Accuracy of abdominal organ motion estimation in radiotherapy using the right hemidiaphragm top as a surrogate during prolonged breath-holds quantified with MRI.

BACKGROUND: Respiratory motion presents a challenge in radiotherapy of thoracic and upper abdominal tumors. Techniques to account for respiratory motion include tracking. Using magnetic resonance imaging (MRI) guided radiotherapy systems, tumors can be tracked continuously. Using conventional linear accelerators, tracking of lung tumors is possible by determining tumor motion on kilo voltage (kV) imaging. But tracking of abdominal tumors with kV imaging is hampered by limited contrast. Therefore, surrogates for the tumor are used. One of the possible surrogates is the diaphragm. However, there is no universal method for establishing the error when using a surrogate and there are particular challenges in establishing such errors during free breathing (FB). Prolonged breath-holding might address these challenges. PURPOSE: The aim of this study was to quantify the error when using the right hemidiaphragm top (RHT) as surrogate for abdominal organ motion during prolonged breath-holds (PBH) for possible application in radiation treatments. METHODS: Fifteen healthy volunteers were trained to perform PBHs in two subsequent MRI sessions (PBH-MRI1 and PBH-MRI2). From each MRI acquisition, we selected seven images (dynamics) to determine organ displacement during PBH by using deformable image registration (DIR). On the first dynamic, the RHT, right and left hemidiaphragm, liver, spleen and right and left kidney were segmented. We used the deformation vector fields (DVF), generated by DIR, to determine the displacement of each organ between two dynamics in inferior-superior (IS), anterior-posterior (AP), left-right (LR) direction and we calculated the 3D vector magnitude (|d|). The displacements of the RHT, both hemidiaphragms and the abdominal organs were compared using a linear fit to determine the correlation (R2 of the fit) and the displacement ratio (DR, slope of the fit) between displacements of the RHT and each organ. We quantified the median difference between the DRs of PBH-MRI1 and PBH-MRI2 for each organ. Additionally, we estimated organ displacement in the second PBH by applying the DR from the first PBH to the displacement of the RHT measured during the second PBH. We compared the estimated organ displacement to the measured organ displacement during the second PBH. The difference between the two values was defined as the estimation error of using the RHT as a surrogate and assuming a constant DR over MRI sessions. RESULTS: The linear relationships were confirmed by the high R2 values of the linear fit between the displacements of the RHT and the abdominal organs (R2 > 0.96) in the IS and AP direction and |d|, and high to moderate correlations in the LR direction (0.93 > R2 > 0.64). The median DR difference between PBH-MRI1 and PBH-MRI2 varied between 0.13 and 0.31 for all organs. The median estimation error of the RHT as a surrogate varied between 0.4 and 0.8 mm/min for all organs. CONCLUSION: The RHT could serve as an accurate surrogate for abdominal organ motion during radiation treatments, for example, in tracking, provided the error of the RHT as motion surrogate is taken into account in the margins. TRIAL REGISTRATION: The study was registered in the Netherlands Trial Register (NL7603).

Effects of deep inspiration breath hold on prone photon or proton irradiation of breast and regional lymph nodes.

We report on a comparative dosimetrical study between deep inspiration breath hold (DIBH) and shallow breathing (SB) in prone crawl position for photon and proton radiotherapy of whole breast (WB) and locoregional lymph node regions, including the internal mammary chain (LN_MI). We investigate the dosimetrical effects of DIBH in prone crawl position on organs-at-risk for both photon and proton plans. For each modality, we further estimate the effects of lung and heart doses on the mortality risks of different risk profiles of patients. Thirty-one patients with invasive carcinoma of the left breast and pathologically confirmed positive lymph node status were included in this study. DIBH significantly decreased dose to heart for photon and proton radiotherapy. DIBH also decreased lung doses for photons, while increased lung doses were observed using protons because the retracting heart is displaced by low-density lung tissue. For other organs-at-risk, DIBH resulted in significant dose reductions using photons while minor differences in dose deposition between DIBH and SB were observed using protons. In patients with high risks for cardiac and lung cancer mortality, average thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 3.12% (photon DIBH), 4.03% (photon SB), 1.80% (proton DIBH) and 1.66% (proton SB). The radiation-related mortality risk could not outweigh the ~ 8% disease-specific survival benefit of WB + LN_MI radiotherapy in any of the assessed treatments.

