Methods and systems for treating chronic obstructive pulmonary disease

Abstract

The disclosure includes methods, systems, and accompanying devices, for treatment of chronic obstructive pulmonary disease through stereotactic irradiation for lung volume reduction.

Description

ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION METHODS AND SYSTEMS FOR TREATING CHRONIC OBSTRUCTIVE PULMONARY DISEASE CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 572,909, which was filed April 2, 2024, is titled METHODS AND SYSTEMS FOR TREATING CHRONIC OBSTRUCTIVE PULMONARY DISEASE, and is incorporated herein by reference in its entirety. FIELD

[0002] The disclosure relates to treatment of chronic obstructive pulmonary disease in a subject. through stereotactic irradiation of emphysematous tissue. BACKGROUND

[0003] Emphysema, a subtype of chronic obstructive pulmonary disease (COPD), is a major public health concern, with a global prevalence of 212.3-391.9 million (1,2). Emphysema results in about 3.2 million deaths annually and thus has a substantial impact on global mortality (3). Moreover, the morbidity associated with emphysema, including dyspnea, reduced exercise capacity, and frequent pulmonary infections, significantly affects quality of life. Therapies directed at reducing hyperinflation have demonstrated symptomatic and functional improvement in many patients and a survival benefit in subsets of patients (4).

[0004] Despite its clear benefits (4), lung volume reduction surgery (LVRS) is appropriate for only a small subset of patients with emphysema, with some estimating that only 15% are suitable for the procedure (5). The procedure also appears to be extremely underutilized, with a mere 0.6% and 22.6% utilization, based on basic and stringent inclusion criteria, respectively (6). This may be due to apprehension surrounding the high 90-day mortality of 16% in the high-risk subgroup defined by the National Emphysema Treatment Trial (NETT) (4) and / or the restriction of the procedure to specialized centers by the Center for Medicare and Medicaid Services (7).

[0005] In an effort to mitigate perceived surgical risk and offer a less invasive approach, several bronchoscopic techniques of lung volume reduction (LVR) have been developed, with endobronchial valves (EBV) the most-studied and now most-used. Extensive studies of EBVs have demonstrated substantial efficacy (though likely less than LVRS), but its application, too,ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION is limited – to patients with heterogeneous emphysema without significant collateral ventilation (8).

[0006] A substantial portion of patients with severe emphysema, then, are ineligible for both surgery and EBVs, depriving them of the benefits of LVR (9,10). This patient-group includes those with heterogeneous disease with collateral ventilation who do not qualify for EBVs and also with FEV1% and DLCO% too low to qualify for LVRS; and those who have some combination of homogeneous disease and low FEV1% and / or DLCO% that places them in the prohibitive-risk LVRS group. SUMMARY OF EMBODIMENTS

[0007] The disclosure relates to a method of treating chronic obstructive pulmonary disease in a subject in need thereof. The method comprises administering to the subject a biologically effective dose of radiation to the lung tissue of the subject. The step of administering may comprise administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 5% to about 25% of total lung volume of the subject. In some embodiments, the step of administering comprises administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject. The target volume of lung tissue in the subject may comprise a significant amount of parenchyma. The administering may be performed a total of about three times over a period of one week.

[0008] The disclosure also relate to a method of treating emphysema in a subject in need thereof. In some embodiments, the method comprises administering to the subject stereotactic irradiation to emphysematous tissue within the lung of the subject at a dose sufficient to cause fibrosis within the emphysematous tissue. In some embodiments, the dose may be from about 40 to about 50 Gy. The dose may be administered a total of about 3 times over a week. In some embodiments, the method further comprises analyzing an image of the lung of a subject to identify a target region comprising the most emphysematous tissue. In some embodiments, the image is generated by CT scan.

[0009] The disclosure relates to a method of treating emphysema and / or hyperinflation of a lung of a subject in need thereof. In some embodiments, the method comprises administering to the subject a biologically effective dose of radiation to the lung tissue of the subject. In some embodiments, the step of administering comprises administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject. In some embodiments, the method further comprises analyzing an image of theATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION lung of a subject to identify a target region comprising the most emphysematous tissue within the lung tissue of a subject. In some embodiments, the method further comprises determining the target lung volume by: (i) imaging the lung tissue of the subject; (ii) identifying a region of the lung tissue with significant emphysematous lung tissue; and (iii) determining the target volume within the region of significant emphysematous lung tissue. In some embodiments, the step of imaging the lung tissue may comprise imaging by CT scan.

[0010] The disclosure relates to a method of improving pulmonary function, exercise capacity and / or dyspnea in a subject in need thereof. In some embodiments, the method comprises administering to the subject a biologically effective dose of radiation to the lung tissue of the subject. In some embodiments, the biologically effective dose is a dose of radiation sufficient to cause fibrosis in a region of lung tissue of the subject comprising emphysematous tissue. In some embodiments, the step of administering may comprise administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject.

[0011] The disclosure relates to a method of treating emphysema in a subject in need thereof. In some embodiments, the method comprises: (a) establishing a region for reduction in emphysematous lung tissue in the subject; (b) delineating a planned target volume for reduction within the region for reduction; and (c) irradiating the planning target volume with a dose of radiation. In some embodiments, the target volume is about 10% of total lung volume of the subject. In some embodiments, the planning target volume may be less than about 30 milliliters or about 30 cc. In some embodiments, the dose is about 45 Gy administered in three fractions. In some embodiments, the emphysematous lung tissue may include a region of most emphysematous lung tissue. In some embodiments, the planning target volume is positioned within the region of most emphysematous lung tissue. In some embodiments, the method further comprises identifying the most emphysematous lung tissue on one or more computed tomography scan images of the subject, manually contouring the images, and editing the images to form the target volume for reduction within the most emphysematous lung tissue.

[0012] The disclosure relates to a system comprising an imaging device, a beam source, a memory storing processor-executable instructions, and a processor configured to execute the processor executable instructions. In some embodiments, the processor executable instructions comprise instructions for: (a) establishing a volume for reduction in emphysematous lung tissue in the subject; (b) delineating a planning target volume for reduction within the volume; and (c) irradiating the planning target volume with a dose of radiation from the beam source. The instructions may further comprise defining the target volume as about 10% of total lung volumeATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION of the subject. In some embodiments, the instructions further comprise defining the planning target volume as equal to or less than about 30 cc of total lung volume. In some embodiments, the instructions for irradiating comprise instructions for irradiating a dose of about 45 Gy in three fractions. In some embodiments, the instructions may comprise determining a region of most emphysematous lung tissue within the emphysematous lung tissue. In some embodiments, the instructions comprise defining the planning target volume within the region of most emphysematous lung tissue. In some embodiments, the instructions may comprise identifying the most emphysematous lung tissue on one or more computed tomography scan images of the subject, contouring the images, and editing the images to form the target volume for reduction within the most emphysematous lung tissue. BRIEF DESCRIPTION OF DRAWINGS

[0013] FIG.1 illustrates a timeline of all events in the conduct of the SILVR trial (SF-36 = Short Form Survey -36, SILVR = Stereotactic Irradiation for Lung Volume Reduction)

[0014] FIG.2 illustrates a CONSORT diagram for the SILVR trial (LVRS = Lung Volume Reduction Surgery, PFT = Pulmonary Function Test, SF-36 = Short Form Survey - 36, DSMB = Data Safety and Monitoring Board)

[0015] FIGS. 3A and 3B depict absolute FEV1% over time and volume of the target lobe over time, respectively. FIG. 3A shows absolute FEV1% over time (Baseline, 6 months, 12 months, and 18 months) post-SILVR for all eight patients. Each line represents the FEV1% for a specific patient. All patients with BODE index ≤5 had at least a transient increase in FEV1% after SILVR (maintained in 3 of 4), whereas only 1 of 4 patients with BODE index ≥6 did (FEV1% – Forced Expiratory Volume in 1 sec (% of predicted)). In Figure 3A, the four patients with BODE scores equal to or less than 5 are depicted with the 4 highest values on the y axis. In the original color graph, such patients are depicted in blue. Four patients with BODE scores of 6 or greater have the four lowest y values after 6 months of tracking the patients. FIG. 3B shows volume of the target lobe over time (Baseline, 6 months, and 18 months) post-SILVR for seven patients (one patient who had pleural effusion on follow-up scans could not be analyzed volumetrically). Each line represents the target lobe volume for a specific patient. Patients with a BODE index ≤5 are represented in blue in the original Figure and are depicted but he four lines in the lowest y axis volumes at and after 5 months post-treatment, and patients with a BODE index ≥6 are represented one the graphs with the highest values on the y axis 5 months post-treatment. All patients with BODE index ≤5 had an absolute reduction in theATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION volume of the target lobe of at least 4.7% of TLV after SILVR, whereas only 1 of 3 patients with BODE index ≥6 did. (* line tracings marked in Fig 3A and 3B were of the same subject).

[0016] FIG.4A illustrates a sequence of images depicts the coronal and sagittal sections of a representative patient who received SILVR to the left lower lobe (target lobe), showing the stereotactic radiotherapy (RT) plan and changes in target and adjacent lobes over time, from baseline to 6- and 18-months post-RT. The target lobe is outlined in blue, and the adjacent lobe is outlined in green. The RT planning images show the volumes receiving biologically equivalent doses (BED3) of ≥100Gy (outlined in red), ≥60Gy (outlined in green), and ≥20Gy (outlined in maroon). The target lobe shows a progressive reduction in volume over time. Meanwhile, the adjacent lobe shows progressive expansion. The fibrosis occurring due to the RT can also be observed in the images at 10- and 18 months post-RT.

[0017] FIG. 4B illustrates a 3D reconstruction images of the left lung of the same patient (as in Fig.2A) at baseline, 10, and 18 months after SILVR. The images show a reduction in the volume of the target lobe (lower lobe, represented in blue) over time, with the most remarkable change observed between the baseline and 10-month images. The expansion of the adjacent lobe (upper lobe, represented in green) can also be observed in the follow-up images at 10- and 18 months post-RT (TLV = Target Lobe Volume).

[0018] FIG. 5A illustrates that the target lobe volume reduction at 18 months correlates with V60BED3.

[0019] FIG. 5B illustrates that expansion in the volume of the ipsilateral lobe adjacent to the target lobe at 6 months correlates with target lobe volume reduction.

[0020] FIG.5C shows that improvement in FEV1% at 6 months correlates with expansion in the volume of the ipsilateral lobe adjacent to the target lobe.

[0021] FIG. 5D illustrates that improvement in FEV1% at 6 months correlates negatively with the BODE index.

[0022] FIGS.6A and 6B illustrate that V60BED3 does not correlate with the reduction in the volume of the target lobe at 6 months, but does so at 18 months (V60BED3= Volume receiving a biologically effective dose≥60Gy).

[0023] FIGS. 7A and 7B illustrate that the mean Hounsfield unit (HU) of V60BED3in lung does not correlate with the absolute ΔFEV1% at 6 months; but does so, at 18 months (V60BED3 = Volume receiving a biologically effective dose≥60Gy, FEV1% = Forced expiratory volume in 1 sec (% of predicted)).

[0024] FIGS. 8A and 8B illustrate that the mean Hounsfield unit (HU) of V20BED3in lung correlates with the absolute ΔFEV1% at 6 months and at 18 months (V20BED3 = VolumeATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION receiving a biologically effective dose≥20Gy, FEV1% = Forced expiratory volume in 1 sec (% of predicted)).

[0025] FIGS.9A and 9B illustrate that BODE index correlates negatively with the absolute ΔFEV1% at 6 months, and negatively with the absolute Δ target lobe volume at 6 months (FEV1% = Forced expiratory volume in 1 sec (% of predicted)).

[0026] FIG.10 depicts a series of steps for a non-transitory computer program product. DETAILED DESCRIPTION OF EMBODIMENTS

[0027] Listed below are definitions of various terms used to describe this disclosure. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0028] As used herein, the terms “a” or “an” means that “at least one” or “one or more” unless the context clearly indicates otherwise. The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising” can refer, in various embodiments, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0029] The term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, “either,” “one of,” “only one of,” or “exactly one of.”

[0030] As used herein, the terms “comprising” (and any form of comprising, such as “comprise,” “comprises,” and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0031] The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. According to certain embodiments, when referring to a measurable value such as an amount and the like, “about” is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.9%,ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2% or ±0.1% from the specified value as such variations are appropriate to perform the disclosed methods. When “about” is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0032] The term “at least” prior to a number or series of numbers (e.g. “at least two”) is understood to include the number adjacent to the term “at least,” and all subsequent numbers or integers that could logically be included, as clear from context. When “at least” is present before a series of numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range. Ranges provided herein are understood to include all individual integer values and all subranges within the ranges.

[0033] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be treated by the methods or systems disclosed herein.

[0034] As used herein, the terms “administering” and “administration” refer to any method of providing a irradiating dose to a subject.

[0035] As used herein, the phrase “in need thereof” means that an animal or mammal has been identified or suspected as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis or observation. In any of the methods and systems described herein, the animal or mammal can be in need thereof. In some embodiments, the subject in need thereof is a human seeking treatment of a chronic obstructive pulmonary disease. In some embodiments, the subject in need thereof has been diagnosed or suspected of having emphysema or severe emphysema.

[0036] As used herein, the term “subject,” “individual” or “patient,” used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans. In some embodiments, the subject is a human. In some embodiments, the subject is a human seeking treatment for a chronic obstructive pulmonary disease and / or emphysema. In some embodiments, the subject is a mammal.

