RAC1 GTPase promotes the survival of breast cancer cells in response to hyper-fractionated radiation treatment.

Radiation therapy is a staple approach for cancer treatment, whereas radioresistance of cancer cells remains a substantial clinical problem. In response to ionizing radiation (IR) induced DNA damage, cancer cells can sustain/activate pro-survival signaling pathways, leading to apoptotic resistance and induction of cell cycle checkpoint/DNA repair. Previous studies show that Rac1 GTPase is overexpressed/hyperactivated in breast cancer cells and is associated with poor prognosis. Studies from our laboratory reveal that Rac1 activity is necessary for G2/M checkpoint activation and cell survival in response to IR exposure of breast and pancreatic cancer cells. In this study, we investigated the effect of Rac1 on the survival of breast cancer cells treated with hyper-fractionated radiation (HFR), which is used clinically for cancer treatment. Results in this report indicate that Rac1 protein expression is increased in the breast cancer cells that survived HFR compared with parental cells. Furthermore, this increase of Rac1 is associated with enhanced activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-κB (NF-κB) signaling pathways and increased levels of anti-apoptotic protein Bcl-xL and Mcl-1, which are downstream targets of ERK1/2 and NF-κB signaling pathways. Using Rac1-specific inhibitor and dominant-negative mutant N17Rac1, here we demonstrate that Rac1 inhibition decreases the phosphorylation of ERK1/2 and inhibitory κBα (IκBα), as well as the levels of Bcl-xL and Mcl-1 protein in the HFR-selected breast cancer cells. Moreover, inhibition of Rac1 using either small molecule inhibitor or dominant-negative N17Rac1 abrogates clonogenic survival of HFR-selected breast cancer cells and decreases the level of intact poly(ADP-ribose) polymerase, which is indicative of apoptosis induction. Collectively, results in this report suggest that Rac1 signaling is essential for the survival of breast cancer cells subjected to HFR and implicate Rac1 in radioresistance of breast cancer cells. These studies also provide the basis to explore Rac1 as a therapeutic target for radioresistant breast cancer cells.

Dose volume histogram comparison between ADAC Pinnacle and Nomos Corvus systems for IMRT.

This paper compares dose volume histograms (DVHs) generated by the ADAC Pinnacle and the Nomos Corvus planning systems. Seven prostate cases and seven head and neck cases were selected for review. Plans computed on both systems possessed exactly the same anatomical contours and IMRT segments. The Pinnacle system used the collapsed cone convolution superposition, while Corvus employed a finite size pencil beam (FSPB) convolution. Prostate DVH results demonstrated similar DVH curves from both systems. For each structure, the ratio of Pinnacle dose value divided by Corvus value was calculated. The high dose structures (which might contain tumour) had ratios close to unity, while the low dose structures (the critical organs) had ratios farther away from unity. Almost all ratios were less than unity, indicating a systematic difference that Pinnacle calculated doses were lower than Corvus ones. Head and neck data provided similar findings. A possible cause for this discrepancy could be the beam modelling. The difference in DVH parameters that we discovered between the two systems was about the same order of magnitude as the measurement-computation difference. When low dose is critical, such difference may affect the clinical planning decision.

Commissioning and quality assurance for MLC-based IMRT.

The commissioning and quality assurance (QA) associated with the implementation of linear accelerator multileaf collimator (MLC)-based intensity-modulated radiation therapy (IMRT) at the University of Nebraska Medical Center are described. Our MLC-based IMRT is implemented using the PRIMUS linear accelerator interface through the IMPAC record and verification system to the CORVUS treatment planning system. The "step-and-shoot" technique is used for this MLC-based IMRT. Commissioning process requires the verification of predefined parameters available on the CORVUS and the collection of some machine data. The machine data required are output factor in air and output factor in phantom, and percent depth dose for a number of field sizes. In addition, inplane and crossplane dose profiles of 4 x 4 cm and 20 x 20 cm field sizes and diagonal dose profiles of a large field size have to be measured. Validation of connectivity and dose model includes the use of uniform intensity bar strips, triangular-shaped nonuniform intensity bar strip, and N-shaped target. QA procedure follows the recommendation of the AAPM Task Group No. 40 report. In addition, the leaf position accuracy and reproducibility of the MLC should be checked at regular intervals. The dose validation is implemented through the hybrid plan where the patient beam parameters are applied to a flat phantom. Independent dose calculation method is used to confirm the dose delivery plan and data input to the CORVUS.

