Functional Lung Imaging Research Articles

SU‐FF‐J‐34: Can Functional Imaging Be Used to Individualize Adaptive Radiation Therapy for Non‐Small Cell Lung Cancer?

Background/purpose: To determine the changes in tumor and lung function during the course of radiation and their potentials in adaptive radiation therapy for non‐small cell lung cancer (NSCLC). Materials/Methods: FDG‐PET‐CT and Ventilation/perfusion (V/Q) SPECT were acquired prior to and after the delivery of 45 Gy during the course of radiation in 15 patients with NSCLC. Tumor activity was measured by relative standard uptake value (RSUV). V/Q SPECT was evaluated blindly by radiobiologist, through comparing to healthy normal controls. Results: After 45 Gy radiation, the mean RSUV decreased from 4.6±1.9 to 2.1±1.0 for primary tumors (p<0.0001) and from 3.2+1.3 to 1.7+0.5 for nodal diseases (p=0.0008). Mean reduction in PET tumor volume was 78% (67–100%). There was 28% (4/15) and 0% (0/15) complete responders on PET and CT, respectively. Three patients achieved a complete CT response at 3 month follow‐up, all of them were PET complete responders at 45 Gy. Boosting after 45 Gy, normal tissue complication probability (NTCP) could be reduced by 50%, V20 by 28%, and mean lung dose by 29% while keeping the total dose constant. Keeping the NTCP constant, dose could be escalated by 50%. Lung functional mapping also changed remarkably at 45 Gy during radiation. Fifteen of 15 patients had V/Q defects at or adjacent to tumor on the baseline SPECT, while 14/15 patients had at least one defect located remotely from tumor. For those defects located adjacent to tumor, 79% improved remarkably, while only 7.9% of the others had notable change (p<0.001). Lung NTCP adjusted by V/Q SPECT obtained during radiation was significantly different from those generated from the pretreatment V/Q SPECT and simulating CT. Conclusions: Tumor and lung functional imaging during the course of radiation may provide useful information for adaptive radiation therapy in patients with NSCLC.

The incorporation of SPECT functional lung imaging into inverse radiotherapy planning for non-small cell lung cancer

Background and purpose Patients with non-small cell lung cancer (NSCLC) often have inhomogeneous lung perfusion. Radiotherapy planning computed tomography (CT) scans have been accurately co-registered with lung perfusion single photon emission computed tomography (SPECT) scans to design radiotherapy treatments which limit dose to healthy ‘perfused’ lung. Patients and methods Patients with localised NSCLC had CT and SPECT scans accurately co-registered in the planning system. The SPECT images were used to define a volume of perfused ‘functioning’ lung (FL). Inverse planning software was used to create 3D-conformal plans, the planning objective being either to minimise the dose to whole lungs (WL) or to minimise the dose to FL. Results Four plans were created for each of six patients. The mean difference in volume between WL and FL was 1011.7 cm 3 (range 596.2–1581.1 cm 3). One patient with bilateral upper lobe perfusion deficits had a 16% reduction in FLV 20 (the percentage volume of functioning lung receiving ≥20 Gy). The remaining patients had inhomogeneous perfusion deficits such that inverse planning was not able to sufficiently optimise beam angles to avoid functioning lung. Conclusion SPECT perfusion images can be accurately co-registered with radiotherapy planning CT scans and may be helpful in creating treatment plans for patients with large perfusion deficits.

Functional Magnetic Resonance Imaging of the Lung

Functional lung imaging has the potential to offer many new insights into mechanisms of pulmonary disease. While the physiologist has access to a number of techniques to evaluate lung function, such as multiple inert gas elimination technique or the injection of microspheres, these techniques have significant disadvantages, including lack of spatial information or low spatial resolution and, in the case of microspheres, an inability to make measurements in humans. The functional imaging techniques based on magnetic resonance (MR), computed tomography (CT), or positron emission tomography (PET) hold substantial promise. In this article, specific issues related to the MR evaluation of pulmonary blood flow, including quantification of heterogeneity, reliability, and validity of the technique, are discussed to highlight some of the important physiologic issues that affect functional imaging. Additional physiologic considerations include the anatomic partitioning of blood flow, and the effects of posture, breath holding, and exercise. The relationships between these many factors and the collection of regional pulmonary perfusion data are explored.