[0037] As used herein, the term “mammal” means any animal in the class Mammalia such as rodent (i.e., mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal refers to any non-human mammal. The present disclosure relates to any of the methods or compositions of matter wherein the sample is taken from a mammal or non-human mammal. The present disclosure relates to any of the methods or compositions of matter wherein the sample is taken from a human or non-human primate.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0038] As used herein, the terms “treat,” “treated,” or “treating” can refer to therapeutic treatment wherein the object is to prevent or slow down (lessen) a chronic obstructive pulmonary disease or obtain beneficial or desired clinical results. For purposes of the embodiments described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of a chronic obstructive pulmonary disease or emphysema; stabilized (i.e., not worsening) state of a chronic obstructive pulmonary disease; amelioration of the a chronic obstructive pulmonary disease, whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of a chronic obstructive pulmonary disease. Treatment can also include eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, the treatment includes prolonging survival of a subject with severe emphysema.

[0039] A “biologically effective dose” or “effective dose” of radiation is a predetermined amount calculated to achieve the desired effect, i.e., to treat, combat, or ameliorate one or more symptoms of a chronic obstructive pulmonary disease, or emphysema. The specific dose of radiation administered according to the present disclosure to obtain therapeutic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the angle of administration, the depth of tissue to reach, the type of radiation, and the chronic obstructive pulmonary disease being treated. It will be understood that the effective amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the angle of administration, the depth of tissue, the type of radiation, and the chronic obstructive pulmonary disease being treated. In some embodiments, a biologically effective dose of radiation of embodiments of the present disclosure is typically an amount such that when it is administered in a physiologically tolerable manner and / or it is sufficient to cause fibrosis within target volume.

[0040] In some embodiments, the subject has been diagnosed with asthma or is suspected of having asthma. In some embodiments, the subject has asthma if the subject comprises FEV1% less than 45% of predicted value for the subject’s size and age, with increased lung volumes as compared to a patient without COPD.

[0041] As used herein, “severe emphysema” refers to heterogenous emphysema resulting in the subject having and FEV1% less than 45%, or homogeneous emphysema as observed by CT scan. In some embodiments, the subject with severe emphysema comprises FEV1% less than 45% of predicted value for the subject’s size and age with diagnosed COPD with chronicATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION bronchitis or COPD with homogeneous emphysema or heterogeneous. In some embodiments, the subject with severe emphysema comprises FEV1% less than 45% of predicted value for the subject’s size and age, with increased lung volumes as compared to a patient without COPD. In some embodiments, a subject with chronic bronchitis comprises subject with severe emphysema comprises FEV1% less than 45% of predicted value for the subject’s size and age, with increased lung volumes as compared to a patient without COPD but does not have evidence of emphysematous parenchymal destruction on an image of the lung tissue. In some embodiments, the image is a CT scan.

[0042] As used herein, an “intermediate dose” of radiation refers to a biologically equivalent dose (BED) to a subject of from about 20 to about 100 Gy. In some embodiments, the biologically equivalent dose is calculated by the equation below:

[0043] BED = n x d(1 + d / α / β) wherein n = number of treatment fractions wherein d = dose per fraction in Gray (Gy) wherein α / β = dose at which the linear and quadratic components of cell kill are equal.

[0044] In some embodiments, the intermediate dose is administered is a circular or semicircular, coronal, ring or other peripheral or circumferential volume surrounding a site an ablative dose from about 30 to 60 Gy at the center of the volume. In some embodiments, the ablative does is about 100 Gy or more of a BED. In some embodiments, the intermediate dose is received in a region of lung tissue surrounding a target volume of lung tissue receiving an ablative dose of radiation.

[0045] As used herein, a region of tissue having “significant emphysematous lung tissue” refers to lung tissue of a subject suffering from emphysema containing at least about a 10% greater number of swollen alveoli than surrounding emphysematous tissue.

[0046] As used herein, “significant amount of parenchyma” refers to lung tissue with a CT density of about −850 to about −970 HU.

[0047] Some embodiments of the disclosure include methods of treating chronic obstructive pulmonary disease, or emphysema, in a subject in need thereof. In some embodiments, the method comprises administering to the subject a biologically effective dose of radiation to the lung tissue of the subject. The biological effective dose of radiation may be from about 35 to about 55 gray (Gy). In some embodiments, the biological effective dose of radiation is about 35, 40, 45, 50, or 55 Gy. In some embodiments, the dose is about 45 Gy. In some embodiments, the biologically effective dose is from about 40 to about 50 Gy. In some embodiments, the biologically effective dose is administered a total of about 3 times over aATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION week, or, in some embodiments, the step of administering is repeated from about 3 to about 4 times in a month.

[0048] In some embodiments, the step of administering is performed a total of about three times over a period of one week. In some embodiments, the administering comprises administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject.

[0049] In some embodiments, the administering further comprises administering an intermediate dose of radiation around the periphery of the target volume of lung tissue. The intermediate dose may be achieved by administering a high dose to the target volume, which results in an intermediate dose being delivered around the periphery of the target volume. In some embodiments, the intermediate dose of radiation around the periphery of the target volume of lung tissue comprises a decreasing gradient of radiation as the distance from the target volume is increased. In some embodiments, the target volume of lung tissue in the subject may comprise a significant amount of parenchyma. In some embodiments, the methods of the disclosure comprise determining the target lung volume before the step of administering.

[0050] Determining the target lung volume may comprise imaging the lung of the subject, identifying emphysematous lung tissue within the subject comprising a region with most emphysematous lung tissue from images obtained in the imaging step, and determining the target volume within the region of most emphysematous lung tissue. Determining the target lung volume may comprise imaging the lung of the subject, identifying emphysematous lung tissue within the subject from images obtained in the imaging step, and determining the target volume within the lung comprising the emphysematous lung tissue. In some embodiments, the target volume is positioned within the upper lobe of the lung of a subject in the lung in which at least one region of emphysematous tissue exists. The step of imaging may comprise imaging by CT scan. In some embodiments, the method is free of accompanying surgical interventions.

[0051] The disclosure relates to a subject in need thereof. In some embodiments, the subject may have a BODE score from about 3 to about 8. A BODE score, or index, takes into account body mass index, airway obstruction, dyspnea, and exercise tolerance, all of which standard measures in the art.

[0052] The disclosure further relates to methods of treating emphysema in a subject in need thereof. In some embodiments, the method comprises administering to the subject stereotactic irradiation to emphysematous tissue within the lung of the subject at a dose sufficient to cause fibrosis within the emphysematous tissue. The dose may be from about 35 to about 55 Gy. The dose may be about 35, 40, 45, 50, or 55 Gy. The dose may be about 45 Gy. The dose may beATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION from about 40 to about 50 Gy. The dose may be administered a total of about 3 times over a week.

[0053] In some embodiments, the method further comprises analyzing one or more images of the lung of a subject to identify a target region comprising the emphysematous tissue. The one or more images may be an image generated by CT scan. In some embodiments, the step of analyzing comprises reviewing and editing an image to identify and to select a region of tissue for administration and treatment.

[0054] The disclosure relates to methods of treating emphysema and / or hyperinflation of a lung of a subject in need thereof. The method comprises administering to the subject a biologically effective dose of radiation to the lung tissue of the subject. The biological effective dose of radiation may be from about 35 to about 55 Gy. The biological effective dose of radiation may be about 35, 40, 45, 50, or 55 Gy. The dose may be about 45 Gy. The biologically effective dose may be from about 40 to about 50 Gy. The biologically effective dose may be administered a total of about 3 times over a week. The step of administering may comprise administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 5% to about 25% of total lung volume of the subject. In some embodiments, the step of administering comprises administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject. In some embodiments, the method further comprises a step of administering to the subject an intermediate dose of radiation around the periphery of the target volume of lung tissue. The intermediate dose may be achieved by administering a high dose to the target volume, which results in an intermediate dose being delivered around the periphery of the target volume. The intermediate dose of radiation around the periphery of the target volume of lung tissue may comprises a decreasing gradient of radiation as the distance from, the target volume is increased. The target volume of lung tissue in the subject may comprise a significant amount of parenchyma. The method may comprise determining the target lung volume.

[0055] The disclosure relates to methods of treating bronchitis and / or hyperinflation of a lung of a subject in need thereof. The method comprises administering to the subject a biologically effective dose of radiation to the lung tissue of the subject. The biological effective dose of radiation may be from about 35 to about 55 Gy. The biological effective dose of radiation may be about 35, 40, 45, 50, or 55 Gy. The dose may be about 45 Gy. The biologically effective dose may be from about 40 to about 50 Gy. The biologically effective dose may be administered a total of about 3 times over a week. The step of administering may comprise administering a dose of radiation to a target volume of lung tissue of the subject equal to noATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION more than about 5% to about 25% of total lung volume of the subject. In some embodiments, the step of administering comprises administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject. In some embodiments, the method further comprises a step of administering to the subject an intermediate dose of radiation around the periphery of the target volume of lung tissue. The intermediate dose may be achieved by administering a high dose to the target volume, which results in an intermediate dose being delivered around the periphery of the target volume. The intermediate dose of radiation around the periphery of the target volume of lung tissue may comprises a decreasing gradient of radiation as the distance from, the target volume is increased. The target volume of lung tissue in the subject may comprise a significant amount of parenchyma. The method may comprise determining the target lung volume.

[0056] The disclosure relates to methods further comprising a step of analyzing an image of the lung of the subject to identify a target region comprising the emphysematous tissue within the lung tissue of the subject.

[0057] Determining the target lung volume may comprise imaging the lung of the subject, identifying emphysematous lung tissue within the subject comprising a region with most emphysematous lung tissue from images obtained in the imaging step, and determining the target volume within the region of most emphysematous lung tissue. The step of imaging may comprise imaging by CT scan.

[0058] In some embodiments, the subject has a BODE score from about 3 to about 8. The BODE score may be at or above about 5. The subject may have been diagnosed with severe emphysema. The subject may have been diagnosed with a significant amount of more intact parenchyma in the lung tissue.

[0059] In some embodiments, the method is performed without accompanying surgical interventions. Alternatively, in some embodiments, the method may be conducted in conjunction with surgical intervention.

[0060] The disclosure relates to methods of improving pulmonary function, exercise capacity and / or dyspnea in a subject in need thereof. In some embodiments, the methods comprise administering to the subject a biologically effective dose of radiation to the lung tissue of the subject. The biologically effective dose is a dose sufficient to cause fibrosis in a region of lung tissue of the subject comprising emphysematous tissue.

[0061] In some embodiments, the biological effective dose of radiation may be from about 35 to about 55 Gy. In some embodiments, the biological effective dose of radiation may be about 35, 40, 45, 50, or 55 Gy. The dose may be about 45 Gy. The biologically effective doseATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION may be from about 40 to about 50 Gy. The biologically effective dose may be administered a total of about 3 times over a week, two weeks, three weeks or a month. In some embodiments, the step of administering comprises administering the dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject. The method may further comprise a step of administering to the subject an intermediate dose of radiation around the periphery of the target volume of lung tissue. The intermediate dose may be achieved by administering a high dose to the target volume, which results in an intermediate dose being delivered around the periphery of the target volume due to diffusion of the dose around the ablative does target region. In some embodiments, the intermediate dose of radiation around the periphery of the target volume of lung tissue comprises a decreasing gradient of radiation as the distance from the target volume is increased. The target volume of lung tissue in the subject may comprise a significant amount of parenchyma.

[0062] Some methods of treatment of the disclosure comprise determining the target lung volume of a subject with chronic obstructive pulmonary disease. In some embodiments, the step of determining a target lung volume comprises evaluating an image of a lung of a subject, for instance a CT scan of the lung, identifying a region of emphysematous tissue and administering a stereotactic and ablative dose of radiation at the target lung volume. In some embodiments, the methods further comprise targeting a lung volume in the upper lobe of one of the lungs of the subject, wherein one of the lungs with the upper lobe being a target of the radiation therapy comprises at least one region of emphysematous tissue.

[0063] The disclosure also relates to methods of administering radiation to the subject, in a target volume of the subject’s lung, with one ablative dose and, optionally, intermediate doses of radiation. Ablative doses are defined, in some embodiments, as BED3>100 Gy. The following are non-limiting examples of prescription doses within the ablative range: about 25 Gy in 1 fraction or dose, about 45 Gy in 3 fractions or doses, and about 50 Gy in from about 4 to about 5 fractions or doses. In some embodiments, the above ablative doses are incorporated as doses for methods of treating COPD, emphysema, and / or bronchitis, such as severe emphysema and / or bronchitis in subjects in need of the treatment.

[0064] In some embodiments, the methods comprise administering intermediate dose ranges, either as a residual dose from ablative therapy or separate doses of diffuse therapy around a periphery of a target volume identified for ablative therapy. In some embodiments the doses of intermediate radiation are from about 20 to about 100 Gy BED3, which is equivalent to a dose from about 9 to about 26 Gy delivered over about three fractions. In some embodiments, the intermediate dose if from about 9.6 to about 25.5 Gy delivered over aboutATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION 3 fractions. In some embodiments, the intermediate dose comprises from about 6 to about 18 Gy delivered in 1 fraction or dose. In some embodiments, the intermediate dose comprises administering radiation to the subject equivalent to about 6.4 to about 16 Gy delivered in 1 fraction.

[0065] In some embodiments, methods may further comprise analyzing an image of the lung of the subject to identify a target region comprising the emphysematous tissue within the lung tissue of the subject.

[0066] In some embodiments, the step of determining the target lung volume may comprise imaging the lung of the subject, identifying emphysematous lung tissue within the subject comprising a region with most emphysematous lung tissue from images obtained in the imaging step, and determining the target volume within the region of most emphysematous lung tissue. In some embodiments, the step of imaging comprises imaging by CT scan.