Hypocapnia Alone Fails to Provoke Important Electrocardiogram Changes in Coronary Artery Diseased Patients.

BACKGROUND: There is still an urgent clinical need to develop non-invasive diagnostic tests for early ischemic heart disease because, once angina occurs, it is too late. Hypocapnia has long been known to cause coronary artery vasoconstriction. Some new cardiology tests are accompanied by the claim that they must have potential diagnostic value if hypocapnia enhances their cardiac effects in healthy subjects. But no previous study has tested whether hypocapnia produces bigger cardiac effects in patients with angina than in healthy subjects. METHODS: Severe hypocapnia (a PetCO2 level of 20 mmHg) lasting >15 min was mechanically induced by facemask, while conscious and unmedicated, in 18 healthy subjects and in 10 patients with angina and angiographically confirmed coronary artery disease, awaiting by-pass surgery. Each participant was their own control in normocapnia (where CO2 was added to the inspirate) and the order of normocapnia and hypocapnia was randomized. Twelve lead electrocardiograms (ECG) were recorded and automated measurements were made on all ECG waveforms averaged over >120 beats. 2D echocardiography was also performed on healthy subjects. RESULTS: In the 18 healthy subjects, we confirm that severe hypocapnia (a mean PetCO2 of 20 ± 0 mmHg, P < 0.0001) consistently increased the mean T wave amplitude in leads V1-V3, but by only 31% (P < 0.01), 15% (P < 0.001) and 11% (P < 0.05), respectively. Hypocapnia produced no other significant effects (p > 0.05) on their electro- or echocardiogram. All 10 angina patients tolerated the mechanical hyperventilation well, with minimal discomfort. Hypocpania caused a similar increase in V1 (by 39%, P < 0.05 vs. baseline, but P > 0.05 vs. healthy controls) and did not induce angina. Its effects were no greater in patients who did not take ß-blockers, or did not take organic nitrates, or had the worst Canadian Cardiovascular Society scores. CONCLUSION: Non-invasive mechanical hyperventilation while awake and unmedicated is safe and acceptable, even to patients with angina. Using it to produce severe and prolonged hypocapnia alone does produce significant ECG changes in angina patients. But its potential diagnostic value for identifying patients with coronary stenosis requires further evaluation.

Mitigating Respiratory Motion in Radiation Therapy: Rapid, Shallow, Non-invasive Mechanical Ventilation for Internal Thoracic Targets.

PURPOSE: Reducing respiratory motion during the delivery of radiation therapy reduces the volume of healthy tissues irradiated and may decrease radiation-induced toxicity. The purpose of this study was to assess the potential for rapid shallow non-invasive mechanical ventilation to reduce internal anatomy motion for radiation therapy purposes. METHODS AND MATERIALS: Ten healthy volunteers (mean age, 38 years; range, 22-54 years; 6 female and 4 male) were scanned using magnetic resonance imaging during normal breathing and at 2 ventilator-induced frequencies: 20 and 25 breaths per minute for 3 minutes. Sagittal and coronal cinematic data sets, centered over the right diaphragm, were used to measure internal motions across the lung-diaphragm interface. Repeated scans assessed reproducibility. Physiologic parameters and participant experiences were recorded to quantify tolerability and comfort. RESULTS: Physiologic observations and experience questionnaires demonstrated that rapid shallow non-invasive ventilation technique was tolerable and comfortable. Motion analysis of the lung-diaphragm interface demonstrated respiratory amplitudes and variations reduced in all subjects using rapid shallow non-invasive ventilation compared with spontaneous breathing: mean amplitude reductions of 56% and 62% for 20 and 25 breaths per minute, respectively. The largest mean amplitude reductions were found in the posterior of the right lung; 40.0 mm during normal breathing to 15.5 mm (P < .005) and 15.2 mm (P < .005) when ventilated with 20 and 25 breaths per minute, respectively. Motion variations also reduced with ventilation; standard deviations in the posterior lung reduced from 14.8 mm during normal respiration to 4.6 mm and 3.5 mm at 20 and 25 breaths per minute, respectively. CONCLUSIONS: To our knowledge, this study is the first to measure internal anatomic motion using rapid shallow mechanical ventilation to regularize and minimize respiratory motion over a period long enough to image and to deliver radiation therapy. Rapid frequency and shallow, non-invasive ventilation both generate large reductions in internal thoracic and abdominal motions, the clinical application of which could be profound-enabling dose escalation (increasing treatment efficacy) or high-dose ablative radiation therapy.