Dynamic NMR spectroscopy of hyperpolarized (129)Xe in human brain analyzed by an uptake model.

Hyperpolarized (129)Xe (HpXe) NMR not only holds promise for functional lung imaging, but for measurements of tissue perfusion as well. To investigate human brain perfusion, several time-series of (129)Xe MR spectra were recorded from one healthy volunteer after HpXe inhalation. The time-dependent amplitudes of the MR spectra were analyzed by using a compartment model for xenon uptake modified to account for the loss of (129)Xe polarization due to RF-excitation and for the breathhold technique used in the experiments. This analysis suggests that the resonances detected at 196.5 +/- 1 ppm and 193 +/- 1 ppm originate from HpXe dissolved in gray and white matter, respectively, and that T(1) relaxation times of HpXe are different in gray and white matter (T(1g) > T(1w)).

Quantitative functional lung imaging with synchrotron radiation using inhaled xenon as contrast agent

Small airways play a key role in the distribution of ventilation and in the matching of ventilation to perfusion. The purpose of this study was to introduce an imaging method that allows measurement of regional lung ventilation and evaluation of the function of airways with a small diameter.The experiments were performed at the Medical Beamline of the European Synchrotron Radiation Facility. Monochromatic synchrotron radiation beams were used to obtain quantitative respiration-gated images of lungs and airways in two anaesthetized and mechanically ventilated rabbits using inhaled stable xenon (Xe) gas as a contrast agent. Two simultaneous images were acquired at two different energies, above and below the K-edge of Xe. Logarithmic subtraction of the two images yields absolute Xe concentrations. This technique is known as K-edge subtraction (KES) radiography. Two-dimensional planar and CT images were obtained showing spatial distribution of Xe concentrations within the airspaces, as well as the dynamics of filling with Xe.Bronchi down to 1 mm in diameter were visible both in the subtraction radiographs and in tomographic images. Absolute concentrations of Xe gas were calculated within the tube carrying the inhaled gas mixture, small and large bronchi, and lung tissue. Local time constants of ventilation with Xe were obtained by following the evolution of gas concentration in sequential computed tomography images.The results of this first animal study indicate that KES imaging of lungs with Xe gas as a contrast agent has great potential in studies of the distribution of ventilation within the lungs and of airway function, including airways with a small diameter.

Hyperpolarised gases in magnetic resonance: a new tool for functional imaging of the lung.

In magnetic resonance imaging (MRI), nuclear spins are the source of the image signal. In the lung, low-proton spin density in alveolar gas and abundant gas-tissue interfaces substantially impair conventional native 1H-MRI. Spin polarisation can be increased in two non-radioactive noble gas isotopes, 3He and 129Xe, by exposure to polarised laser light. When inhaled, such "magnetized" gases provide high-intensity MR images of the pulmonary airspaces. Thus, hyperpolarised gas (HPG) MRI opens up new routes to a) morphologic imaging of airways and alveolar spaces, and b) analysis of the intrapulmonary distribution of inhaled aliquots of these tracer gases; c) diffusion-sensitive MRI-techniques allow mapping of the "apparent diffusion coefficient" (ADC) of 3He within lung airspaces, where ADC is physically related to local bronchoalveolar dimensions; d) also, 3He magnetisation decays in an oxygen-containing atmosphere at a rate proportional to ambient PO2. This property allows image-based determination of regional broncho-alveolar PO2 and its decrease during a breathhold. Currently, these modalities of functional lung imaging are being assessed by several European and American research groups in animal models, human volunteers and patients. First results show good imaging quality with excellent spatial and unprecedented temporal resolution, and attest to the reproducibility, feasibility and safety of the technique. Regionally impaired ventilation of both structural and functional origin is detected with high sensitivity, e.g. in smokers, asthmatics, patients with COPD or after lung transplantation. Studies into regional ADC and PO2 measurement demonstrate good agreement with reference methods and physiological predictions. The present limitations of HPG-MRI include the HPG production rate and the US and EU health authorities' still pending final approval for clinical use.

Hyperpolarised gases in magnetic resonance: a new tool for functional imaging of the lung.