[0067] The disclosure relates to a computer tomography (CT) device which enables volume reconstruction to be performed by capturing an image of the lung tissue, identifying a emphysematous lung tissue. Generally, operation of a CT device is known. Briefly, an image is achieved by means of a computer tomography device according to the invention which includes an X-ray source for emitting an X-ray beam and a detector system for picking up density profiles of cross-sections of an object to be examined, such detector system includes a plurality of X-ray sensitive detector elements which are arranged, in some embodiments, in a two-dimensional pattern, in which detector elements in different positions along a transverse direction, parallel to the cross-sections, have substantially the same effective cross-section whereas at least some of the detector elements in different positions along a longitudinal direction, transversely of the cross-sections, have different effective cross-sections, and an X- ray collimator for spatially limiting the X-ray beam in the longitudinal direction, and substantially equal surfaces of detector groups, consisting of detector elements and / or parts of detector elements situated along the transverse direction, can be reached by the limited X-ray beam.

[0068] The disclosure relates to a system comprising a CT device that enables simultaneous measurement of density profiles of individual cross-sections by means of the individual detector groups. Consequently, only a small amount of time is required to measure the density profiles of a substantial volume of the patient to be examined. Each of the density profiles represents density values in a cross-section of the patient to be examined. The individual cross- sections always relate to a part of the patient to be examined for the relevant, essentially the same longitudinal positions. Mathematically, cross-sections are planes at fixed longitudinalATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION positions. The transverse direction extends perpendicularly to the longitudinal direction, so parallel to the cross-sections. It is not necessary to compute density profiles by interpolation: for individual cross-sections density values are measured for the longitudinal position of the relevant cross-section. Because density profiles are measured for the relevant longitudinal position, it is not necessary to compute these density profiles so that more accurate values can be obtained for the density profiles. Moreover, no time is wasted on carrying out the computations.

[0069] The respective detector groups of detector elements which have the same longitudinal positions and are reached by the X-rays over substantially the same surface areas pick up density values of essentially parallel cross-sections of the patient to be examined. From the incident X-rays, the individual detector elements derive a detector signal whose signal level represents the intensity of the incident X-rays. In order to ensure that substantially the same surfaces areas of detector elements of one and the same detector group are reached by X-rays, parts of detector elements are shielded by the X-ray collimator if the surface area of a relevant detector element per se is larger than the surface area to be reached, or detector signals of individual detector elements are combined when the surface area of the relevant detector elements that is reached by the X-rays is smaller than the surface area to be reached. Because reached surface areas of substantially the same size are formed by partly shielding detector elements, it is achieved that the density profiles are measured with a high spatial resolution despite the use of comparatively large detector elements. The resolution is determined by the effective surface area of the smallest effective surface area of the detector elements. Using a computer tomography device according to the invention, simultaneous measurement of density profiles of a larger part of the patient to be examined requires a number of detector elements which increases less than linearly as a function of the ratio of the smallest effective surface area to the linear dimension of the part of the patient for which density profiles are simultaneously measured. It is thus achieved that as a volume scan is made of a larger part of the patient in one operation, comparatively fewer additional, expensive detector elements will be required.

[0070] The detector system may be provided, for example with a sensor matrix with semiconductor photodiodes which are sensitive to X-rays and are connected to read-out lines via thin-film transistors per column. The gate contacts of the thin film transistors are connected to the addressing lines per row. Addressing signals, supplied via the addressing lines, open thin film transistors per row so as to read-out electric charges generated by the X-rays in the photodiodes in the relevant row. Said electric charges are thus read out via the readout lines.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION An electronic multiplexer converts the electric charges read into an electric signal which represents the density profiles.

[0071] In some embodiments, an alternative detector system comprises a plurality of detector elements. The detector elements include respective scintillators and photosensors. The scintillators convert x-rays in a low-energy radiation such as visible light, ultraviolet radiation or infrared radiation. The photosensors, such as photodiodes and phototransistors, are sensitive for the low-energy radiation from the scintillator. The photosensors derive an electronic signal, such as an electric current or an electric voltage, from the low-energy radiation from the scintillators. Further the detector elements are provided with respective amplifiers which amplifies the electronic signal from the respective photosensors. Preferably, photosensors and their respective associated amplifiers are integrated in semiconductor technology, such as C- MOS on a substrate. In some embodiments of the detector system, the amplifiers are placed in the separate detector elements adjacent to the respective photosensors of which the amplifier amplifies the electronic signal. In another embodiment of the detector system the amplifiers are placed on the boundary of the substrate. The integration of the photosensors and the amplifiers on the same substrate achieves that the parasitic capacitances of the electrical lines that connect the photosensors to the amplifiers are reduced, so that the electrical noise level of the electronic signals that are applied to the amplifiers is reduced. The amplifiers can more specifically be charge-sensitive capacitive feedback amplifiers. Such a be charge-sensitive capacitive feedback amplifier collects electric charge on a feedback capacitor during subsequent integration period and is reset by discharging the feedback capacitor after each integration period. The amplifiers can alternatively be transimpedance amplifiers. Such integrate the input photocurrent from the relevant photosensor and are continuously discharged. Both charge-sensitive capacitive feedback amplifiers and transimpedance amplifiers have a wide dynamic range and are have a highly linear characteristic. Thus, these amplifiers generate amplified electronic signals which have a low noise level and hardly any non-linear distortion, so that these amplified electronic signals can be employed to display the image information with a high diagnostic quality. An electronic multiplexer converts the amplified electric signals into an electric signal which represents the density profiles.

[0072] For individual adjustments of the X-ray collimator it is possible to select substantially parallel cross-sections, having selectable transverse dimensions, for which density profiles are simultaneously measured. It is thus achieved that the dimensions of the part of the subject to be examined for which a volume scan is to be performed in one operation and the spatial resolution are selected by simple adjustment of the X-ray collimator.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0073] In some embodiments, the volume image signal is sent to a display and the image can be manipulated via movement around user-selected axes of a computer program product integrated into the system, spatial selection criteria within the image by user-specific adjustment of image coordinates and editing of the image around certain user-selected coordinates. In some embodiments, methods of the disclosure relate to imaging lung tissue of a subject, editing an image of a subject (including, in some embodiments, contouring of an image); identifying and selecting a region of the lung tissue within the subject with significant emphysematous lung tissue and determining the target volume within the region of significant emphysematous lung tissue.

[0074] The disclosure relates to a system comprising a detector system for generating an image of tissue of a subject; a controller, a storage memory, a display, and a computer program product with instructions for: identifying and selecting a region of the lung tissue within the subject with significant damage of tissue and determining the target volume within the region of significant damage. In some embodiments, the computer program product comprises instructions for: identifying and selecting a region of lung tissue within the subject with significant emphysematous lung tissue and determining the target volume within the region of significant emphysematous lung tissue. In some embodiments, the computer program product comprises instructions for editing the image of the lung tissue and determining in a target volume within the region for targeting administration of one or a plurality of radiation doses. In some embodiments, the computer program product further comprises instructions for selecting the target volume in a subject using a real-time image captured during performance of the method by correlating the target volume selection to a position within the patient selected for radiation treatment during performance of one or a plurality of administration steps.

[0075] Radiation therapy (or each radiation therapy fraction in the case of a fractionated radiation therapy regimen) is administered by a radiation therapy delivery device. In some embodiments, the radiation therapy delivery device is a linear accelerator that generates therapeutic radiation by accelerating electrons to high energy (typically above 1 MeV). The therapeutic radiation may be the high energy electrons, or may be X-rays generated by directing the high energy electron beam to an X-ray generating target such as a tungsten target. In other embodiments, the radiation therapy delivery device may be some other type of particle accelerator, e.g. generating therapeutic radiation in the form of a proton beam, as another non- limiting illustrative example. Preparatory to performing the radiation therapy fraction, the patient is positioned on a solid, patient support. This is done in a precise manner, using fiduciary markers and / or anatomical markers to ensure alignment of the patient anatomy with itsATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION positioning during acquisition of the radiation therapy planning image, and, in some embodiments, may entail applying appropriate restraints to hold the patient in the appropriate position.

[0076] To assist in positioning the patient and to assess whether major changes in patient anatomy have occurred since acquisition of the radiation therapy planning image, an imaging device is configured to image the patient disposed on the patient support of the radiation therapy delivery device. In some embodiments, the imaging device is an MRI, CT scanner or other scanner comprising a CBCT imaging component. In some embodiments, the imaging device is a cone beam computed tomography (CBCT) imaging component of the radiation therapy delivery device, and includes a cone beam X-ray source and an x-ray detector array or panel positioned across the patient support from the X-ray source. A CBCT imaging component has certain advantages - it provides an image which has transmission CT contrast making it directly comparable with the radiation therapy planning image captured at a time period prior to the administration step. However, more generally the imaging device associated with the radiation therapy delivery device may be any medical imaging device capable of acquiring the current image of the patient that can be compared with the radiation therapy planning image.

[0077] As another example, the imaging device associated with the radiation therapy delivery device may be a magnetic resonance imaging (MRI) device, either standalone or integrated with the linac to form an MR-LINAC in which the MR imaging device is part of the LINAC itself. Since MRI does not transmit ionizing radiation into (or through) the subject, it can be used on daily basis to acquire a current image prior to each radiation therapy session without concern about increasing the cumulative radiation dose to the patient. The availability of MR images can be leveraged, and the ART recommendation calculations performed in the background so as to alert the linac operator if something is wrong. As yet another example, the imaging device associated with the radiation therapy delivery device may be an MR / CT imaging device providing both MR and CT imaging modalities, in which the MR and CT images may be aligned or correlated. MR / CT advantageously provides different and sometimes complementary contrast mechanisms that can elucidate more information than either MR or CT alone. The illustrative imaging device associated with the radiation therapy delivery device is a component of the radiation therapy delivery device, e.g. mounted to the housing of the illustrative linac. However, this is not required - in another embodiment, the imaging device associated with the radiation therapy delivery device may be a portable imaging device on a wheeled support, which is rolled over to and aligned with the solid patient support to acquire the image.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0078] In some embodiments, the radiation therapy delivery device and the imaging device are controlled by a console comprising a controller operably linked to a display and one or more user input devices (e.g. a keyboard and trackpad or other pointing device, optionally one or more such user input pointing devices may be implemented by making one or more of the displays a touch-sensitive display). In some embodiments, the console comprises a processor (e.g. microprocessor, microcontroller, et cetera) that reads and executes instructions stored on a non-transitory storage medium to control the radiation therapy delivery device which is operatively connected with the console and to control the imaging device which is operatively connected and in electrical communication with the console, and to perform an adaptive radiotherapy (ART) recommendation method as disclosed herein. In some embodiments, the console is disposed proximate to the radiation therapy delivery device; however, it will be understood that this proximity can be implementation-dependent, and that moreover some components of the console may be located remotely. For example, depending upon radiation exposure control practices, the console may be located in a different room from the radiation therapy delivery device so as to limit the potential for stray radiation exposure to users. The electronic processor and non-transitory storage medium may be located remotely (e.g. implemented at a central hospital server). In some embodiments, console has a “remote app” component, e.g. oncologists associated with the radiation therapy facility may be provided with cellphone, tablet, and / or desktop computer applications (“apps”) that provide for remote review of radiation therapy sessions, any data collection including an image of the tissue or organ of a subject.

[0079] Some methods of the disclosure are performed at the linac console by acquisition of an image is acquired as usual, prior to commencement of delivery of the therapeutic radiation by the linac. Additionally, the radiation therapy planning image is retrieved from the database. Deformable image registration (DIR) and feature contouring processing is performed at the linac console to spatially register the current image with the planning image and to define contours of the tumor and OARs (and / or other features of interest) in the current image. In some embodiments, users of the system, such as the radiation physicist and / or oncologist or other medical professional as part of the radiation treatment planning, optionally contour the image prior to administration of radiation dose and the contours are preferably stored in the database with the image as part of (or as additional data associated with) the stored radiation therapy plan. Thus, in some embodiments, only a second image taken immediately before treatment needs to be contoured. In some embodiments, where two images of the subject tissue are used prior to administration of any radiotherapy, an adaptive radiotherapy recommendationATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION score is computed, which indicates whether adaptive radiotherapy should be performed. The operation includes determining at least one perturbation of the current image compared with the radiation therapy planning image (which, again, was used to generate a radiation therapy plan), and applying the radiation therapy plan-specific perturbation model (PSPM that is specific to the radiation therapy plan for the patient. Each perturbation is determined as a change in the at least one feature contoured in the current image compared with the at least one feature contoured in the spatially registered radiation therapy planning image.

[0080] As previously discussed, the PSPM is functionally dependent on the determined at least one perturbation. In the case of a fractionated radiation therapy regimen, the PSPM may be further functionally dependent on a number of remaining fractions of a fractionated radiation therapy regimen. If the total number of fractions in the regimen is denoted as N and some number n fractions have been performed thus far, then the remaining number of fractions is equal to N-n. For example, if the current radiation therapy session is the first session then n=0 (the ART recommendation method is performed before actually applying therapeutic radiation in the current session, hence no fractions have yet been performed), then the number of remaining fractions 64 is N. In some embodiments, a decision made as to whether ART should be performed is executed by a non-transitory computer programmable product within the system.

