Non-ablative doses of focal ionizing radiation alters function of central neural circuits.

BACKGROUND: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. OBJECTIVE: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). METHODS: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. RESULTS: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. CONCLUSION: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.

Isotoxic dose prescription level strategies for stereotactic liver radiotherapy: the price of dose uniformity.

Introduction: To find the optimal dose prescription strategy for liver SBRT, this study investigated the tradeoffs between achievable target dose and healthy liver dose for a range of isotoxic uniform and non-uniform prescription level strategies.Material and methods: Nine patients received ten liver SBRT courses with intrafraction motion monitoring during treatment. After treatment, five VMAT treatment plans were made for each treatment course. The PTV margin was 5 mm (left-right, anterior-posterior) and 10 mm (cranio-caudal). All plans had a mean CTV dose of 56.25 Gy in three fractions, while the PTV was covered by 50%, 67%, 67 s% (steep dose gradient outside CTV), 80%, and 95% of this dose, respectively. The 50%, 67 s%, 80%, and 95% plans were then renormalized to be isotoxic with the standard 67% plan according to a Lyman-Kutcher-Burman normal tissue complication probability model for radiation induced liver disease. The CTV D98 and mean dose of the iso-toxic plans were calculated both without and with the observed intrafraction motion, using a validated method for motion-including dose reconstruction.Results: Under isotoxic conditions, the average [range] mean CTV dose per fraction decreased gradually from 21.2 [20.5-22.7] Gy to 15.5 [15.0-16.6] Gy and the D98 dose per fraction decreased from 20.4 [19.7-21.7] Gy to 15.0 [14.5-15.5] Gy, as the prescription level to the PTV rim was increased from 50% to 95%. With inclusion of target motion the mean CTV dose was 20.5 [16.5-22.5] Gy (50% PTV rim dose) and 15.4 [13.9-16.7] Gy (95% rim dose) while D98 was 17.8 [7.4-20.6] Gy (50% rim dose) and 14.6 [8.8-15.7] Gy (95% rim dose).Conclusion: Requirements of a uniform PTV dose come at the price of excess normal tissue dose. A non-uniform PTV dose allows increased CTV mean dose at the cost of robustness toward intrafraction motion. The increase in planned CTV dose by non-uniform prescription outbalanced the dose deterioration caused by motion.

Simulated multileaf collimator tracking for stereotactic liver radiotherapy guided by kilovoltage intrafraction monitoring: Dosimetric gain and target overdose trends.

PURPOSE: To investigate the potential benefit of multileaf collimator (MLC) tracking guided by kilovoltage intrafraction monitoring (KIM) during stereotactic body radiotherapy (SBRT) in the liver, and to understand trends of target overdose with MLC tracking. METHODS: Six liver SBRT patients with 2-3 implanted gold markers received SBRT delivered with volumetric modulated arc therapy (VMAT) in three fractions using daily cone-beam CT setup. The CTV-to-PTV margins were 5 mm in the axial plane and 10 mm in the cranio-caudal directions, and the plans were designed to give minimum target doses of 95% (CTV) and 67% (PTV). The three-dimensional marker trajectory estimated by post-treatment analysis of kV fluoroscopy images acquired throughout treatment delivery was assumed to represent the tumor motion. MLC tracking guided by real-time KIM was simulated. The reduction in CTV D95 (minimum dose to 95% of the clinical target volume) relative to the planned D95 (ΔD95) was compared between actual non-tracking and simulated MLC tracking treatments. RESULTS: MLC tracking maintained a high CTV dose coverage for all 18 fractions with ΔD95 (mean: 0.2 percentage points (pp), range: -1.7 to 1.9 pp) being significantly lower than for the actual non-tracking treatments (mean: 6.3 pp range: 0.6-16.0 pp) (p = 0.002). MLC tracking of large target motion perpendicular to the MLC leaves created dose artifacts with regions of overdose in the CTV. As a result, the mean dose in spherical volumes centered in the middle of the CTV was on average 2.4 pp (5 mm radius sphere) and 1.3 pp (15 mm radius sphere) higher than planned (p = 0.002). CONCLUSIONS: Intrafraction tumor motion can deteriorate the CTV dose of liver SBRT. The planned CTV dose coverage may be restored with KIM-guided MLC tracking. However, MLC tracking may have a tendency to create hotspots in the CTV.