Independent dose calculations for the corvus MLC IMRT.

Two independent dose calculation methods have been explored to validate MLC-based IMRT plans from the NOMOS CORVUS system. After the plan is generated on the CORVUS planning system, the beam parameters are imported into an independent workstation. The beam parameters consist of intensity maps at each gantry angle. In addition, CT scans of the patient are imported into the independent workstation to obtain the external contour of the patient. The coordinate system is defined relative to the alignment point chosen in the CORVUS plan. The 2 independent calculation methods are based on a pencil beam kernel convolution and a Clarkson-type differential scatter summation, respectively. The pencil beam data for a 1 x 1-cm beam, as formed by the multileaf collimator, were measured for the 6-MV photon beam from a Siemens PRIMUS linear accelerator using film dosimetry. In the pencil beam method, the dose at a point is calculated using the depth and off-axis distance from a given pencil beam, corrected for beam intensity. The scatter summation method used the conversion of measured depth dose data into scatter maximum ratios. In this method, the differential scatter from each pencil beam is corrected for the beam intensity. Isodose distributions were generated using the independent dose calculations and compared to the CORVUS plans. Although isodose distributions from both methods show good agreement with the CORVUS plan, our implementation of the differential scatter summation approach seems more favorable. The 2 independent dose calculation algorithms are described in this paper.

Leaf sequencing techniques for MLC-based IMRT.

The nonuniform fields required by intensity-modulation radiation therapy (IMRT) can be delivered using conventional multileaf collimators (MLC) as beam modulators. In MLC-based IMRT, the nonuniform field is initially converted into an intensity map represented as a matrix of beam intensities. The intensity map is then decomposed into a series of subfields or segments of uniform intensities. Although there are many ways of segmenting the beam intensity matrix, a resulting subfield is only deliverable if it satisfies the constraints imposed by the MLC. These constraints exist as a result of the design of the MLC. The simplest constraint of the MLC is that its pairs of leaves can only move in and out in one dimension. Additional constraints include collision of opposing leaves and the need to match the tongue-and-groove to reduce interleaf leakage. The practical aspect of MLC-based IMRT requires that an optimized algorithm decomposes the nonuniform field into the least number of segments and therefore reduces the delivery time. This paper examines the static use and the dynamic use of MLCs to perform MLC-based IMRT.

Independent dose calculations for the PEACOCK System.

An independent dose calculation method has been developed to validate intensity-modulated radiation therapy (IMRT) plans from the NOMOS PEACOCK System. After the plan is generated on the CORVUS planning system, the beam parameters are imported into an independent workstation. The beam parameters consist of intensity maps at each gantry angle and each arc position. In addition, CT scans of the patient are imported into the independent workstation to obtain the external contour of the patient. The coordinate system is defined relative to the alignment point chosen in the CORVUS plan. The independent calculation uses the pencil beam data viz tissue maximum ratio (TMR) and beam profiles for a single 1 x 0.8-cm beamlet formed by the NOMOS multileaf intensity-modulating collimator (MIMiC) leaf. The pencil beam data were measured for the 6-MV photon beam from Siemens PRIMUS linear accelerator using film dosimetry. The dose at a point is calculated using the depth and off-axis distance from a given pencil beam, corrected for its beam intensity. Isodose distributions are generated using the independent dose calculations and compared to the CORVUS plans. Isodose distributions show good agreement with the CORVUS plans for a number of clinical cases. The independent dose calculation algorithm is described in this paper.

Commissioning of Peacock System for intensity-modulated radiation therapy.

The Peacock System was introduced to perform tomographic intensity-modulated radiation therapy (IMRT). Commissioning of the Peacock System included the alignment of the multileaf intensity-modulating collimator (MIMiC) to the beam axis, the alignment of the RTA device for immobilization, and checking the integrity of the CRANE for indexing the treatment couch. In addition, the secondary jaw settings, couch step size, and transmission through the leaves were determined. The dosimetric data required for the CORVUS planning system were divided into linear accelerator-specific and MIMiC-specific. The linear accelerator-specific dosimetric data were relative output in air, relative output in phantom, percent depth dose for a range of field sizes, and diagonal dose profiles for a large field size. The MIMiC-specific dosimetric data were the in-plane and cross-plane dose profiles of a small and a large field size to derive the penumbra fit. For each treatment unit, the Beam Utility software requires the data be entered into the CORVUS planning system in modular forms. These modules were treatment unit information, angle definition, configuration, gantry and couch angles range, dosimetry, results, and verification plans. After the appropriate machine data were entered, CORVUS created a dose model. The dose model was used to create known simple dose distribution for evaluation using the verification tools of the CORVUS. The planned doses for phantoms were confirmed using an ion chamber for point dose measurement and film for relative dose measurement. The planning system calibration factor was initially set at 1.0 and will be changed after data on clinical cases are acquired. The treatment unit was released for clinical use after the approval icon was checked in the verification plans module.