[0081] The disclosure relates to a computer program product with instructions for: (a) receiving image data from a subject comprising the degree of emphysematous tissue damage; (b) determining a region within the tissue comprising significant emphysematous tissue; and (c) determining a target volume of tissue within the subject and within the region. In some embodiments, the instructions further comprise a step of: (d) comparing a second set of image data taken prior to step (a) and identifying perturbations between the imaging data of step (a) and the second set of imaging data. In some embodiments, the instruction further comprises a step of: contouring a target volume by correlating the image data from the subject to a set of positions within the subject for administration of treatment; and / or a step of executing a command to administer a dose of radiation at or within the target volume. In some embodiments, the instructions further comprise a step of: adjusting a setting of an X-ray collimator to focus a radiation dose of the subject prior to the step of administration such that (i) a dose of radiation is administered to the subject at the target volume; and (ii) a gradient of radiation at an intermediate dose is administered around the periphery of the target volume.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION In some embodiments, the periphery of the target volume represents a spherical or roughly spherical volume surrounding the target for an ablative dose of radiation. In some embodiments, In some embodiments, the periphery of the target volume represents a spherical or roughly spherical volume surrounding the target for an ablative dose of radiation, such that the longest circumferential dimension around the ablative target tissue is from about 2 centimeters to about 6 centimeters. A non-limiting example of a non-transitory computer program product is depicted in Figure 6, wherein an image of lung tissue is 101 analyzed to identify a target area of the lung comprising emphysematous tissue. In some embodiments, the computer program product analyzes an image supplied by a separate, conventional CT scanning device provided a transmittable file saved in a tangible memory device. After a total target volume is determined 102, in some embodiments, by reviewing the image for perturbations in signal corresponding to emphysematous tissue or tissue presenting with bronchitis, a user of the product can input boundaries within he total target volume to administer the radiation therapy 103. The instructions for the computer program product further comprise a step of calculating the dose distribution concurrently with or after determining ablative and intermediate dose regions of the lung of a subject relative to target and normal tissue constraints within the image. If multiple ablative or intermediate doses are to be administered to a subject, method steps of the instructions may comprise an option to identify and targeting volumes and positioning within the lungs to repeat steps of calculating dose and determining target volume boundaries 103, 104. Finally, instructions of some embodiments may comprise a step of one or a combination of: output of a dose or doses sufficient to affect the ablative and intermediate dose regions of lung of the subject, output of a patient treatment plan comprising the same dose or doses, and, optionally, providing a command to execute the dose or doses of radiation if a system for administering radiation is in operable communication with a memory and controller comprising the non-transitory computer program product.

[0082] In some embodiments, disclosed is a system comprising a disclosed computer program product, and one or more of: (a) a processor operable to execute programs; and (b) a memory associated with the processor.

[0083] Further, it should be appreciated that a computer may be embodied in any of a number of forms, such as a rack-mounted computer, a desktop computer, a laptop computer, or a tablet computer. Additionally, a computer may be embedded in a device not generally regarded as a computer but with suitable processing capabilities, including a Personal Digital Assistant (PDA), a smart phone, or any other suitable portable or fixed electronic device.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0084] Also, a computer may have one or more input and output devices. These devices can be used, among other things, to present a user interface. Examples of output devices that can be used to provide a user interface include printers or display screens for visual presentation of output and speakers or other sound generating devices for audible presentation of output. Examples of input devices that can be used for a user interface include keyboards, and pointing devices, such as mice, touch pads, and digitizing tablets. As another example, a computer may receive input information through speech recognition or in other audible format.

[0085] Such computers may be interconnected by one or more networks in any suitable form, including a local area network or a wide area network, such as an enterprise network, and intelligent network (IN) or the Internet. Such networks may be based on any suitable technology and may operate according to any suitable protocol and may include wireless networks, wired networks, or fiber optic networks.

[0086] A computer employed to implement at least a portion of the functionality described herein may include a memory, coupled to one or more processing units (also referred to herein simply as “processors”), one or more communication interfaces, one or more display units, and one or more user input devices. The memory may include any computer-readable media, and may store computer instructions (also referred to herein as “processor-executable instructions”) for implementing the various functionalities described herein. The processing unit(s) may be used to execute the instructions. The communication interface(s) may be coupled to a wired or wireless network, bus, or other communication means and may therefore allow the computer to transmit communications to and / or receive communications from other devices. The display unit(s) may be provided, for example, to allow a user to view various information in connection with execution of the instructions. The user input device(s) may be provided, for example, to allow the user to make manual adjustments, make selections, enter data or various other information, and / or interact in any of a variety of manners with the processor during execution of the instructions.

[0087] The various methods or processes outlined herein may be coded as software that is executable on one or more processors that employ any one of a variety of operating systems or platforms. The disclosure also relates to a computer readable storage medium comprising executable instructions. Additionally, such software may be written using any of a number of suitable programming languages and / or programming or scripting tools, and also may be compiled as executable machine language code or intermediate code that is executed on a framework or virtual machine.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0088] In this respect, embodiments of the disclosure include computer readable storage medium (or multiple computer readable storage media) (e.g., a computer memory, one or more floppy discs, compact discs, optical discs, magnetic tapes, flash memories, circuit configurations in Field Programmable Gate Arrays or other semiconductor devices, or other non-transitory medium or tangible computer storage medium) encoded with one or more non- transitory programs that, when executed on one or more computers or other processors, perform methods that implement the various embodiments disclosed herein. The computer readable medium or media can be transportable, such that the program or programs stored thereon can be loaded onto one or more different computers or other processors to implement various aspects of the present invention as discussed above. In some embodiments, the system comprises cloud-based software that executes one or all of the steps of each disclosed method instruction.

[0089] The terms “program” or “software” are used herein in a generic sense to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computer or other processor to implement various aspects of embodiments as discussed above. Additionally, it should be appreciated that according to one aspect, one or more computer programs that when executed perform methods of the present disclosure need not reside on a single computer or processor, but may be distributed in a modular fashion amongst a number of different computers or processors to implement various aspects of the present invention.

[0090] Computer-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types. Typically, the functionality of the program modules may be combined or distributed as desired in various embodiments.

[0091] Also, data structures may be stored in computer-readable media in any suitable form. For simplicity of illustration, data structures may be shown to have fields that are related through location in the data structure. Such relationships may likewise be achieved by assigning storage for the fields with locations in a computer-readable medium that convey relationship between the fields. However, any suitable mechanism may be used to establish a relationship between information in fields of a data structure, including through the use of pointers, tags or other mechanisms that establish relationship between data elements.

[0092] Also, the disclosure relates to various embodiments in which one or more methods. The acts performed as part of the method may be ordered in any suitable way. Accordingly,ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0093] Computer-implemented embodiments of the disclosure relate to methods of determining a target volume of tissue in a subject to irradiate comprising steps of: (a) acquiring a first and second image of tissue of a subject (b) classifying a region of tissue as significantly emphysematous based upon results of comparing of the first and second image relative to the first and / or second threshold of emphysematous tissue.

[0094] In some embodiments, the disclosure relates to a system that comprises at least one processor, a program storage, such as memory, for storing program code executable on the processor, and one or more input / output devices and / or interfaces, such as data communication and / or peripheral devices and / or interfaces. In some embodiments, the user device and computer system or systems are communicably connected by a data communication network, such as a Local Area Network (LAN), the Internet, or the like, which may also be connected to a number of other client and / or server computer systems. The user device and client and / or server computer systems may further include appropriate operating system software. In some embodiments, the system comprises a processor comprising a computer program product for calculating the alignment of known telomeric repeat sequences to the data from a sample registered with the computer program product. In some embodiments, the system comprises a device that interacts with one or more communication channels or mediums or links, such that alignment processes for telomere sequences of a sample are compared to control sequences stored on a memory and shared with a network in operable communication with the device.

[0095] In some embodiments, components and / or units of the devices described herein may be able to interact through one or more communication channels or mediums or links, for example, a shared access medium, a global communication network, the Internet, the World Wide Web, a wired network, a wireless network, a combination of one or more wired networks and / or one or more wireless networks, one or more communication networks, an a-synchronic or asynchronous wireless network, a synchronic wireless network, a managed wireless network, a non-managed wireless network, a burstable wireless network, a non-burstable wireless network, a scheduled wireless network, a non-scheduled wireless network, or the like.

[0096] Discussions herein utilizing terms such as, for example, “processing,” “computing,” “calculating,” “determining,” or the like, may refer to operation(s) and / or process(es) of a computer, a computing platform, a computing system, or other electronic computing device, that manipulate and / or transform data represented as physical (e.g., electronic) quantitiesATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION within the computer's registers and / or memories into other data similarly represented as physical quantities within the computer’s registers and / or memories or other information storage medium that may store instructions to perform operations and / or processes.

[0097] Some embodiments may take the form of an entirely hardware embodiment, an entirely software embodiment, or an embodiment including both hardware and software elements. Some embodiments may be implemented in software, which includes but is not limited to firmware, resident software, microcode, or the like.

[0098] Furthermore, some embodiments may take the form of a computer program product accessible from a computer-usable or computer-readable medium providing program code for use by or in connection with a computer or any instruction execution system. For example, a computer-usable or computer-readable medium may be or may include any apparatus that can contain, store, communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device.

[0099] In some embodiments, the medium may be or may include an electronic, magnetic, optical, electromagnetic, InfraRed (IR), or semiconductor system (or apparatus or device) or a propagation medium. Some demonstrative examples of a computer-readable medium may include a semiconductor or solid state memory, magnetic tape, a removable computer diskette, a Random Access Memory (RAM), a Read-Only Memory (ROM), a rigid magnetic disk, an optical disk, or the like. Some demonstrative examples of optical disks include Compact Disk- Read-Only Memory (CD-ROM), Compact Disk-Read / Write (CD-R / W), DVD, or the like.

[0100] In some embodiments, a data processing system suitable for storing and / or executing program code may include at least one processor coupled directly or indirectly to memory elements, for example, through a system bus. The memory elements may include, for example, local memory employed during actual execution of the program code, bulk storage, and cache memories which may provide temporary storage of at least some program code in order to reduce the number of times code must be retrieved from bulk storage during execution.

[0101] In some embodiments, input / output or I / O devices (including but not limited to keyboards, displays, pointing devices, etc.) may be coupled to the system either directly or through intervening I / O controllers. In some embodiments, network adapters may be coupled to the system to enable the data processing system to become coupled to other data processing systems or remote printers or storage devices, for example, through intervening private or public networks. In some embodiments, modems, cable modems and Ethernet cards are demonstrative examples of types of network adapters. Other suitable components may be used.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0102] Some embodiments may be implemented by software, by hardware, or by any combination of software and / or hardware as may be suitable for specific applications or in accordance with specific design requirements. Some embodiments may include units and / or sub-units, which may be separate of each other or combined together, in whole or in part, and may be implemented using specific, multi-purpose or general processors or controllers. Some embodiments may include buffers, registers, stacks, storage units and / or memory units, for temporary or long-term storage of data or in order to facilitate the operation of particular implementations.

[0103] Some embodiments may be implemented, for example, using a machine-readable medium or article which may store an instruction or a set of instructions that, if executed by a machine, cause the machine to perform a method steps and / or operations described herein. Such machine may include, for example, any suitable processing platform, computing platform, computing device, processing device, electronic device, electronic system, computing system, processing system, computer, processor, or the like, and may be implemented using any suitable combination of hardware and / or software. The machine- readable medium or article may include, for example, any suitable type of memory unit, memory device, memory article, memory medium, storage device, storage article, storage medium and / or storage unit; for example, memory, removable or non-removable media, erasable or non-erasable media, writeable or re-writeable media, digital or analog media, hard disk drive, floppy disk, Compact Disk Read Only Memory (CD-ROM), Compact Disk Recordable (CD-R), Compact Disk Re-Writeable (CD-RW), optical disk, magnetic media, various types of Digital Versatile Disks (DVDs), a tape, a cassette, or the like. The instructions may include any suitable type of code, for example, source code, compiled code, interpreted code, executable code, static code, dynamic code, or the like, and may be implemented using any suitable high-level, low-level, object-oriented, visual, compiled and / or interpreted programming language, e.g., C, C++, Java™, BASIC, Pascal, Fortran, Cobol, assembly language, machine code, or the like.

[0104] A circuit may also be implemented in programmable hardware devices such as field programmable gate arrays, programmable array logic, programmable logic devices or the like.

[0105] In some embodiment, the circuits may also be implemented in machine-readable medium for execution by various types of processors. An identified circuit of executable code may, for instance, comprise one or more physical or logical blocks of computer instructions, which may, for instance, be organized as an object, procedure, or function. Nevertheless, the executables of an identified circuit need not be physically located together, but may compriseATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION disparate instructions stored in different locations which, when joined logically together, comprise the circuit and achieve the stated purpose for the circuit. In some embodiments, a circuit of computer readable program code may be a single instruction, or many instructions, and may even be distributed over several different code segments, among different programs, and across several memory devices. Similarly, operational data may be identified and illustrated herein within circuits, and may be embodied in any suitable form and organized within any suitable type of data structure. The operational data may be collected as a single data set, or may be distributed over different locations including over different storage devices, and may exist, at least partially, merely as electronic signals on a system or network.

[0106] The computer readable medium (also referred to herein as machine-readable media or machine-readable content) may be a tangible computer readable storage medium storing the computer readable program code. The computer readable storage medium may be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, holographic, micromechanical, or semiconductor system, apparatus, or device, or any suitable combination of the foregoing. As alluded to above, examples of the computer readable storage medium may include but are not limited to a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), a portable compact disc read-only memory (CD-ROM), a digital versatile disc (DVD), an optical storage device, a magnetic storage device, a holographic storage medium, a micromechanical storage device, or any suitable combination of the foregoing. In the context of this document, a computer readable storage medium may be any tangible medium that can contain, and / or store computer readable program code for use by and / or in connection with an instruction execution system, apparatus, or device.