Abdominal organ motion during inhalation and exhalation breath-holds: pancreatic motion at different lung volumes compared.

PURPOSE: Contrary to what is commonly assumed, organs continue to move during breath-holding. We investigated the influence of lung volume on motion magnitude during breath-holding and changes in velocity over the duration of breath-holding. MATERIALS AND METHODS: Sixteen healthy subjects performed 60-second inhalation breath-holds in room-air, with lung volumes of ∼100% and ∼70% of the inspiratory capacity, and exhalation breath-holds, with lung volumes of ∼30% and ∼0% of the inspiratory capacity. During breath-holding, we obtained dynamic single-slice magnetic-resonance images with a time-resolution of 0.6s. We used 2-dimensional image correlation to obtain the diaphragmatic and pancreatic velocity and displacement during breath-holding. RESULTS: Organ velocity was largest in the inferior-superior direction and was greatest during the first 10s of breath-holding, with diaphragm velocities of 0.41mm/s, 0.29mm/s, 0.16mm/s and 0.15mm/s during BH100%, BH70%, BH30% and BH0%, respectively. Organ motion magnitudes were larger during inhalation breath-holds (diaphragm moved 9.8 and 9.0mm during BH100% and BH70%, respectively) than during exhalation breath-holds (5.6 and 4.3mm during BH30% and BH0%, respectively). CONCLUSION: Using exhalation breath-holds rather than inhalation breath-holds and delaying irradiation until after the first 10s of breath-holding may be advantageous for irradiation of abdominal tumors.

Safely prolonging single breath-holds to >5 min in patients with cancer; feasibility and applications for radiotherapy.

OBJECTIVE: Multiple, short and deep inspiratory breath-holds with air of approximately 20 s are now used in radiotherapy to reduce the influence of ventilatory motion and damage to healthy tissue. There may be further clinical advantages in delivering each treatment session in only one single, prolonged breath-hold. We have previously developed techniques enabling healthy subjects to breath-hold for 7 min. Here, we demonstrate their successful application in patients with cancer. METHODS: 15 patients aged 37-74 years undergoing radiotherapy for breast cancer were trained to breath-hold safely with pre-oxygenation and mechanically induced hypocapnia under simulated radiotherapy treatment conditions. RESULTS: The mean breath-hold duration was 5.3 ± 0.2 min. At breakpoint, all patients were normocapnic and normoxic [mean end-tidal partial pressure of carbon dioxide was 36 ± 1 standard error millimetre of mercury, (mmHg) and mean oxygen saturation was 100 ± 0 standard error %]. None were distressed, nor had gasping, dizziness or disturbed breathing in the post-breath-hold period. Mean blood pressure had risen significantly from 125 ± 3 to 166 ± 4 mmHg at breakpoint (without heart rate falling), but normalized within approximately 20 s of the breakpoint. During breath-holding, the mean linear anteroposterior displacement slope of the L breast marker was <2 mm min(-1). CONCLUSION: Patients with cancer can be trained to breath-hold safely and under simulated radiotherapy treatment conditions for longer than the typical beam-on time of a single fraction. We discuss the important applications of this technique for radiotherapy. ADVANCES IN KNOWLEDGE: We demonstrate for the first time a technique enabling patients with cancer to deliver safely a single prolonged breath-hold of >5 min (10 times longer than currently used in radiotherapy practice), under simulated radiotherapy treatment conditions.