Geometric and dosimetric comparison of four intrafraction motion adaptation strategies for stereotactic liver radiotherapy.

The accuracy of stereotactic body radiotherapy (SBRT) in the liver is limited by tumor motion. Selection of the most suitable motion mitigation strategy requires good understanding of the geometric and dosimetric consequences. This study compares the geometric and dosimetric accuracy of actually delivered respiratory gated SBRT treatments for 15 patients with liver tumors with three simulated alternative motion adaptation strategies. The simulated alternatives are MLC tracking, baseline shift adaptation by inter-field couch corrections and no intrafraction motion adaptation. The patients received electromagnetic transponder-guided respiratory gated IMRT or conformal treatments in three fractions with a 3-4 mm gating window around the full exhale position. The CTV-PTV margin was 5 mm axially and 7-10 mm cranio-caudally. The CTV and PTV were covered with 95% and 67% of the prescribed mean CTV dose, respectively. The time-resolved target position error during treatments with the four investigated motion adaptation strategies was used to calculate motion margins and the motion-induced reduction in CTV D 95 relative to the planned dose (ΔD 95). The mean (range) number of couch corrections per treatment session to compensate for tumor drift was 2.8 (0-7) with gating, 1.4 (0-5) with baseline shift adaptation, and zero for the other strategies. The motion margins were 3.5 mm (left-right), 9.4 mm (cranio-caudal) and 3.9 mm (anterior-posterior) without intrafraction motion adaptation, approximately half of that with baseline shift adaptation, and 1-2 mm with MLC tracking and gating. With 7 mm CC margins the mean (range) of ΔD 95 for the CTV was 8.1 (0.6-29.4)%-points (no intrafraction motion adaptation), 4.0 (0.4-13.3)%-points (baseline shift adaptation), 1.0 (0.3-2.2)%-points (MLC tracking) and 0.8 (0.1-1.8)%-points (gating). With 10 mm CC margins ΔD 95 was instead 4.8 (0.3-14.8)%-points (no intrafraction motion adaptation) and 2.9 (0.2-9.8)%-points (baseline shift adaptation). In conclusion, baseline shift adaptation can mitigate gross dose deficits without the requirement of real-time motion adaptation. MLC tracking and gating, however, more effectively ensure high similarity between planned and delivered doses.

Automatic online and real-time tumour motion monitoring during stereotactic liver treatments on a conventional linac by combined optical and sparse monoscopic imaging with kilovoltage x-rays (COSMIK).

The purpose of this study was to develop, validate and clinically demonstrate fully automatic tumour motion monitoring on a conventional linear accelerator by combined optical and sparse monoscopic imaging with kilovoltage x-rays (COSMIK). COSMIK combines auto-segmentation of implanted fiducial markers in cone-beam computed tomography (CBCT) projections and intra-treatment kV images with simultaneous streaming of an external motion signal. A pre-treatment CBCT is acquired with simultaneous recording of the motion of an external marker block on the abdomen. The 3-dimensional (3D) marker motion during the CBCT is estimated from the auto-segmented positions in the projections and used to optimize an external correlation model (ECM) of internal motion as a function of external motion. During treatment, the ECM estimates the internal motion from the external motion at 20 Hz. KV images are acquired every 3 s, auto-segmented, and used to update the ECM for baseline shifts between internal and external motion. The COSMIK method was validated using Calypso-recorded internal tumour motion with simultaneous camera-recorded external motion for 15 liver stereotactic body radiotherapy (SBRT) patients. The validation included phantom experiments and simulations hereof for 12 fractions and further simulations for 42 fractions. The simulations compared the accuracy of COSMIK with ECM-based monitoring without model updates and with model updates based on stereoscopic imaging as well as continuous kilovoltage intrafraction monitoring (KIM) at 10 Hz without an external signal. Clinical real-time tumour motion monitoring with COSMIK was performed offline for 14 liver SBRT patients (41 fractions) and online for one patient (two fractions). The mean 3D root-mean-square error for the four monitoring methods was 1.61 mm (COSMIK), 2.31 mm (ECM without updates), 1.49 mm (ECM with stereoscopic updates) and 0.75 mm (KIM). COSMIK is the first combined kV/optical real-time motion monitoring method used clinically online on a conventional accelerator. COSMIK gives less imaging dose than KIM and is in addition applicable when the kV imager cannot be deployed such as during non-coplanar fields.