[0107] The computer readable medium may also be a computer readable signal medium. A computer readable signal medium may include a propagated data signal with computer readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electrical, electro-magnetic, magnetic, optical, or any suitable combination thereof. A computer readable signal medium may be any computer readable medium that is not a computer readable storage medium and that can communicate, propagate, or transport computer readable program code for use by or in connection with an instruction execution system, apparatus, or device. As also alluded to above, computer readable program code embodied on a computer readable signal medium may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, Radio FrequencyATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION (RF), or the like, or any suitable combination of the foregoing. In one embodiment, the computer readable medium may comprise a combination of one or more computer readable storage mediums and one or more computer readable signal mediums. For example, computer readable program code may be both propagated as an electro-magnetic signal through a fiber optic cable for execution by a processor and stored on RAM storage device for execution by the processor.

[0108] Computer readable program code for carrying out operations for aspects of the present disclosure may be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the “C” programming language or similar programming languages. The computer readable program code may execute entirely on a user's computer, partly on the user’s computer, as a stand-alone computer-readable package, partly on the user’s computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user’s computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).

[0109] The program code may also be stored in a computer readable medium that can direct a computer, other programmable data processing system, or other devices to function in a particular manner, such that the instructions stored in the computer readable medium produce an article of manufacture including instructions which implement the function / act.

[0110] The disclosure relates to methods of treating a subject. In some embodiments, the subject has a BODE score from about 3 to about 8. The BODE score may be at or above about 5. In some embodiments, the subject has been diagnosed with severe emphysema. In some embodiments, the subject is diagnosed with a significant amount of parenchyma in the lung tissue.

[0111] The method may be conducted without accompanying surgical interventions. Alternatively, the method may be conducted in conjunction with surgical intervention.

[0112] The disclosure relates to methods of treating emphysema in a subject in need thereof. The method comprises establishing a volume for reduction in emphysematous lung tissue in the subject, delineating a planning target volume for reduction within the volume for reduction, and irradiating the planning target volume with a dose of radiation. In some embodiments, the methods include a method of treating severe emphysema. The disclosure also relates to methods of treating bronchitis in a subject in need thereof. The method comprisesATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION establishing a volume for reduction in lung tissue in the subject, delineating a planning target volume for reduction within the volume for reduction, and irradiating the planning target volume with a dose of radiation. The disclosure also relates to a method of inducing fibrosis of lung tissue in a subject in need thereof. The method comprises establishing a volume for reduction in lung tissue in the subject, delineating a planning target volume for the reduction within the volume for reduction, and irradiating the planning target volume with a dose of radiation. Any of the aforementioned methods may comprise administration steps wherein doses of radiation are administered to the subject in any of the values provided herein. In some embodiments, the any of the aforementioned methods comprise administering at least one ablative dose and at least one intermediate dose of radiation around the target volume receiving the ablative dose.

[0113] In some embodiments, the target volume is from about 5% to about 25% of the total lung volume of the subject. In some embodiments, the target volume is about 10% of total lung volume of the subject. The planning target volume may less than about 30 cc. In some embodiments, the dose is about 45 Gy in administered in one, two or three fractions. In some embodiments, the emphysematous lung tissue includes a region of most emphysematous lung tissue and the planning target volume may be within the region of most emphysematous lung tissue. In some embodiments, the method further comprises a step of identifying the most emphysematous lung tissue on one or more computed tomography scan images of the subject, manually contouring the images, and editing the images to form the target volume for reduction within the most emphysematous lung tissue.

[0114] An embodiment comprises as system that comprises an imaging device, a beam source, a memory storing processor-executable instructions, and a processor configured to execute the processor executable instructions. The processor executable instructions may comprise instructions for: establishing a volume for reduction in emphysematous lung tissue in the subject, delineating a planning target volume for reduction within the volume; and irradiating the planning target volume with a dose of radiation from the beam source. In some embodiments, the instructions may further comprise defining the target volume as about 10% of total lung volume of the subject and the planning target volume as equal to or less than about 30 cc of total lung volume.

[0115] The instructions for irradiating may comprise instructions for irradiating a dose of about 45 Gy in three fractions. The instructions may be for a dose from about 35 to about 55 Gy. The instructions may be for a dose of about 35, 40, 45, 50, or 55 Gy. The instructions may be for a dose from about 40 to about 50 Gy. The instructions may be to administer the dose aATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION total of about 3 times over a week. In some embodiments, the dose may be administered a total of three times, once per day for three consecutive days.

[0116] The instructions may further include instructions for administering to the subject an intermediate dose of radiation around the periphery of the target volume of lung tissue. The instructions may achieve the intermediate dose by instructing administration of a high dose to the target volume, which results in the intermediate dose being delivered around the periphery of the target volume. The intermediate dose of radiation around the periphery of the target volume of lung tissue comprises a decreasing gradient of radiation as the distance from a center point of target volume is increased. The center point of the target volume is, in some embodiments, a position centrally located within target volume with a highest level of emphysematous tissue density relative to the other regions with the region of significant emphysematous tissue. In some embodiments, the intermediate dose of radiation is caused by residual exposure to one focal dose of radiation administered to the subject with expected gradient exposure on the periphery of the target volume of the lung due natural degradation of the of radiation intensity around the site of administration. In some embodiments, methods of the disclosure relate to administering one focal dose of radiation to the target volume and administering one or a plurality of smaller, less intense doses of radiation in the target volume periphery. In such embodiments, the step of administering radiation to the subject is repeated such that the doses of radiation are a total of about 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses per subject per visit to a clinic. In some embodiments, the method comprises a single administration step per subject per visit to a clinic, however, the same does is administered in about 2, 3, or 4 visits to a clinic in three day, seven day, ten day or 14 day intervals.

[0117] The instructions may further comprise determining a region of most emphysematous lung tissue within the emphysematous lung tissue includes and defining the planning target volume within the region of most emphysematous lung tissue.

[0118] The instructions may comprise identifying the most emphysematous lung tissue on one or more computed tomography scan images of the subject, contouring the images, and editing the images to form the target volume for reduction within the most emphysematous lung tissue.

[0119] Methods and systems herein may incorporate devices, methods, and system utilized in stereotactic ablative radiotherapy (SBRT) and adapt them to stereotactic irradiation for lung volume reduction (SILVR). The embodiments of methods and systems herein may be implemented for SILVR.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0120] Briefly, the SILVR devices, methods, and systems may be characterized as including patient immobilization, target localization and tracking software, limiting normal tissue exposure to high-dose radiation, preventing or accounting for organ motion (e.g., respiratory motion), the use of stereotaxy, and the subcentimeter accuracy of the delivered dose. Factors used to determine if SILVR may an appropriate procedure may include the extent and character of chronic obstructive pulmonary disorder. Non-limiting factors are presented in the example section, below. Components of a SILVR procedure may include target delineation, a simulation study, treatment planning, and treatment delivery. The treatment team may include one or more of a physician, a pulmonologist, a medical physicist, a radiation therapist, and, depending on the body site and indication, a diagnostic radiologist, nurse, anesthetist, and dosimetrist as needed.

[0121] In some embodiments, a simulation study may be performed for SILVR with computed tomography (CT) prior to the treatment planning. The CT table matches the treatment table and the dataset is then imported into the treatment-planning system. In some embodiments, treatment planning includes patient marking (e.g., tattoos, fiducials), preplanning imaging, plan development, and patient positioning. Along with CT simulation images, the treatment-planning system may also import and fuse diagnostic magnetic resonance imaging (MRI), positron emission tomography (PET), combined PET / CT, angiography images, single-photon emission computed tomography (SPECT), Xenon MRI, Xenon-enhanced computed tomography (Xe / CT), and / or single-inhalation, single-energy XeCT with the CT simulation images to add functional data to optimize the treatment plan. In some embodiments, the treatment-planning system comprises Xe The treatment team develops a plan for the procedure using software to select the shape, size, intensity, and entry point of the radiation beam to treat the targeted tumor. In some embodiments, treatment planning comprises Xenon MRI, Xe / CT, and / or single-inhalation, single-energy XeCT. In some embodiments, Xe / CT comprises multiple breathhold technique in which patients inhale xenon for a period of time; for example, about 1 to about 2 minutes, to reach equilibrium before image acquisition and xenon washout. In some embodiments, single-inhalation, single-energy Xe / CT comprises increasing the relative xenon concentration; for example by a factor of about two relative to prior Xe / CT, but reducing the xenon exposure time; for example, to a single breath- hold duration before image acquisition and xenon washout. Methods of single-inhalation, single-energy XeCT are described in Pinkham, D. W. et al. “A Feasibility Study of Single- inhalation, Single-energy Xenon-enhanced CT for High-resolution Imaging of Regional LungATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION Ventilation in Humans” (2018) Acad. Radiol. 26: 38–49, which is incorporated herein by reference in its entirety.

[0122] In some embodiments, methods of the disclosure relate to methods of treating hyperinflation of the lung and / or emphysema in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of radiation further comprising determining the target lung volume before administering to the subject by:

[0123] (i) imaging the lung tissue of the subject;(ii) identifying a region of the lung tissue with significant emphysematous lung tissue; and (iii) determining the target volume within the region of significant emphysematous lung tissue, wherein the step of imaging the lung tissue comprises imaging by CT scan or MRI. In some embodiments, the step of imaging is performed by Xenon MRI, Xe / CT, and / or single-inhalation, single-energy XeCT. In some embodiments the step of identifying and / or determining comprises performing a computer-implemented method of visualizing a digital image of the lung of the subject and selecting a region of the digital image that corresponds to the region of emphysematous tissue in the subject with a manipulable cursor or selection tool on a display in digital communication with a controller, memory, user device all operably linked to an imaging device comprising a computer program product configured to capture an image of the lung tissue of a subject. In some embodiments, steps (i), (ii), (iii), (i) and (ii), (i) and (iii), or (ii) and (iii) are performed in part of by computer program product with executable instructions to generate and manipulate an image of subject tissue. In some embodiments, steps (i), (ii), (iii), (i) and (ii), (i) and (iii), or (ii) and (iii) are performed in part of by computer program product operably linked to a system configured to dispense hyperpolarized gas into a subject by inhalation. In some embodiments, steps (i), (ii), (iii), (i) and (ii), (i) and (iii), or (ii) and (iii) are performed at least in part by a system configured to dispense hyperpolarized gas into a subject by inhalation. In some embodiments, the system is disclosed in WO2024205826, which is incorporated by reference in its entirety. Briefly, methods of the disclosure relate to image generation and / or calculation of lung volume of the subject comprising a gas dispensing control system using a gas expansion chamber to measure volumes of gas dispensed to a dose container for medicinal use based in part on measured local atmospheric conditions. Embodiments of the present invention provide an automated system with a display panel and graphic user interface with defined control inputs and status indicators for various actions associated with a gas control dispensing system particularly suitable for dispensing medical grade hyperpolarized gas or gas mixtures. Still other aspects are directed to a flow-through spin exchange optical pumping (SEOP) hyperpolarized gas production system for producing hyperpolarized gas that includes: a pressurized gas mixture; a flow-ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION through optical pumping cell in fluid communication with the pressurized gas mixture; and an automated gas dispensing control system with a large volume expansion chamber enclosing a plunger (floatable piston) downstream of and in fluid communication with the flow-through optical pumping cell. The flow-through SEOP gas production system can further include a flexible patient dose delivery bag downstream of the dispensing system configured to receive an inhalable bolus of hyperpolarized129Xe gas.

[0124] Target motion with natural physiologic processes (e.g., respiration) may be considered. Techniques used to assist in decreasing organ or body motion may be utilized and may include full body immobilization (e.g., vacuum pillows), abdominal compression devices, breath-hold techniques, gating, and tracking methods. Delivering a high precision dose in the setting of fractionated stereotactic radiotherapy has led to the development of image-guided radiotherapy. SILVER devices, methods, and systems can use image guidance (kV or MV5 x- ray imaging, CT, ultrasound) to intermittently monitor the position of the target by tracking bony structures or implanted fiducials. Imaging may also visualize soft tissues (e.g., lung, or lung portions) with or without referencing bony structures or fiducials. Before treatment begins the patient may be positioned on the treatment couch with or without an immobilization device and reoriented to the SILVR system.

[0125] In order to deliver treatment accurately in accordance with the treatment plan, the patient may be accurately positioned on the treatment system. On-board CT images or x-ray images may be acquired with the patient positioned on the treatment couch and these images are compared with the treatment plan images to ensure a match between the planning geometry and the treatment geometry. If the geometries do not match, the treatment table may be adjusted so that the treatment geometry then accurately aligns with the planned geometry.

[0126] Amedical linear accelerator (linac) may be used for the delivery of SILVR. A linac emits x-ray photon radiation with typical energies ranging from about 6 to about 10 MV for SILVR. The angle of the radiation beam can be changed by either the rotation of the linac gantry or by the movement of a linac mounted to a robotic arm. The treatment table can also be adjusted to allow changes in the angle of the delivery beams. EXAMPLES

[0127] Based on the fibrotic scarring that occurs following lung irradiation, and with stereotactic ablative radiotherapy (SABR) in particular, (11,12) it was hypothesized that SABR would create LVR in patients with COPD, and that this might be used therapeutically. One study from 1977 reported mainly subjective improvements after intentional, traditionalATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION radiotherapy in emphysema.13Prior studies have reported that among patients with lung cancer treated with SABR, many of whom had COPD, there is indeed a relationship between the radiation dose-volume and the amount of lung volume reduction observed,14and a suggestion of an associated improvement in pulmonary function.(15,16). Based upon these findings, it was envisioned that targeting areas of parenchymal destruction and hyper-expansion in patients with emphysema, as one does during LVRS, but using SABR, would create LVR that may translate into clinical benefits in appropriately selected patients. Therefore, a prospective, phase 1, single-arm clinical trial was initiated of SILVR in patients with severe emphysema who were suboptimal candidates for LVRS / EBVs, with safety (incidence of grade≥3 adverse events) as the primary outcome. Secondarily, functional efficacy of SILVR was explored by certain descriptive metrics.