In magnetic resonance imaging (MRI), nuclear spins are the source of the image signal. In the lung, low-proton spin density in alveolar gas and abundant gas-tissue interfaces substantially impair conventional native 1H-MRI. Spin polarisation can be increased in two non-radioactive noble gas isotopes, 3He and 129Xe, by exposure to polarised laser light. When inhaled, such "magnetized" gases provide high-intensity MR images of the pulmonary airspaces. Thus, hyperpolarised gas (HPG) MRI opens up new routes to a) morphologic imaging of airways and alveolar spaces, and b) analysis of the intrapulmonary distribution of inhaled aliquots of these tracer gases; c) diffusion-sensitive MRI-techniques allow mapping of the "apparent diffusion coefficient" (ADC) of 3He within lung airspaces, where ADC is physically related to local bronchoalveolar dimensions; d) also, 3He magnetisation decays in an oxygen-containing atmosphere at a rate proportional to ambient PO2. This property allows image-based determination of regional broncho-alveolar PO2 and its decrease during a breathhold. Currently, these modalities of functional lung imaging are being assessed by several European and American research groups in animal models, human volunteers and patients. First results show good imaging quality with excellent spatial and unprecedented temporal resolution, and attest to the reproducibility, feasibility and safety of the technique. Regionally impaired ventilation of both structural and functional origin is detected with high sensitivity, e.g. in smokers, asthmatics, patients with COPD or after lung transplantation. Studies into regional ADC and PO2 measurement demonstrate good agreement with reference methods and physiological predictions. The present limitations of HPG-MRI include the HPG production rate and the US and EU health authorities' still pending final approval for clinical use.

Regional wall motion and abnormalities of electrical depolarization and repolarization in patients after surgical repair of tetralogy of Fallot

Advanced imaging techniques allow functional information to be derived and integrated into treatment planning.A systematic review was conducted with the primary objective to evaluate the ability of functional lung imaging to predict risk of radiation pneumonitis. Secondary objectives were to evaluate dose–response relationships on post treatment functional imaging and assess the utility in including functional lung information into treatment planning. A structured search for publications was performed following PRISMA guidelines and registered on PROSPERO.814 articles were screened against review criteria and 114 publications met criteria. Methods of identifying functional lung included using CT, MRI, SPECT and PET to image ventilation or perfusion. Six studies compared differences between functional and anatomical lung imaging at predicting radiation pneumonitis. These found higher predictive values using functional lung imaging. Twenty-one studies identified a dose–response relationship on post-treatment functional lung imaging. Nineteen planning studies demonstrated the ability of functional lung optimised planning techniques to spare regions of functional lung. Meta-analysis of these studies found that mean (95% CI) functional volume receiving 20 Gy was reduced by 4.2% [95% CI: 2.3: 6.0] and mean lung dose by 2.2 Gy [95% CI: 1.2: 3.3] when plans were optimised to spare functional lung. There was significant variation between publications in the definition of functional lung.Functional lung imaging may have potential utility in radiation therapy planning and delivery, although significant heterogeneity was identified in approaches and reporting. Recommendations have been made based on the available evidence for future functional lung trials.

Contrast-enhanced MRI of the lung

The lung has long been neglected by MR imaging. This is due to unique intrinsic difficulties: (1) signal loss due to cardiac pulsation and respiration; (2) susceptibility artifacts caused by multiple air-tissue interfaces; (3) low proton density. There are many MR strategies to overcome these problems. They consist of breath-hold imaging, respiratory and cardiac gating procedures, use of short repetition and echo times, increase of the relaxivity of existing spins by administration of intravenous contrast agents, and enrichment of spin density by hyperpolarized noble gases or oxygen. Improvements in scanner performance and frequent use of contrast media have increased the interest in MR imaging and MR angiography of the lung. They can be used on a routine basis for the following indications: characterization of pulmonary nodules, staging of bronchogenic carcinoma, in particular assessment of chest wall invasion; evaluation of inflammatory activity in interstitial lung disease; acute pulmonary embolism, chronic thromboembolic pulmonary hypertension, vascular involvement in malignant disease; vascular abnormalities. Future perspectives include perfusion imaging using extracellular or intravascular (blood pool) contrast agents and ventilation imaging using inhalation of hyperpolarized noble gases, of paramagnetic oxygen or of aerosolized contrast agents. These techniques represent new approaches to functional lung imaging. The combination of visualization of morphology and functional assessment of ventilation and perfusion is unequalled by any other technique.