A Prospective Cohort Study of Gated Stereotactic Liver Radiation Therapy Using Continuous Internal Electromagnetic Motion Monitoring.

PURPOSE: Intrafraction motion can compromise the treatment accuracy in liver stereotactic body radiation therapy (SBRT). Respiratory gating can improve treatment delivery; however, gating based on external motion surrogates is inaccurate. The present study reports the use of Calypso-based internal electromagnetic motion monitoring for gated liver SBRT. METHODS AND MATERIALS: Fifteen patients were included in a study of 3-fraction respiratory gated liver SBRT guided by 3 implanted electromagnetic transponders. The planning target volume was created by a 5-mm axial and 7-mm (n = 12) or 10-mm (n = 3) craniocaudal expansion of the clinical target volume (CTV) and covered with 67% of the prescribed CTV mean dose. Treatment was gated to the end-exhale phase of the respiratory cycle with beam-on when the target deviated <3 mm (left-right/anteroposterior) and 4 mm (craniocaudal) from the planned position, according to the monitored (25-Hz) transponder centroid position. The couch was adjusted remotely if baseline drifts >1 to 2 mm occurred. Log files of transponder motion were used to determine the geometric error and reconstruct the delivered CTV dose in the actual gated treatments and in simulated nongated treatments. RESULTS: No severe side effects were observed in relation to transponder implantation. All 45 treatment fractions were successfully guided using the Calypso system. The mean number of couch corrections during each gated fraction was 2.8 (range 0-7). The mean duty cycle during gated treatment was 62.5% (range 29.1%-84.9%). Without gating, the mean 3-dimensional geometric error during a fraction would have been 5.4 mm (range 2.7-12.1). Gating reduced this error to 2.0 mm (range 1.2-3.0). The patient mean reduction in minimum dose to 95% of the CTV relative to the planned dose was 6.0 percentage points (range 0.7-22.0) without gating and 0.8 percentage point (range 0.2-2.0) with gating. CONCLUSIONS: Gating using internal motion monitoring was successfully applied for liver SBRT. It markedly improved the geometric and dosimetric accuracy compared with nongated standard treatment.

Fiducial marker guided stereotactic liver radiotherapy: Is a time delay between marker implantation and planning CT needed?

To minimize the risk of marker migration in fiducial marker guided liver SBRT it is common to add a delay of a week between marker implantation and planning CT. This study found that such a delay is unnecessary and could be avoided to minimize the treatment preparation time.

Time-Resolved Intrafraction Target Translations and Rotations During Stereotactic Liver Radiation Therapy: Implications for Marker-based Localization Accuracy.