[0128] Stereotactic Irradiation for Lung Volume Reduction (SILVR) may represent an alternative to Endobronchial Valves and Lung Volume Reduction Surgery for patients with severe emphysema. This study shows safety / efficacy, particularly in patients with lower BODE index, homogeneous disease, and / or less parenchymal destruction.

[0129] Eligible patients with emphysema were prospectively treated with unilateral Stereotactic Ablative Radiotherapy (45 Gy in 3 fractions) to a target within the most emphysematous region. Outcomes were collected for 18 months.

[0130] Eight subjects received the intervention. Median (range) baseline characteristics were age 73 years (63-78), FEV1% 28.5% (19.0-42.0), DLCO% 40% (24.0-67.0), and BODE index 5.5 (5-9). The incidence of grade≥3 adverse events was 3 / 8 (37.5%). The relative Δtarget lobe volume was -23.1% (-1.6,-41.5) and -26.5% (-20.6,-40.8) at six and 18 months, respectively. Absolute ΔFEV1% was greater in subjects with BODE index ≤5 vs. ≥6 (+12.0% vs. -2.0%). The mean baseline lung density (in Hounsfield units, reflecting the amount of preserved parenchyma) within the intermediate dose volume (V60BED3) correlated with the absolute Δtarget lobe volume at 18 months.

[0131] Stereotactic Irradiation for Lung Volume Reduction appears to be safe, with a signal for efficacy as a novel therapeutic alternative for patients with severe emphysema. SILVR may be most safe / effective in patients with lower BODE index and / or less parenchymal destruction. Methods Study design and patients

[0132] Subjects were offered enrollment after being deemed poor candidates for LVRS (and later, EBVs) during evaluation in thoracic surgical clinics but meeting study inclusion / exclusion criteria (Table 1).ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION Table 1 — Inclusion and exclusion criteria for the SILVR trial Inclusion criteria Exclusion criteria Severe COPD with a severe reduction in Predominant chronic bronchitis (none or mild quality of life due to dyspnea emphysematous destruction of lung on chest CT) Moderate to Severe emphysematous Pulmonary function tests / lung volumes that destruction of lung parenchyma on chest CT do not meet inclusion criteria FEV1% <45% predicted and ≥18% predicted Active coronary ischemia (stress test required if clinical symptoms) FEV1 / FVC <0.7 Inability to complete 16 sessions of pulmonary rehabilitation DLCO% ≥18% predicted Pregnancy Residual Volume ≥160% predicted (by plethysmography) Arterial blood gases: paO2 ≥40 on room air Arterial blood gases: paCO2<55 on room air Revised criteria after DSMB interim review* Unilateral only for the entire cohort n=10 Steroid pulses or hospital admissions within 3 months of the study intervention Cardiac left ventricular ejection fraction ≥40% Arterial blood gas: paO2≥58 on room air COPD = chronic obstructive pulmonary disease, CT = computed tomography; FEV1% = forced expiratory volume in the first second (% of predicted value); FVC = forced vital capacity; DLCO% = diffusing capacity of the lungs for carbon monoxide (% of predicted value); SILVR = Stereotactic Irradiation for Lung Volume Reduction; DSMB = Data Safety and Monitoring Board. *The DSMB met after the incidence of grade ≥3 adverse events and revised the inclusion criteria to be somewhat more stringent. The initial protocol planned 5 unilateral, then potentially 5 bilateral SILVR subjects.

[0133] Subjects underwent 16 sessions of pulmonary rehabilitation and optimization of medical management in accordance with Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines before receiving the experimental intervention. All subjects underwent a diagnostic computed tomography (CT) of the chest within 6 months of enrollment. Despite most having a relatively homogeneous distribution of emphysema, the SILVR therapyATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION was designed to target any patchy areas of more severe parenchymal destruction, during a multidisciplinary review by the senior author thoracic surgeon and radiation oncologist.

[0134] The study was conducted under the close supervision of an independent Data and Safety Monitoring Board (DSMB) in accordance with the protocol. At one of the scheduled DSMB meetings, a review of adverse events led to several changes in the inclusion criteria (Table 1). Table 2 provides baseline subject characteristics. Table 2 — A summary of Pulmonary function tests, CT Volumetry results, and Quality of Life outcomes stratified by BODE index at 6 months. Overall BODE ≤5 BODE ≥6 Characteristic Median (range) Median (range) Median (range) n = 8 n = 4 n = 4 Target lobe V60BED3(%) 9.1 (6.6, 11.3) 8.29 (6.8, 9.8) 10.7 (6.6, 11.3) 1 +5.0 (-3.0, Absolute ΔFEV % (%) +18.0)+12.0 (+7.0, +18.0) -2.0 (-3.0, +3.0)Relative ΔFEV1% (% of +14.1 (-16.7, baseline)+30.5)+27.5 (+17.1, +30.5) -9.2 (-16.7, +11.1)Absolute ΔDLCO% (%)-8.0 (-20.0,+11.0) +3.5 (-19.0, +11.0) -11.0 (-20.0, -8.0)Relative ΔDLCO% (% of -17.3 (-54.0, baseline)+45.8)-8.5 (-28.3, +45.8) -45.8 (-54.0, -17.3)Absolute Δtarget lobevolume (%TLV)-5.4 (-7.8, -8.2) -6.8 (-4.7, -8.2) -1.6 (-0.3, -5.9)Relative Δtarget lobe -23.1 (-1.7, - volume (% of baseline)32.5)-28.4 (-23.1, -41.5) -4.9 (-1.7, -23.1)Absolute Δadjacent lobe +3.04 (-4.4, expansion (%TLV)+7.2)+3.9 (+0.5, +7.2) +0.2 (-4.4, +4.2)Relative Δadjacent lobe +11.3 (-13.1, expansion (% of baseline)+41.8)+16.3 (+1.5, +41.8) +1.2 (-13.2, +20.1)Absolute ΔPCS score of SF- -2.4 (-19.8, 36+7.9)+2.5 (-19.7, +7.9) -5.6 (-9.9, -2.3)Absolute ΔMCS score of SF- +6.1 (-10.6, 36+9.5)+6.2 (-0.7, +9.5) -6.8 (-10.6, +9.3)Values are Median (range). BODE = BMI, Obstruction (FEV1%), Dyspnea grade, Exercise capacity (6MWD); V60BED3= Volume of lung receiving aATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION biologically equivalent dose of 60 gray or more (as a % of TLV); FEV1% = Forced Expiratory Volume in one second % of predicted value; FEV1(L) = Forced Expiratory Volume in one second in Liters; DLCO% = Diffusion capacity of lungs for carbon monoxide % of predicted value; Δ = change from baseline value; Relative Δ = relative change from baseline value as a proportion of baseline value; %TLV = value as a percentage of total lung volume; PCS = Physical component summary; SF = Short Form – 36; MCS = Mental component summary.

[0135] Clinical studies exploring secondary outcomes of efficacy were planned over 18 months of post-SILVR follow-up (Figure 1). This included measurement of radiological lung volume changes by CT volumetry, pulmonary function tests (PFTs), six-minute walk test (6MWT), and subjective symptom and quality-of-life scores by the St. George’s Respiratory Questionnaire and the Short Form-36 (SF-36) Health Survey, respectively.

[0136] SILVR treatment planning and technique

[0137] All patients underwent a treatment planning CT acquired at natural end-expiration breath hold (1.25-mm slice thickness) in the Department of Radiation Oncology, which was used to determine the SILVR target. The concept of SILVR target definition was derived from the inventors’ experience in stereotactic ablative radiotherapy (SABR) for lung tumors, in which a small target volume within the lung (i.e., the tumor) receives a high ablative dose of radiation surrounded by a dose gradient region in which the dose falls off with distance from the target. Consequently, a zone of lung tissue around the target receives an intermediate dose. A prior study on lung tumors treated with SABR found that the volume reduction in the treated lobe was closely associated with the volume receiving a biologically effective dose (BED3, using the linear-quadratic model with α / β=3 for late effects) of ≥60 Gy (V60BED3). (14) When treatment is delivered in 3 fractions, a BED3of 60 Gy corresponds to a physical dose of 19.2 Gy, which is substantially lower than the tumor prescription dose. This suggests that the portion of the lung undergoing volume reduction after SABR corresponds to an intermediate dose zone around the high dose target. Furthermore, to limit the risk of subacute radiation pneumonitis, clinical trials of SABR for lung tumors typically constrain the volume of lung tissue receiving ≥20 Gy (V20) in three fractions to no more than 10% of the total lung volume (TLV). (17,18,19) The approach was to create an analogous heterogeneous dose distribution in which there would be a small target receiving an ablative dose surrounded by an intermediate dose zone corresponding to the region of the lung to be volume-reduced.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0138] The target for LVR was defined through a multidisciplinary review by a thoracic surgeon (JBS) and a radiation oncologist (BWL) as follows. While none of the subjects strictly met the NETT trial criteria for upper lobe predominant (heterogeneous) disease, all subjects nevertheless had regions that could be identified on CT scan as having at least slightly greater emphysematous destruction than other areas. These areas were selected to be the target without regard to left vs. right side or upper vs. lower lobe. This most emphysematous portion of the lung was manually contoured on the CT images, then edited to occupy approximately 10% of TLV to form the target for volume reduction (TVR). Within this volume, a smaller planning target volume (PTV) was delineated, generally <30 cc in volume, to receive the prescribed dose of 45Gy in 3 fractions. During radiotherapy planning, the PTV could be modified iteratively such that the V20 (which is also close to the V19.2=V60BED3) was simultaneously <10% TLV while conforming approximately to the TVR, such that the V20was typically about 6-10% of TLV. The treatment planning and delivery techniques were published protocols of SABR for lung tumor. (17,20)

[0139] CT-based volumetry and dosimetric analysis

[0140] The treatment planning CT scans, acquired at end-expiration, were used to quantify the baseline volume of the treated / target lobes within two weeks prior to SILVR. Since these baseline scans were compared to post-SILVR scans which had varying inhalation volumes, the lobar volumes were computed as volumes relative to the total lung volume (TLV), a method validated by a prior study to provide a consistent metric. (14)

[0141] Lung lobes were manually contoured on axial CT slices at treatment planning and follow-up time points using lung window settings (window=1400HU, level=-500HU) by a single observer blinded to clinical outcomes (DNK) using the MIM Maestro software suite, version 7.1.2 (Cleveland, OH) and validated by an experienced thoracic radiation oncologist (MSB). V60BED3, defined above, was measured as a percentage of TLV from the dose-volume histograms of the radiotherapy treatment plan.

[0142] Outcome measures

[0143] The primary outcome was safety, evaluated primarily by the incidence of grade ≥3 adverse events over the follow-up period of 18 months, as graded by the National Cancer Institute Clinical Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. All adverse events were classified as definitely, probably, possibly, unlikely, or unrelated to the treatment.

[0144] FIG. 1 shows the studies planned to preliminarily explore the secondary outcomes i.e., efficacy of the intervention. These were selected to evaluate pulmonary function,ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION radiological response, exercise capacity, dyspnea, and quality of life over 18 months following intervention. The SF-36 Health Survey responses are reported as physical component summary (PCS) and mental component summary (MCS) scores computed using well-validated methods. (21,22,23)

[0145] Although not a predefined outcome, the BODE index (Table 2) was explored as a prognostic tool for these patients.24In this post-hoc analysis, patients were divided by the median value of the cohort into subgroups of ≤5 and ≥6 BODE index and compared for efficacy. The BODE index is a composite score on a scale of 0-10 based on Body Mass Index (BMI), Obstruction (FEV1% predicted), Dyspnea (grading by Modified Medical Research Council (mMRC) dyspnea scale), and Exercise capacity (6-minute walk test).

[0146] Statistical analysis

[0147] Descriptive statistics were used for baseline variables. Continuous data were presented as median (range) due to the skewed distribution of the small sample. Categorical data were presented as frequency and proportions. Terms employing Δ (delta) were used to represent changes in outcome measures from baseline: the term absoluteΔ was used to denote when changes were measured as an absolute difference [current minus baseline]; the term relativeΔ was used when changes measured as a proportion of baseline [(current minus baseline) / baseline]. The median follow-up period was calculated using the reverse Kaplan- Meier method. Correlations between continuous independent and dependent variables of interest were represented using scatter plots. All statistical analyses were performed using SPSS (version 28.0, IBM Corp., Armonk, NY, USA). All tests were two-sided. The ggplot2 package of R version 4.2.2 was used for data visualization. RESULTS:

[0148] Patient demographics and treatment characteristics

[0149] 20 patients with severe emphysema were screened for enrollment. Among them, nine were enrolled, with eight ultimately receiving the study intervention. One subject died due to unrelated causes prior to receiving the intervention. The reasons for exclusion are presented in the CONSORT flow diagram (Fig. 2). The most common contributors to LVRS non- eligibility among subjects were homogeneous / patchy distribution of emphysema (75%) and anticipated adhesions (50%). The baseline characteristics of the patients who received SILVR are presented in Table 3. The median age was 73 years (range, 63.0-78.0), and the median BODE index was 5.5 (range, 5.0-9.0). Major comorbidities included hypertension (62.5%), coronary artery disease (CAD) (50%), atrial fibrillation (50%), and left ventricular ejection fraction <40% (25%). The target lobe was the left upper lobe in five (62.5%) and the left lowerATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION lobe in three (37.5%). The median V60BED3 within the target lobe was 9.1% (range, 6.6-11.3) of total (bilateral) lung volume (TLV). The median spillover of V60BED3into the adjacent lobe was 0% (range, 0-4.0) of TLV.