Reducing the within-patient variability of breathing for radiotherapy delivery in conscious, unsedated cancer patients using a mechanical ventilator.

OBJECTIVE: Variability in the breathing pattern of patients with cancer during radiotherapy requires mitigation, including enlargement of the planned treatment field, treatment gating and breathing guidance interventions. Here, we provide the first demonstration of how easy it is to mechanically ventilate patients with breast cancer while fully conscious and without sedation, and we quantify the resulting reduction in the variability of breathing. METHODS: 15 patients were trained for mechanical ventilation. Breathing was measured and the left breast anteroposterior displacement was measured using an Osiris surface-image mapping system (Qados Ltd, Sandhurst, UK). RESULTS: Mechanical ventilation significantly reduced the within-breath variability of breathing frequency by 85% (p < 0.0001) and that of inflation volume by 29% (p < 0.006) when compared with their spontaneous breathing pattern. During mechanical ventilation, the mean amplitude of the left breast marker displacement was 5 ± 1 mm, the mean variability in its peak inflation position was 0.5 ± 0.1 mm and that in its trough inflation position was 0.4 ± 0.0 mm. Their mean drifts were not significantly different from 0 mm min(-1) (peak drift was -0.1 ± 0.2 mm min(-1) and trough drift was -0.3 ± 0.2 mm min(-1)). Patients had a normal resting mean systolic blood pressure (131 ± 5 mmHg) and mean heart rate [75 ± 2 beats per minute (bpm)] before mechanical ventilation. During mechanical ventilation, the mean blood pressure did not change significantly, mean heart rate fell by 2 bpm (p < 0.05) with pre-oxygenation and rose by only 4 bpm (p < 0.05) during pre-oxygenation with hypocapnia. No patients reported discomfort and all 15 patients were always willing to return to the laboratory on multiple occasions to continue the study. CONCLUSION: This simple technique for regularizing breathing may have important applications in radiotherapy. ADVANCES IN KNOWLEDGE: Variations in the breathing pattern introduce major problems in imaging and radiotherapy planning and delivery and are currently addressed to only a limited extent by asking patients to breathe to auditory or visual guidelines. We provide the first demonstration that a completely different technique, of using a mechanical ventilator to take over the patients' breathing for them, is easy for patients who are conscious and unsedated and reduces the within-patient variability of breathing. This technique has potential advantages in radiotherapy over currently used breathing guidance interventions because it does not require any active participation from or feedback to the patient and is therefore worthy of further clinical evaluation.

Does modifying electrode placement of the 12 lead ECG matter in healthy subjects?

BACKGROUND: Limb electrodes for the 12 lead ECG are routinely placed on the torso during exercise stress testing or when limbs are clinically inaccessible. It is unclear whether such electrode modification produces ECG changes in healthy male or female subjects that are clinically important according to the 2009 AHA, ACCF, HRS guidelines. We therefore measured whether ECG modification produced clinically important or false positive ECG changes e.g., appearance of Q waves in leads V(1-3), ST changes greater than 0.1 mV, T wave changes greater than 0.5 mV (frontal plane) or 1 mV (transverse plane), QRS axis shifts or alterations to QTc/P-R/QRS intervals. METHODS: The 12 lead ECG was measured in 18 healthy and semi-recumbent subjects using the standard and Takuma modified limb placements. RESULTS: In the frontal plane we demonstrate that the modification of limb electrode placement produces small Q, R and T wave amplitude and QRS axis changes that are statistically but not clinically significant. In the transverse plane it produces no statistically or clinically significant changes in the ECG or in ST segment morphology, P-R, QRS or QTc intervals. CONCLUSIONS: We provide better and more robust evidence that routine modification of limb electrode placement produces only minor changes to the ECG waveform in healthy subjects. These are not clinically significant according to the 2009 guidelines and thus have no effect on the clinical specificity of the 12 lead ECG.