Non-invasive imaging of regional lung function using x-ray computed tomography.

The use of imaging technologies has progressed beyond the depiction of anatomic abnormalities to providing non-invasive regional structure and functional information in intact subjects. These data are particularly valuable in studies of the lung, since lung disease is heterogeneous and significant loss of function may occur before it is detectable by traditional whole lung measurements such as oxygenation, compliance, or spirometry. While many imaging modalities are available, X-ray computed tomography (CT) is emerging as the preferred method for imaging the lung because of its widespread availability, resolution, high signal/noise ratio for lung tissue, and speed. Utilizing the quantitative density and dimensional information available from conventional CT images, it is possible to measure whole and regional lung volumes, distribution of lung aeration and recruitment behavior under various clinical conditions and interventions, and important regional mechanical properties. In addition, using the radiodense gas xenon (Xe) as a contrast agent, regional ventilation or gas transport may also be obtained. This communication will review recent advances in CT based techniques for the measurement of regional lung function.

Quantification of Regional Intrapulmonary Oxygen Partial Pressure Evolution during Apnea by 3He MRI

We present a new method to determine in vivo the temporal evolution of intrapulmonary oxygen concentrations by functional lung imaging with hyperpolarized 3Helium (3He→). Single-breath, single-bolus visualization of 3He→ administered to the airspaces is used to analyze nuclear spin relaxation caused by the local oxygen partial pressure pO2(t). We model the dynamics of hyperpolarization in the lung by rate equations. Based hereupon, a double acquisition technique is presented to separate depolarization by RF pulses and oxygen induced relaxation. It permits the determination of pO2 with a high accuracy of up to 3% with simultaneous flip angle calibration using no additional input parameters. The time course of pO2 during short periods of breathholding is found to be linear in a pig as well as in a human volunteer. We also measured the wall relaxation time in the lung and deduced a lower limit of 4.3 min.

The role of three dimensional functional lung imaging in radiation treatment planning: The functional dose-volume histogram

During thoracic irradiation (XRT), treatment fields are usually designed to minimize the volume of nontumor-containing lung included. Generally, functional heterogeneities within the lung are not considered. The three dimensional (3D) functional information provided by single photon emission computed tomography (SPECT) lung perfusion scans might be useful in designing beams that minimize incidental irradiation of functioning lung tissue. We herein review the pretreatment SPECT scans in 86 patients (56 with lung cancer) to determine which are likely to benefit from this technology. Prior to thoracic XRT, SPECT lung perfusion scans were obtained following the intravenous injection of approximately 4 mCi of 99mcTc-labeled macro-aggregated albumin. The presence of areas of decreased perfusion, their location relative to the tumor, and the potential clinical usefulness of their recognition, were scored. Patients were grouped and compared (two-tailed chi-square) based on clinical factors. Conventional dose-volume histograms (DVHs) (DVFHs) are calculated based on the dose distribution throughout the computed tomography (CT)-defined lung and SPECT-defined perfused lung, respectively. Among 56 lung cancer patients, decreases in perfusion were observed at the tumor, adjacent to the tumor, and separate from the tumor in 94%, 74%, and 42% of patients, respectively. Perfusion defects adjacent to the tumor were often large with centrally placed tumors. Hypoperfusion in regions separate from the tumor were statistically most common in patients with relatively poor pulmonary function and chronic obstructive pulmonary disease (COPD). Considering all SPECT defects adjacent to and separate from the tumor, corresponding CT abnormalities were seen in only approximately 50% and 20% of patients, respectively, and were generally not as impressive. Following XRT, hypoperfusion at and separate from the tumor persisted, while defects adjacent to the tumor improved in several patients. In four patients who achieved a complete response scored by CT with chemotherapy prior to XRT, persistent hypoperfusion was present at and adjacent to the tumor site in three. Among 30 patients with cancers not arising in the lung (14 breast, 12 lymphoma, 4 others), perfusion defects were seen in only 4 (2 adjacent and 2 apart). Recognition of decreases in perfusion mainly impacted on treatment planning for a few patients with poor pulmonary function and limited target volumes. DVFHs have been useful in beam selection for patients with marked perfusion heterogeneities. Lung perfusion scans provide functional information not provided by CT scans that can be useful in designing radiation treatment beams that minimize incidental irradiation of the function regions of the lung. This approach appears to be most helpful in patients with gross intrathoracic lung cancer, especially those with small targets and relatively poor pulmonary function. One limitation of this approach is that some of the defects adjacent to the tumor site reperfuse following treatment, indicating that these scans identify perfusion rather than potential perfusion. Three dimensional functional data can be used to generate DVFHs that may be more predictive of the physiological consequences of the radiation than conventional DVHs. Additional work is currently underway to test this hypothesis.