[0150] Trial Follow-up

[0151] 87.5% of patients were followed to the last planned study follow-up at 18 months or to death. The median time to last follow-up or death was 20.0 months (range, 8.0-21.0). The CONSORT diagram (Fig. 2) shows the proportion of the planned outcome studies carried out at each follow-up time point. The median times for all follow-up studies are presented in Table A1. Patient comorbidities and the remoteness of many of their homes from the institution made completion of all planned studies challenging. Table A1 — Median time to follow-up studies post-SILVR Time to follow-up Follow-up studies (months) Median (range) Median time to follow-up Pulmonary Function tests At 6 months (n=8) 5.5 (5.0, 11.0) At 12 months (n=3) 12.0 (12.0, 15.0) At 18 months (n=4) 18.0 (18.0, 21.0) Median time to follow-up Radiographic studies (CT Chest) At 6 months (n=7) 6.0 (5.0, 10.0) At 18 months (n=4) 18.0 (18.0, 21.0) Median time to follow-up 6-MWT At 6 months (n=6) 6.0 (6.0, 18.0) Median time to SF-36 Health Survey At 6 months (n=7) 6.0 (5.0, 8.0) Values are all median (range). CT = Computed tomography; 6-MWT = 6-minute walk test; SF = Short Form.

[0152] Safety Outcomes

[0153] Over 18 months, the incidence of grade ≥3 adverse events was 3 / 8 (37.5%) on a per patient basis. The rate of early (≤30 days), intermediate (31-90 days), and late (91 days-18ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION months) grade ≥3 adverse events was 0 / 8 (0%), 0 / 8 (0%) and 3 / 8 (37.5%), respectively. No patient with a BODE index ≤5 had any grade ≥3 adverse event. To summarize all adverse events: grade 1,2 adverse events included atrial fibrillation (12.5%), COPD exacerbation (25%), and rib pain (12.5%); and grade ≥3 adverse events short of death included heart failure (25%), pleural effusion (25%), atrial fibrillation (12.5%), COPD exacerbation (12.5%), radiation pneumonitis (12.5%), and pneumonia (12.5%) (Table A2). Table A2 — The list of adverse events stratified by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade and clinical characteristics (BODE index). BODE Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 index BODE ≤5 Related / Rib pain (1) (n=4) Possibly related Unrelated COPD exacerbation (1) BODE ≥6 Related / Pneumonitis Death (1) (n=4) Possibly (radiation- related induced?) (1), Pleural effusion (1) Unrelated Atrial fibrillation Atrial fibrillation Death (2) (1), COPD (1), COPD exacerbation (1) exacerbation (1), Pleural effusion (1), BODE = BMI, Obstruction (FEV1), Dyspnea grade, Exercise capacity (6- minute walk distance); COPD = Chronic Obstructive Pulmonary Disease.

[0154] There were three deaths [3 / 8 (37.5%)] at a median of 11.0 months post-SILVR. All of the grade ≥3 adverse events occurred in these three patients. The DSMB deemed two [2 / 8 (25%)] of these deaths as unrelated, and one [1 / 8 (12.5%)] as only possibly related to SILVR. The DSMB also deemed all of these deaths not to be unexpected as there were several severe pre-existing conditions in these subjects.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0155] The causes of the death were right upper lobe pneumonia with acute COPD exacerbation in a patient receiving left-sided SILVR (nine months); progressive right pleural effusion with uncontrollable atrial fibrillation, and congestive heart failure (CHF) in a patient with pre-existing loculated right pleural effusion, also after left SILVR (11 months); and atrial fibrillation with progressive bilateral pleural effusions and CHF in a patient with history of CAD with left ventricular dysfunction (11 months).

[0156] After review completed following the enrollment of the 7thsubject, the DSMB recommended three modifications to the subsequent inclusion criteria: increasing the lower limit of ejection fraction to 40%, allowing only unilateral treatment for all patients (the initial protocol had planned for bilateral treatment in the last 5 patients if there were no safety concerns), and excluding patients who required steroid pulse or hospital admission within three months prior to the intervention. There were no grade ≥3 adverse events after these modifications to the inclusion criteria. Prior to the DSMB review, the investigators made a clinical decision to treat the 6thand 7thsubjects unilaterally only.

[0157] Secondary outcomes: Efficacy

[0158] The secondary outcomes of efficacy at pre-determined follow-up intervals of six-, 12-, and 18-months is presented in the Table A3. Table A3 — Results of Pulmonary function tests, CT Volumetry. Quality of Life survey and the change in these outcomes at follow-up intervals of 6-months, 12-months, and 18-months. Characteristic Study Cohort Pre-SILVR PFT (n=8) (range) Median FEV1% 28.5 (19.0, 42.0) Median FEV1(L) 0.79 (0.53, 1.29) Median DLCO% 40.0 (24.0, 67.0) Post-SILVR PFT at 6 months (n=8) (range) Median FEV1% 33.0 (17.0, 60.0) Median FEV1(L) 0.92 (0.45, 1.75) Median DLCO% 38.0 (13.0, 63.0) Post-SILVR PFT at 12 months (n=3) (range) Median FEV1% 42.0 (37.0, 52..0) Median FEV1(L) 1.43 (0.89, 1.50) Median DLCO% 53.0 (52.0, 54.0) Post-SILVR PFT at 18 months (n=4) (range)ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION Characteristic Study Cohort Median FEV1% 38.0 (31.0, 48.0) Median FEV1(L) 1.06 (0.76, 1.4) Median DLCO% 47.0 (35.0, 51.0) 6MWD (in m) (n=6) (range) Median Pre-SILVR 6MWD 289.0 (48.0, 430.0) Median Post-SILVR 6MWD 406.0 (79.0, 629.0) SF-36 Health Survey Median Pre-SILVR PCS score (n=8) 31.9 (24.1, 43.8) Median Post-SILVR PCS score at 6 months (n=7) 24.9 (21.1, 48.6) Median Pre-SILVR MCS score (n=8) 48.0 (21.0, 58.3) Median Post-SILVR MCS score at 6 months (n=7) 51.5 (34.6, 57.9) Median change at 6 months (n=8) (range) Absolute ΔFEV1% +5.0 (-3.0, +18.0) Absolute ΔFEV1 (L) +0.13 (-0.08, +0.50) Absolute ΔDLCO% -8.0 (-20.0, +11.0) Median change at 12 months (n=3) (range) Absolute ΔFEV1% +3.0 (+3.0, +10.0) Absolute ΔFEV1(L) +0.14 (-0.03, +0.25) Absolute ΔDLCO% -10.0 (-14.0, +9.0) Median change at 18 months (n=4) (range) Absolute ΔFEV1% +5.5 (-2.0, +6.0) Absolute ΔFEV1 (L) +0.02 (-0.06, +0.15) Absolute ΔDLCO% -3.5 (-22.0, +11.0) Median Absolute Δ6-minute walking distance at 6 months (m) +27.0 (+11.0, +301.0) (n=6) (range) Median change (as a percent of baseline) at 6 months (n=8) (range)ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION Characteristic Study Cohort Relative ΔFEV1% +14.1 (-16.7, +30.5) Relative ΔFEV1(L) (%) +14.9 (-17.8, +28.6) Relative ΔDLCO% -17.3 (-54.0, +45.8) Median change (as a percent of baseline) at 12 months (n=3) (range) Relative ΔFEV1% +8.8 (+7.7, +23.8) Relative ΔFEV1(L) (%) +10.8 (-3.3, +20.0) Relative ΔDLCO% -15.6 (-20.9, +20.9) Median change (as a percent of baseline) at 18 months (n=4) (range) Relative ΔFEV1% +13.5 (-5.9, +24.0) Relative ΔFEV1 (L) (%) +3.2 (-4.6, +12.0) Relative ΔDLCO% -3.2 (-32.8, +45.8) Median Absolute Δ SF-36 Survey scores at 6 months (n=7) (range) PCS score -2.4 (-19.8, +7.8) MCS score +6.1 (-10.6, +9.5) Median target lobe V60BED3(% of TLV) (n=7) (range) 9.1 (6.6, 11.3) Median target lobe volume (% of TLV) Pre-SILVR (n=7) (range) 23.8 (19.3, 33.5) Post-SILVR at 6 months (n=7) (range) 18.4 (11.5, 31.8) Post-SILVR at 18 months (n=4) (range) 16.7 (11.6, 18.0) Median absolute Δ Target lobe volume (% of TLV) at 6 months -5.4 (-0.3, -8.2) (n=7) (range) Median absolute Δ Target lobe volume (% of TLV) at 18 months -6.52 (-3.9, -8.0) (n=4) (range)ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION Characteristic Study Cohort Median relative Δ Target lobe volume (as a percent of baseline) At 6 months (%) (n=7) (range) -23.14 (-1.7, -41.5) At 18 months (%) (n=4) (range) -26.5 (-20.2, -40.9) Median adjacent lobe volume (% of TLV) Pre-SILVR (n=7) (range) 22.9 (17.3, 33.6) Post-SILVR at 6 months (n=7) (range) 27.8 (19.2, 32.6) Post-SILVR at 18 months (n=4) (range) 29.1 (24.5, 34.7) Median absolute Δ Adjacent lobe volume (% of TLV) at 6 months +3.0 (-4.4, +7.25) (n=7) (range) Median absolute Δ Adjacent lobe volume (% of TLV) at 18 months +4.2 (+2.6, +7.1) (n=4) (range) Median relative Δ Adjacent lobe volume (as a percent of baseline) At 6 months (%) (n=7) (range) +11.34 (-13.1, +41.8) At 18 months (%) (n=4) (range) +17.4 (+8.1, +41.1) Values are n (%) for categorical variables and median (range) for continuous variables. SILVR=Stereotactic Irradiation for Lung Volume Reduction; PFT=Pulmonary function test; FEV1% = Forced Expiratory Volume in one second (% of predicted value); FEV1 (L) = Forced Expiratory Volume in one second in Liters; DLCO% = Diffusion capacity of lungs for carbon monoxide (% of predicted value); 6MWD = 6-minute walking distance; SF-36 = Short Form – 36; PCS = Physical component summary; MCS = Mental component summary; Δ = change from baseline value; Relative Δ = relative change from baseline value as a proportion of baseline value; V60BED3= Volume of lung receiving a biologically equivalent dose of 60 gray or more (as a % of TLV); TLV = Total lung volume.

[0159] Pulmonary function tests and exercise capacity

[0160] The FEV1% predicted at baseline, six-month, 12-month, and 18-month follow-up is presented in Figure 3A. At 6 months, the median relative ΔFEV1% was +14.1% (range -16.7 to +30.5) and the median relative ΔDLCO% was -17% (-54.0 to +45.8). The relative Δ6- MWD was +5.5% (+2.6 to +91.7). At 12 months, the relative ΔFEV1% persisted at +8.8%ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION (range, +7.7 to +23.8) and the relative ΔDLCO% remained at -15.6% (range, -20.9 to +20.9). At 18 months, the relative ΔFEV1% was +13.5% (-5.8 to +24.0), whereas the relative ΔDLCO% was -3.2% (-32.8 to -45.8). Thus, following SILVR, there was an improvement in FEV1% and exercise capacity, perhaps with a decrement in gas exchange (the latter, particularly early post-intervention).