Immobilization devices for intensity-modulated radiation therapy (IMRT).

Three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) plans show radiation dose distribution that is highly conformal to the target volume. The successful clinical implementation of these radiotherapy modalities requires precise positioning of the target to avoid a geographical miss. Effective reduction in target positional inaccuracies can be achieved with the proper use of immobilization devices. This paper reviews some of the immobilization devices that have been used and/or have the potential of being used for IMRT. The immobilization devices being reviewed include stereotactic frame, Talon system, thermoplastic molds, Alpha Cradles, and Vac-Lok system. The implementation of these devices at various anatomical sites is discussed.

Quality assurance procedures for the Peacock system.

The Peacock system is the product of technological innovations that are changing the practice of radiotherapy. It uses dynamic beam modulation technique and inverse planning algorithm, both of which are new methodologies, to perform intensity-modulation radiation therapy (IMRT). The quality assurance (QA) procedure established by Task Group No. 40 did not adequately consider these emerging modalities. A review of literature indicates that published articles on QA procedures concentrate primarily on the verification of dose delivered to phantom during commissioning of the system and dose delivered to phantom before treating patients. Absolute dose measurements using ion chambers and relative dose measurements using film dosimetry have been used to verify delivered doses. QA on equipment performance and equipment safety is limited. This paper will discuss QA on equipment performance, equipment safety, and patient setup reproducibility.

Dosimetric evaluation of abutted fields using asymmetric collimators for treatment of head and neck.

PURPOSE: The objective of this study was to reevaluate the dose nonuniformity of abutted fields defined using asymmetric collimators and one isocenter for treatment of the head and neck region. METHODS AND MATERIALS: Bilateral parallel-opposed fields abutted to the anterior field at one isocenter were implemented in the treatment of head and neck. The effect of digital display tolerance can produce dose nonuniformity at the junction of the abutted fields. The amount of dose nonuniformity was quantified using both mathematical summation of dose profiles and by direct measurement of doses at the junction of the two abutted fields. The dose nonuniformity was obtained by irradiating the superior part of a film using bilateral parallel-opposed fields and the inferior part by an anterior field with a gap or an overlap. Dose profiles were taken at the depth of maximum dose for the anterior field across the abutted fields. The dose nonuniformity was determined for the case where the asymmetric jaw was set at -2 mm, -1 mm, 0, +1 mm, and +2 mm from the beam central axis. RESULTS: The dose at the junction increases systematically as the abutment of the fields changes from a gap to an overlap. The dose nonuniformity with 1-mm gap and 1-mm overlap is about 15% underdose and overdose, respectively. CONCLUSION: Imperfect abutment of split fields due to digital display tolerance (+/-1 mm) of asymmetric collimator can cause an underdose or overdose of 15% of the delivered dose.

Periocular lymphoproliferative diseases: natural history, prognostic factors, and treatment.

A study was undertaken to assess the natural history of periocular lymphoproliferative diseases, identify key prognostic factors, and clarify the role of orbital irradiation. Thirty-four patients with periocular lymphoproliferative disease were treated with orbital irradiation between 1975 and 1990. Eight patients had atypical lymphoid infiltrate, and 26 had malignant lymphoma. Forty-three eyes were irradiated with en-face electrons or 6-MV photons. Five-year disease-free survival for all stages was 65%; it was not significantly affected by bilaterality or site. Stage, distinction between atypical lymphoid infiltrate and malignant lymphoma, and working formulation grade were important prognostic indicators. A complete response during irradiation was achieved in 24 of 43 (56%) eyes at a median dose of 2,400 cGy, and a partial response was achieved in 19 (44%), with resolution at a median of 2.8 months. Patients with periocular reactive lymphoid hyperplasia or atypical lymphoid infiltrate may have or are at significant risk of developing lymphoma and dissemination. Local treatment remains important; orbital irradiation achieves prompt local control with acceptable morbidity.