The role of 3-dimensional functional lung imaging in treatment planning: The functional DVH

The role of 3-dimensional functional lung imaging in treatment planning: The functional DVH

Low carbon monoxide transfer factor ( TlCO) in HI V-infected patients without lung disease

It is well recognized that HIV-infected patients who develop P. carinii pneumonia have a reduced carbon monoxide transfer factor (TLCO). We have previously shown that many HIV-infected patients without overt lung disease (i.e. no respiratory symptoms, chest signs and normal chest radiographs and who in addition do not develop lung disease over the next 3 months) have a low cai'bon monoxide transfer factor (7LCO) (1). In this study we asked whether other lung function tests or imaging techniques could further identify this subgroup of asymptomatic HIV-infected patients with reductions in 7LCO. The aim of this study was to investigate this abnormality further.

Sites of airway dilatation in asthma following inhaled versus subcutaneous terbutaline: Comparison of physiologic tests with radionuclide lung images

In 12 asthmatic subjects with mild to severe airways obstruction, we compared the relative magnitude and sites of airway dilatation of a beta-adrenergic stimulant administered by different routes. Specific airway conductance (SG aw), peak expiratory flow, the sum of the absolute volume of isoflow and residual volume as a percentage of total lung capacity (capacity of isoflow) and the ratio of maximal expiratory flow at 50 per cent of vital capacity breathing 80 per cent helium-20 per cent oxygen to that breathing air (ratio V̇max 5) were determined before and after the administration of aerosolized terbutaline (0.5 mg), subcutaneous terbutaline (0.5 mg) or placebo. Increases in SG aw and peak expiratory flow of ≥ 25 per cent were considered to indicate significant dilatation of central airways; increases in ratio Vmax 50 of ≥ 0.10 and decreases in capacity of isoflow of ≥10 per cent were assumed to reflect dilatation of peripheral airways. In addition, radioaerosol and radioxenon lung imaging was performed to determine the relationship between changes in lung imaging patterns and changes in physiologic indices in response to bronchodilator therapy. Placebo caused little change in lung function or lung imaging. After inhaled terbutaline, SG aw and peak expiratory flow increased ≥25 per cent in seven subjects, ratio Vmax 50 increased ≥0.10 in only three subjects, capacity of isoflow decreased ≥10 per cent in only one subject, radioaerosol images showed less central deposition in nine subjects and radioxenon images showed improved distribution and/or washout of xenon in five subjects. After the administration of subcutaneous terbutaline, SG aw and peak expiratory flow increased ≥25 per cent in 10 subjects, ratio Vmax 50 increased ≥0.10 in 10 subjects, capacity of isoflow decreased ≥10 per cent in 11 subjects, and radioaerosol and xenon images showed improvement in 11 and eight subjects, respectively. These findings are consistent with the action of inhaled terbutaline mainly on large airways and of subcutaneous terbutaline on both large and small airways. Although reduced central radioaerosol deposition correlated well with physiologic evidence of large airway dilatation, improvement in xenon distribution and washout could be attributed to dilatation of either large and/or small airways.

Physiological and Radiographic Assessment During the Development of Pulmonary Radiation Fibrosis

Repeated regional measurements of pulmonary blood flow and ventilation were performed in 25 patients irradiated for breast cancer. Patients were studied before and at varying times after (16 to 47 days) the start of radiotherapy. At the same time, chest radiographs were taken and symptoms recorded. Of all the parameters measured, blood flow showed the earliest and greatest decrease. Since changed in blood flow at 60 days are predictive of the changes at 300 days, we believe that earlier studies during the course of irradiation could be useful in predicting long-term effects.

Airway closure in children.

Airway closure in children.