PURPOSE: Image guided liver stereotactic body radiation therapy (SBRT) often relies on implanted fiducial markers. The target localization accuracy decreases with increased marker-target distance. This may occur partly because of liver rotations. The aim of this study was to examine time-resolved translations and rotations of liver marker constellations and investigate if time-resolved intrafraction rotational corrections can improve localization accuracy in liver SBRT. METHODS AND MATERIALS: Twenty-nine patients with 3 implanted markers received SBRT in 3 to 6 fractions. The time-resolved trajectory of each marker was estimated from the projections of 1 to 3 daily cone beam computed tomography scans and used to calculate the translation and rotation of the marker constellation. In all cone beam computed tomography projections, the time-resolved position of each marker was predicted from the position of another surrogate marker by assuming that the marker underwent either (1) the same translation as the surrogate marker; or (2) the same translation as the surrogate marker corrected by the rotation of the marker constellation. The localization accuracy was quantified as the root-mean-square error (RMSE) between the estimated and the actual marker position. For comparison, the RMSE was also calculated when the marker's position was estimated as its mean position for all the projections. RESULTS: The mean translational and rotational range (2nd-98th percentile) was 2.0 mm/3.9° (right-left), 9.2 mm/2.9° (superior-inferior), 4.0 mm/4.0° (anterior-posterior), and 10.5 mm (3-dimensional). Rotational corrections decreased the mean 3-dimensional RMSE from 0.86 mm to 0.54 mm (P<.001) and halved the RMSE increase per millimeter increase in marker distance. CONCLUSIONS: Intrafraction rotations during liver SBRT reduce the accuracy of marker-guided target localization. Rotational correction can improve the localization accuracy with a factor of approximately 2 for large marker-target distances.

Moving metal artifact reduction in cone-beam CT scans with implanted cylindrical gold markers.

PURPOSE: Implanted gold markers for image-guided radiotherapy lead to streaking artifacts in cone-beam CT (CBCT) scans. Several methods for metal artifact reduction (MAR) have been published, but they all fail in scans with large motion. Here the authors propose and investigate a method for automatic moving metal artifact reduction (MMAR) in CBCT scans with cylindrical gold markers. METHODS: The MMAR CBCT reconstruction method has six steps. (1) Automatic segmentation of the cylindrical markers in the CBCT projections. (2) Removal of each marker in the projections by replacing the pixels within a masked area with interpolated values. (3) Reconstruction of a marker-free CBCT volume from the manipulated CBCT projections. (4) Reconstruction of a standard CBCT volume with metal artifacts from the original CBCT projections. (5) Estimation of the three-dimensional (3D) trajectory during CBCT acquisition for each marker based on the segmentation in Step 1, and identification of the smallest ellipsoidal volume that encompasses 95% of the visited 3D positions. (6) Generation of the final MMAR CBCT reconstruction from the marker-free CBCT volume of Step 3 by replacing the voxels in the 95% ellipsoid with the corresponding voxels of the standard CBCT volume of Step 4. The MMAR reconstruction was performed retrospectively using a half-fan CBCT scan for 29 consecutive stereotactic body radiation therapy patients with 2-3 gold markers implanted in the liver. The metal artifacts of the MMAR reconstructions were scored and compared with a standard MAR reconstruction by counting the streaks and by calculating the standard deviation of the Hounsfield units in a region around each marker. RESULTS: The markers were found with the same autosegmentation settings in 27 CBCT scans, while two scans needed slightly changed settings to find all markers automatically in Step 1 of the MMAR method. MMAR resulted in 15 scans with no streaking artifacts, 11 scans with 1-4 streaks, and 3 scans with severe streaking artifacts. The corresponding numbers for MAR were 8 (no streaks), 1 (1-4 streaks), and 20 (severe streaking artifacts). The MMAR method was superior to MAR in scans with more than 8 mm 3D marker motion and comparable to MAR for scans with less than 8 mm motion. In addition, the MMAR method was tested on a 4D CBCT reconstruction for which it worked equally well as for the 3D case. The markers in the 4D case had very low motion blur. CONCLUSIONS: An automatic method for MMAR in CBCT scans was proposed and shown to effectively remove almost all streaking artifacts in a large set of clinical CBCT scans with implanted gold markers in the liver. Residual streaking artifacts observed in three CBCT scans may be removed with better marker segmentation.

