B cells, is currently used to treat many subtypes of B cell lymphomas. However, treatment is not curative and response rates are variable. Recombinant interleukin-21 (rIL-21) is a cytokine that enhances immune effector function and affects both primary and transformed B cell differentiation. We hypothesized that the combination of rIL-21 plus rituximab would be a more efficacious treatment for B cell malignancies than rituximab alone. We cultured human and cynomolgus monkey NK cells with rIL-21 and found that their activity was increased and proteins associated with antibody dependent cytotoxicity were up-regulated. Studies in cynomolgus monkeys modeled the effects of rIL-21 on rituximab activity against CD20 B cells. In these studies, rIL-21 activated innate immune effectors, increased ADCC and mobilized B cells into peripheral blood. When rIL-21 was combined with rituximab, deeper and more durable B cell depletion was observed. In another series of experiments, IL-21 was shown to have direct antiproliferative activity against a subset of human lymphoma cell lines, and combination of murine IL-21 with rituximab yielded significant survival benefits over either agent alone in xenogeneic mouse tumor models of disseminated lymphoma. Therefore, our results do suggest that the therapeutic efficacy of rituximab may be improved when used in combination with rIL-21.

Use of cone-beam imaging to correct for catheter displacement in high dose-rate prostate brachytherapy.

PURPOSE: To determine the magnitude of catheter displacement between time of planning and time of treatment delivery for patients undergoing high dose-rate (HDR) brachytherapy, the dosimetric impact of catheter displacement, and the ability to improve dosimetry by catheter readjustment. METHODS AND MATERIALS: Twenty consecutive patients receiving single fraction HDR brachytherapy underwent kilovoltage cone-beam CT in the treatment room before treatment. If catheter displacement was apparent, catheters were adjusted and imaging repeated. Both sets of kilovoltage cone-beam CT image sets were coregistered off-line with the CT data set used for planning with rigid fusion of anatomy based on implanted fiducials. Catheter displacement was measured on both sets of images and dosimetry calculated. RESULTS: Mean internal displacement of catheters was 11mm. This would have resulted in a decrease in mean volume receiving 100% of prescription dose (V(100)) from the planned 97.6% to 77.3% (p<0.001), a decrease of the mean dose to 90% of the prostate (D(90)) from 110.5% to 72.9% (p<0.001), and increase in dose to 10% of urethra (urethra D(10)) from 118% to 125% (p=0.0094). Each 1cm of catheter displacement resulted in a 20% decrease in V(100) and 36% decrease in D(90). Catheter readjustment resulted in a final treated mean V(100) of 90.2% and D(90) of 97.4%, both less than planned. Mean urethra D(10) remained higher at126% (p=0.0324). CONCLUSIONS: Significantly, internal displacement of HDR catheters commonly occurs between time of CT planning and treatment delivery, even when only a single fraction is used. The adverse effects on dosimetry can be partly corrected by readjustment of catheter position.

Quantification and reduction of peripheral dose from leakage radiation on Siemens Primus accelerators in electron therapy mode.

In this work, leakage radiation from EA200 series electron applicators on Siemens Primus accelerators is quantified, and its penetration ability in water and/or the shielding material Xenolite-NL established. Initially, measurement of leakage from 10 x 10 - 25 x 25 cm2 applicators was performed as a function of height along applicator and of lateral distance from applicator body. Relative to central-axis ionization maximum in solid water, the maximum leakage in air observed with a cylindrical ion chamber with 1 cm solid water buildup cap at a lateral distance of 2 cm from the front and right sidewalls of applicators were 17% and 14%, respectively; these maxima were recorded for 18 MeV electron beams and applicator sizes of >or=20 x 20 cm2. In the patient plane, the applicator leakage gave rise to a broad peripheral dose off-axis distance peak that shifted closer to the field edge as the electron energy increases. The maximum peripheral dose from normally incident primary electron beams at a depth of 1 cm in a water phantom was observed to be equal to 5% of the central-axis dose maximum and as high as 9% for obliquely incident beams with angles of obliquity

Initial investigation on the use of MR spectroscopy and micro-MRI of GAFCHROMIC EBT radiotherapy film.

PURPOSE: This article presents an initial investigation of the efficacy of using 1H MRS and micro-MRI as analysis techniques for irradiated GAFCHROMIC EBT radiotherapy films. METHODS: GAFCHROMIC EBT radiotherapy film was irradiated with 6 MV x rays to known doses ranging from 5 to 1000 cGy. 24 h following irradiation 1H MRS measurements were performed to access the degree of post-irradiation polymer cross-linking. 2D 1H micro-MRI experiments were also performed for film irradiations of 0 and 300 cGy. RESULTS: Linear response of the 1H MRS linewidth to dose in the range from 0 to 400 cGy (R2 = 0.98) was observed. Such linearity is not seen when analyzed under conventional light analysis. The sensitivity of the film, as measured by the slope of the curve between 0 and 400 cGy, is 0.0042 +/- 0.0003 kHz/cGy, demonstrating the sensitivity of the 1H MRS technique used to analyze the film. The film saturates at a dose of approximately 900 cGy. Broadline 1H MRS provides a quantitative measure of the degree of polymerization of the film. CONCLUSIONS: A quantitative measurement of the degree of polymerization of GAFCHROMIC EBT film has been presented using 1H MRS. The saturation of the film at approximately 900 cGy is corroborated by that observed with light analysis. Further MR spectroscopic experiments are needed to investigate the response of the film to dose, allowing for a better understanding of the relationship between polymer cross-linking in the active layer.

High-dose-rate prostate brachytherapy in a patient with bilateral hip prostheses planned using megavoltage computed tomography images acquired with a helical tomotherapy unit.

PURPOSE: The presence of hip prostheses results in significant image artifacts making delineation of anatomy for planning difficult with traditional kilovoltage CT images. This report presents the use of megavoltage computed tomography (MVCT) imaging acquired with a helical tomotherapy unit to plan a high-dose-rate (HDR) prostate brachytherapy treatment for a patient with bilateral hip prostheses. METHODS AND MATERIALS: A 77-year-old man presented with a localized clinical Stage T3a, Gleason 7 prostate cancer. Past history was also significant for bilateral hip prostheses. Staging workup included a negative bone scan and CT of abdomen and pelvis. The pelvic CT exhibited significant streak artifacts obscuring the prostate. HDR monotherapy with adjuvant androgen deprivation therapy was proposed. On the day of the implant and after catheter insertion, MVCT imaging of the pelvic area of the patient was obtained using a commercial helical tomotherapy unit. The MVCT images were transferred to Nucletron PLATO (v14.3.2) for planning with optimization of catheter dwell positions and times. RESULTS: MVCT images acquired with the helical tomotherapy unit allow good visualization of bony anatomy and of the hip prosthesis. No reconstruction streak artifacts are visible in the images as seen in the diagnostic kilovoltage CT images. Sufficient soft tissue contrast exists to allow delineation of the bladder and rectum. The absence of streak artifacts provides good quantification of Hounsfield number in the region surrounding the hip prosthesis and allows for good dose quantification. CONCLUSIONS: MVCT images obtained using the commercial helical tomotherapy unit have been shown to provide good soft tissue contrast and no streak artifacts when planning a patient for prostate HDR brachytherapy having bilateral prosthetic hip replacements. The rectum and bladder can be clearly seen in the MVCT images and contoured independently. Prostate delineation is assumed from the position of the brachytherapy catheters.