Kilovoltage intrafraction motion monitoring and target dose reconstruction for stereotactic volumetric modulated arc therapy of tumors in the liver.

PURPOSE: To use intrafraction kilovoltage (kV) imaging during liver stereotactic body radiotherapy (SBRT) delivered by volumetric modulated arc therapy (VMAT) to estimate the intra-treatment target motion and to reconstruct the delivered target dose. METHODS: Six liver SBRT patients with 2-3 implanted gold markers received SBRT in three fractions of 18.75 Gy or 25 Gy. CTV-to-PTV margins of 5 mm in the axial plane and 10 mm in the cranio-caudal directions were applied. A VMAT plan was designed to give minimum target doses of 95% (CTV) and 67% (PTV). At each fraction, the 3D marker trajectory was estimated by fluoroscopic kV imaging throughout treatment delivery and used to reconstruct the actually delivered CTV dose. The reduction in D95 (minimum dose to 95% of the CTV) relative to the planned D95 was calculated. RESULTS: The kV position estimation had mean root-mean-square errors of 0.36 mm and 0.47 mm parallel and perpendicular to the kV imager, respectively. Intrafraction motion caused a mean 3D target position error of 2.9 mm and a mean D95 reduction of 6.0%. The D95 reduction correlated with the mean 3D target position error during a fraction. CONCLUSIONS: Kilovoltage imaging for detailed motion monitoring with dose reconstruction of VMAT-based liver SBRT was demonstrated for the first time showing large dosimetric impact of intrafraction tumor motion.

Variations in magnitude and directionality of respiratory target motion throughout full treatment courses of stereotactic body radiotherapy for tumors in the liver.

PURPOSE: To investigate the stability of target motion amplitude and motion directionality throughout full stereotactic body radiotherapy (SBRT) treatments of tumors in the liver. MATERIAL AND METHODS: Ten patients with gold markers implanted in the liver received 11 courses of 3-fraction SBRT on a conventional linear accelerator. A four-dimensional computed tomography (4DCT) scan was obtained for treatment planning. The time-resolved marker motion was determined throughout full treatment field delivery using the kV and MV imagers of the accelerator. The motion amplitude and motion directionality of all individual respiratory cycles were determined using principal component analysis (PCA). The variations in motion amplitude and directionality within the treatment courses and the difference from the motion in the 4DCT scan were determined. RESULTS: The patient mean (± 1 standard deviation) peak-to-peak 3D motion amplitude of individual respiratory cycles during a treatment course was 7.9 ± 4.1 mm and its difference from the 4DCT scan was -0.8 ± 2.5 mm (max, 6.6 mm). The mean standard deviation of 3D respiratory cycle amplitude within a treatment course was 2.0 ± 1.6 mm. The motion directionality of individual respiratory cycles on average deviated 4.6 ± 1.6° from the treatment course mean directionality. The treatment course mean motion directionality on average deviated 7.6 ± 6.5° from the directionality in the 4DCT scan. A single patient-specific oblique direction in space explained 97.7 ± 1.7% and 88.3 ± 10.1% of all positional variance (motion) throughout the treatment courses, excluding and including baseline shifts between treatment fields, respectively. CONCLUSION: Due to variable breathing amplitudes a single 4DCT scan was not always representative of the mean motion amplitude during treatment. However, the motion was highly directional with a fairly stable direction throughout treatment, indicating a potential for more optimal individualized motion margins aligned to the preferred direction of motion.

Three-dimensional, time-resolved, intrafraction motion monitoring throughout stereotactic liver radiation therapy on a conventional linear accelerator.

PURPOSE: To investigate the time-resolved 3-dimensional (3D) internal motion throughout stereotactic body radiation therapy (SBRT) of tumors in the liver using standard x-ray imagers of a conventional linear accelerator. METHODS AND MATERIALS: Ten patients with implanted gold markers received 11 treatment courses of 3-fraction SBRT in a stereotactic body-frame on a conventional linear accelerator. Two pretreatment and 1 posttreatment cone-beam computed tomography (CBCT) scans were acquired during each fraction. The CBCT projection images were used to estimate the internal 3D marker motion during CBCT acquisition with 11-Hz resolution by a monoscopic probability-based method. Throughout the treatment delivery by conformal or volumetric modulated arc fields, simultaneous MV portal imaging (8 Hz) and orthogonal kV imaging (5 Hz) were applied to determine the 3D marker motion using either MV/kV triangulation or the monoscopic method when marker segmentation was unachievable in either MV or kV images. The accuracy of monoscopic motion estimation was quantified by also applying monoscopic estimation as a test for all treatments during which MV/kV triangulation was possible. RESULTS: Root-mean-square deviations between monoscopic estimations and triangulations were less than 1.0 mm. The mean 3D intrafraction and intrafield motion ranges during liver SBRT were 17.6 mm (range, 5.6-39.5 mm) and 11.3 mm (2.1-35.5mm), respectively. The risk of large intrafraction baseline shifts correlated with intrafield respiratory motion range. The mean 3D intrafractional marker displacement relative to the first CBCT was 3.4 mm (range, 0.7-14.5 mm). The 3D displacements exceeded 8.8 mm 10% of the time. CONCLUSIONS: Highly detailed time-resolved internal 3D motion was determined throughout liver SBRT using standard imaging equipment. Considerable intrafraction motion was observed. The demonstrated methods provide a widely available approach for motion monitoring that, combined with motion-adaptive treatment techniques, has the potential to improve the accuracy of radiation therapy for moving targets.

On-line use of three-dimensional marker trajectory estimation from cone-beam computed tomography projections for precise setup in radiotherapy for targets with respiratory motion.

PURPOSE: To develop and evaluate accurate and objective on-line patient setup based on a novel semiautomatic technique in which three-dimensional marker trajectories were estimated from two-dimensional cone-beam computed tomography (CBCT) projections. METHODS AND MATERIALS: Seven treatment courses of stereotactic body radiotherapy for liver tumors were delivered in 21 fractions in total to 6 patients by a linear accelerator. Each patient had two to three gold markers implanted close to the tumors. Before treatment, a CBCT scan with approximately 675 two-dimensional projections was acquired during a full gantry rotation. The marker positions were segmented in each projection. From this, the three-dimensional marker trajectories were estimated using a probability based method. The required couch shifts for patient setup were calculated from the mean marker positions along the trajectories. A motion phantom moving with known tumor trajectories was used to examine the accuracy of the method. Trajectory-based setup was retrospectively used off-line for the first five treatment courses (15 fractions) and on-line for the last two treatment courses (6 fractions). Automatic marker segmentation was compared with manual segmentation. The trajectory-based setup was compared with setup based on conventional CBCT guidance on the markers (first 15 fractions). RESULTS: Phantom measurements showed that trajectory-based estimation of the mean marker position was accurate within 0.3 mm. The on-line trajectory-based patient setup was performed within approximately 5 minutes. The automatic marker segmentation agreed with manual segmentation within 0.36 ± 0.50 pixels (mean ± SD; pixel size, 0.26 mm in isocenter). The accuracy of conventional volumetric CBCT guidance was compromised by motion smearing (≤21 mm) that induced an absolute three-dimensional setup error of 1.6 ± 0.9 mm (maximum, 3.2) relative to trajectory-based setup. CONCLUSIONS: The first on-line clinical use of trajectory estimation from CBCT projections for precise setup in stereotactic body radiotherapy was demonstrated. Uncertainty in the conventional CBCT-based setup procedure was eliminated with the new method.

Inter- and intrafractional localisation errors in cone-beam CT guided stereotactic radiation therapy of tumours in the liver and lung.

BACKGROUND: Localisation errors in cone-beam CT (CBCT) guided stereotactic body radiation therapy (SBRT) were evaluated and compared to positioning using the external coordinates of a stereotactic body frame (SBF) alone. Possible correlations to patient- or treatment-specific factors such as body mass index (BMI), planning time, treatment delivery time, and distance between tumour and spinal cord were explored to determine whether they influenced on the benefit of image-guidance. MATERIAL AND METHODS: A total of 34 patients received SBRT (3 fractions) for tumours in the liver (15 patients) or the lung (19 patients). Immobilisation and positioning was obtained with a SBF. Pre- and post-treatment CBCT scans were registered with the bony anatomy of the planning CT to find inter- and intrafractional patient positioning errors (PPE). For lung tumour patients, matching was also performed on the tumours to find the tumour positioning errors (TPE) and baseline shifts relative to bony anatomy. RESULTS: The mean inter- and intrafractional 3D vector PPE was 4.5 ± 2.7 mm (average ± SD) and 1.5 ± 0.6 mm, respectively, for the combined group of patients. For lung tumours, the interfractional misalignment was 5.6 ± 1.8 mm. The baseline shift was 3.9 ± 2.0 mm. Intrafractional TPE and baseline shifts were 2.1 ± 0.7 mm and 1.9 ± 0.6 mm, respectively. The magnitude of interfractional baseline shift was closely correlated with the distance between the tumour and the spinal cord. Intrafractional errors were independent of patient BMI, age or gender. CONCLUSION: Image-guidance reduced setup errors considerably. The study demonstrated the benefit of CBCT-guidance regardless of patient specific factors such as BMI, age or gender. Protection of the spinal cord was facilitated by the correlation between the tumour position relative to the spinal cord and the magnitude of baseline shift.

On the mechanism of electron-capture-induced dissociation of peptide dications from 15n-labeling and crown-ether complexation.

15N-labeling of di- and tripeptides reveals that electron capture to doubly protonated peptides results almost exclusively in ammonia loss from the N-terminal end, which clearly shows that a significant fraction of electron capture occurs at this end. In accordance with this finding, the competing channel of N-Calpha bond breakage leads to z+* ions and neutral c fragments after electron capture to small dications. In larger peptides that live long enough for internal proton exchanges to occur, c+ ions are also formed and in some cases in dominant yield. Attachment of one or two crown ethers to ammonium groups is likely to reduce the probability of proton transfer, which enhances the formation of z+* relative to c+. The total yield of z+* and c+ is, however, more or less unchanged, which indicates that proton transfer or hydrogen transfer from a NH3 group to the amide group is not required for the N-Calpha bond breakage.

On the survival of peptide cations after electron capture: role of internal hydrogen bonding and microsolvation.

Electron capture by both bare and microsolvated small peptide dications was investigated by colliding these ions with sodium vapor in an accelerator mass spectrometer to provide insight into processes that occur on the microsecond time frame. Survival of the intact peptide monocation after electron capture depends strongly on molecular size. For dipeptides, no intact reduced species were observed; the predominant ions correspond to loss of hydrogen and ammonia. In contrast, the intact reduced species was observed for larger peptides. Calculated structures indicate that the diprotonated dipeptide ions form largely extended structures with low probability of internal ionic hydrogen bonding (i.e., charge solvation) whereas internal ionic H-bonding occurs extensively for larger peptide dications. Solvation of the peptide ions with between one to seven methanol molecules reduces the total extent of H loss even for dipeptides where intact reduced species can survive more than a microsecond after electron capture. The yield of ions corresponding to cleavage of NCalpha bonds (c+ and z+* ions) does not depend strongly on peptide size but decreases with the extent of microsolvation for the dipeptide dications. H-bonding appears to play an important role for the survival of the intact reduced ions but less so for the formation of c+ and z+* ions. Our results indicate that electron capture predominantly occurs at the ammonium groups (at least 70 to 80%), and provides important new insights into the electron capture dissociation process.