[0161] An exploratory sub-group analysis, analyzing results in sub-groups with BODE index ≤5 and ≥6, is presented in Table 2. At 6 months, there was a better response in subjects with low BODE index (≤5) [+27.5% (+17.1 to +30.5)] vs. high BODE index (≥6) [-9.2% (- 16.7 to +11.1)] groups in the relative ΔFEV1%. There was lesser reduction in the relative ΔDLCO% in subjects with BODE index ≤5 [-8.5% (-28.3 to +45.8)]compared to subjects with BODE index ≥6 [-45.8 (-54.0 to -17.3)]. A subgroup analysis of the outcomes according to what lobe was treated showed similar responses regarding most outcomes at six months (Table A4). Table 3 — Baseline subject characteristics Study Cohort, Characteristic n = 8 Median age in years (range) 73.0 (63.0, 78.0) Sex Female 1 (12.5%) Male 7 (87.5%) Median Body Mass Index (range) 21.8 (18.5, 34.0) Contributors to LVRS ineligibility Prior Thoracic Surgery 4 (50%) Homogeneous / patchy distribution of emphysema 6 (75%) DLCO% <20% 2 (25%) FEV1% <20% 1 (12.5%) Pulmonary hypertension 1 (12.5%) Substantial chronic bronchitis 1 (12.5%) Treated lung lobe Left lower lobe 3 (37.5%) Left upper lobe 5 (62.5%)ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION Study Cohort, Characteristic n = 8 GOLD COPD stage Gold 3: Severe 4 (50%) Gold 4: Very severe 4 (50%) mMRC dyspnea scores (range) 2 (1, 3) BODE index (range) 5.5 (5.0, 9.0) Charlson’s comorbidity index (range) 4.5 (3.0, 8.0) Inhalational steroid usage 5 (62.5%) Systemic steroid usage (oral) 1 (12.5%) Median cigarette pack years (range) 40.0 (20.0, 100.0) Hypertension 5 (62.5%) Diabetes 1 (12.5%) Left ventricular dysfunction (EF <40%) 1 (12.5%) Atrial fibrillation 4 (50%) Coronary artery disease 4 (50%) Pulmonary hypertension 2 (25%) Chronic kidney disease Stage 3 1 (12.5%) Values are Median (range). BODE = BMI, Obstruction (FEV1%), Dyspnea grade, Exercise capacity (6MWD); V60BED3= Volume of lung receiving a biologically equivalent dose of 60 gray or more (as a % of TLV); FEV1% = Forced Expiratory Volume in one second % of predicted value; FEV1 (L) = Forced Expiratory Volume in one second in Liters; DLCO% = Diffusion capacity of lungs for carbon monoxide % of predicted value; Δ = change from baseline value; Relative Δ = relative change from baseline value as a proportion of baseline value; %TLV = value as a percentage of total lung volume; PCS = Physical component summary; SF = Short Form – 36; MCS = Mental component summary.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION *Mann-Whitney U test (exact significance) comparing BODE ≤5 with BODE ≥6 Table A4 — A summary of Pulmonary function tests and CT Volumetry outcomes between left lower lobe and left upper lobe targets at 6 months. Left lower lobe Left upper lobe Characteristic Median (range) Median (range) n = 3 n = 5 Median target lobe V60BED3(%) 8.3 (6.8, 9.8) 9.1 (6.6, 11.3) Median absolute Δ FEV1% +7.0 (-2.0, +13.0) +3.0 (-3.0, +18.0) +0.15 (-0.07, Median absolute Δ FEV1(L) +0.28)+0.12 (-0.08, +0.5)Median absolute Δ DLCO% (n)(2) -8.0 (-20.0, +11.0)Median relative ΔFEV1% (% of baseline) +25.0) +11.1 (-16.7, +30.6)+14.01 (-14.0, Median relative ΔFEV1(L) (% of baseline) +17.8)+15.8 (-17.8, +28.6)Median relative ΔDLCO% (% of baseline) (n)-17.4 (-54.0, +45.8)Median absolute ΔTarget lobe volume (% TLV)-6.4 (-4.7, -8.1) -5.4 (-0.3, -8.2)relative ΔTarget lobe volume (%) (%-32.9 (-24.3, -41.5) - -32.5)Median absolute ΔAdjacent lobe volume (% TLV)+1.8 (+0.5, +3.0) +4.2 (-4.4, +7.2)Median relative ΔAdjacent lobe volume (% TLV) (% of baseline)+6.4 (+1.5, +11.3) +4.2 (-13.1, +41.8)Values are n (%) for categorical variablesvariables. V60BED3= Volume of lung receiving a biologically equivalent dose of 60 gray or more (as a % of TLV); FEV1% = Forced Expiratory Volume in one second (% of predicted value); FEV1 (L) = Forced Expiratory Volume in one second in Liters; DLCO% = Diffusion capacity of lungs for carbon monoxide (% of predicted value); Δ = change from baseline value.

[0162] Lung volumetric changes and correlated factorsATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0163] On radiologic assessment by three independent observers, all but one subject who had a reduction in volume of the target lobe demonstrated band-like scarring on all post- treatment CTs, while the subjects who did not have a reduction in volume of the target lobe did not show such scarring.

[0164] The target lobe volume by CT volumetry at baseline, six-month, and 18-month follow-up intervals in all patients is presented in Figure 3B. There was a reduction in relative Δtarget lobe volume: -23.1% (-1.7 to -41.5) at six months; which was even greater at 18 months: -26.5% (-20.2 to -40.9). There was also a higher relative Δadjacent lobe volume: +11.3% (-13.1 to +41.8) at six months and that was even greater at 18 months: +17.4% (+8.1 to +41.1) (p=0.07). Images of the reduction in the volume of the target lobe and expansion in the volume of the adjacent lobe in a representative SILVR-responder are demonstrated in FIGS. 4A and 4B.

[0165] The correlation between several imaging and clinical variables (V60BED3, mean Hounsfield units [HU] within the V60BED3at baseline, BODE index) were evaluated with volumetric changes to determine the variables that correlated with response to SILVR. FIGS. 5A–D. The V60BED3 did not correlate with the absolute Δtarget lobe volume at six months (Figure 6A) but did so at 18 months (Figure 5A, Figure 6B). The absolute Δtarget lobe volume at six months correlated with the absolute Δadjacent lobe volume at six months (Figure 5B). The absolute Δadjacent lobe volume at six months correlated with the absolute ΔFEV1% at six months (Figure 5C).

[0166] It was wondered if targets containing relatively preserved parenchyma were required to effect LVR with SILVR. To determine if the degree of parenchymal preservation within the target region correlated with response to treatment, the BODE index and mean HU of the V60BED3 and V20BED3 were used. The mean HU of the V60BED3 at baseline correlated with absolute ΔFEV1% at six months and 18 months, respectively (Figure 7A and 7B). The mean HU of the V20BED3 at baseline also correlated with the absolute ΔFEV1% at six months and 18 months (Figure 8A and 8B). BODE index showed a negative correlation with the absolute ΔFEV1% at six months (Figure 5D) and with absolute Δtarget lobe volume at six months (Figure 9A and 9B).

[0167] Subjects with BODE index ≤5 demonstrated a relative Δtarget lobe volume of - 28.4% (-23.1, -41.5) and a relative ΔFEV1% of +27.5% (+17.1, +30.5).

[0168] SF-36 Health Survey outcomes

[0169] Quality of LifeATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION

[0170] At 6 months post-SILVR, the change in the PCS and MCS scores from baseline in the overall cohort is presented in Table A3.There was a better response in the MCS and PCS scores in patients with BODE index≤5 vs. ≥6 (Table 2). DISCUSSION

[0171] Herein are reported results of a phase I, prospective clinical trial of a novel, non- surgical method (SILVR) of achieving unilateral LVR in patients with COPD and hyperexpansion. The hypotheses upon embarking on this project were that a safe, non-surgical LVR could be achieved by capitalizing upon the fibrotic effect of SABR, and that this would translate into improvements in pulmonary function. It was also interesting to determine if SILVR might be particularly effective in COPD with homogeneous disease and / or less parenchymal destruction, given that patients with these characteristics are not ideal candidates for surgical LVRS or EBVs, and given the likelihood that a substantial amount of parenchyma would likely need to be present for SABR to achieve its fibrotic effect. The clinical trial was embarked on based on sound evidence from retrospective studies that lung SABR in patients with lung cancer indeed produces volume reduction. (13,14,15)

[0172] The results of the study herein demonstrate the safety and feasibility of SILVR in patients with severe emphysema.37.5% of subjects did experience grade ≥3 adverse events – the same three patients who died at a median of 11 months post-SILVR. However, only one of the three deaths was deemed even “possibly” related to the experimental intervention; two were exacerbations of pre-existing cardiac conditions. Further, all enrolled subjects had marked co- morbidities and / or severity of emphysema that rendered them poor candidates for LVRS and reduced their expected survival dramatically. The four-year survival probability for patients with these 3 subjects’ median BODE index of eight is 18% (24), and many of the subjects (all of those who died) also had major cardiovascular co-morbidities. The occurrence of a death in one patient between the time he provided consent and the time he was to receive the intervention highlights the fragility of the enrolled patients. No subject with BODE index ≤5 suffered any grade ≥3 adverse events. Also, after additional tightening of the inclusion criteria by the DSMB, there were no deaths. The utilization of conformal radiotherapy appeared to allow a reasonably low rate of grade ≥3 adverse events attributable to SILVR; it allowed the creation of clinically significant volume reduction with acceptable risk.

[0173] In addition to establishing acceptable safety, this study also demonstrates promising preliminary efficacy outcomes with regard to lobar reduction in volume, improvement in pulmonary function, and increase in exercise capacity. The lobar volume change after SILVR shown in Figure 4 is impressive. The relative ΔFEV1% of +14.1% six months after unilateralATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION SILVR is in the same range as the 13.1-20.7% improvement achieved by unilateral EBVs. (25,26,27) With regard to functional outcomes, there was an improvement in 6-MWD in addition to the improved FEV1%. One would, of course, expect the bilateral application of SILVR to effect a larger treatment response.

[0174] To identify predictors of response to SILVR, it was hypothesized that more preserved parenchyma in the SABR target region would allow the creation of more fibrosis and, thus, a greater degree of volume reduction. The BODE index (≤5 vs >5) was used as a clinical proxy for severity of emphysema and mean HU within the target region as a radiologic measure of parenchymal destruction. The finding that, indeed, these measures show a greater reduction in target lobe volume and improvement in FEV1% is consistent with the hypothesis. COPD patients with relatively preserved pulmonary parenchyma often have a substantial component of airways disease, and this group partially overlaps with patients with homogeneous emphysema distribution. Neither of these subgroups of patients are considered ideal candidates for LVRS or EBVs, but the data herein suggest that they may be appropriate candidates for SILVR. It is important to note that homogeneous distribution describes 52.5- 77% of patients with severe emphysema.27,28,29Notably, fibrotic scarring, produced by SILVR, would not be impacted by collateral ventilation. Thus, the subgroup of patients with collateral ventilation who are not candidates for EBVs would likely be candidates for SILVR.

[0175] While this was a prospective study of a novel technique, it does have several limitations and thus must be interpreted with caution. First, the sample size was small, with high dropout from follow-up and incomplete adherence to planned studies. Hence, it was not possible to deduce inferential statistics robust enough to generalize over a population of representative patients. Secondly, the lack of a control group precludes definitive assessment of the benefit / risk from the intervention over placebo or best medical management. Lastly, the efficacy outcomes were only exploratory and the subset analyses were post-hoc in nature. Hence, these can only be considered hypothesis-generating and need to be confirmed with phase II studies adequately powered to demonstrate this efficacy. CONCLUSIONS

[0176] This first-in-human, prospective clinical trial of stereotactic radiation for severe emphysema provides evidence of acceptable safety and a preliminary signal of efficacy of SILVR in patients who were not candidates for LVRS / EBVs. This experimental therapy appears particularly appropriate for patients with BODE index ≤5. It is believed that with additional prospective study adequately powered to demonstrate efficacy, SILVR may become established as an effective treatment for selected patients with severe COPD, serving as anATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION alternative to LVRS and EBVs – and perhaps providing an option for patients who are not ideal candidates for either of those therapies. Future larger prospective phase II clinical trials are appropriate, likely focused on patients with BODE index ≤5, homogeneous disease, and / or a substantial component of airways disease. REFERENCES

[0177] References cited below or elsewhere herein are incorporated by reference herein as if fully set forth. 1. Safiri S, Carson-Chahhoud K, Noori M, et al. Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990-2019: results from the Global Burden of Disease Study 2019. BMJ.2022; 378:e069679. 2. Adeloye D, Song P, Zhu Y, Campbell H, Sheikh A, Rudan I; NIHR RESPIRE Global Respiratory Health Unit. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med.2022; 10:447–58. 3. GOLD. (Published 2022, September 21). World Lung Day 2022 - Global Initiative for Chronic Obstructive Lung Disease. (Accessed July 3, 2023), from https: / / goldcopd.org / world-lung-day-2022 / 4. et al. National Emphysema Treatment TrialResearch Group. 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Trakul N, Chang CN, Harris J, et al. Tumor volume-adapted dosing in stereotactic ablative radiotherapy of lung tumors. Int J Radiat Oncol Biol Phys.2012; 84:231-7. 21. RAND Corporation. (n.d.). 36-Item Short Form Survey from the RAND Medical Outcomes Study. (Accessed on August 17, 2023) from https: / / www.rand.org / health- care / surveys_tools / mos / 36-item-short-form.htmlATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION 22. Ware JE Jr, Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczek A. Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Med Care.1995; 33:AS264–79. 23. Ware, J. E., Kosinski, M. Scoring Algorithms. SF-36 Physical & Mental Health Summary Scales: A Manual for Users of Version 1. (5thPrinting, pp. 4:1- 4:6). QualityMetric. (Accessed on August 18, 2023) from https: / / www.researchgate.net / profile / John-Ware-6 / publication / 292390260_SF- 36_Physical_and_Mental_Health_Summary_Scales_a_User%27s_Manual / links / 5af5 80264585157136caee31 / SF-36-Physical-and-Mental-Health-Summary-Scales-a- Users-Manual.pdf 24. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med.2004; 350:1005–12. 25. Criner GJ, Sue R, Wright S, et al. LIBERATE Study Group. A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (LIBERATE). Am J Respir Crit Care Med.2018; 198:1151–64. 26. Kemp SV, Slebos DJ, Kirk A, et al. TRANSFORM Study Team. A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (TRANSFORM). Am J Respir Crit Care Med. 2017; 196:1535–43. 27. Klooster K, Hartman JE, Ten Hacken NH, Slebos DJ. 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Claims

ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION CLAIMS 1. A method of treating chronic obstructive pulmonary disease in a subject in need thereof comprising: administering to the subject a biologically effective dose of radiation to the lung tissue of the subject.

2. The method of claim 1, wherein the step of administering comprises administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject.

3. The method of either of claims 1 or 2 further comprising a step of administering to the subject an intermediate dose of radiation around the periphery of the target volume of lung tissue.

4. The method of any of claims 1 through 3, wherein the subject has a BODE score from about 3 to about 8.

5. The method of any of claims 1 through 3, wherein the target volume of lung tissue in the subject comprises a significant amount of parenchyma.

6. The method of any of claims 1 through 5, wherein the method is free of performing a surgery.

7. The method of any of claims 1 through 6, wherein the biological effective dose of radiation is from about 35 to about 55 Gy.

8. The method of claim 7, wherein the dose is about 45 Gy.

9. The method of any of claims 1 through 8, wherein the step of administering is performed a total of about three times over a period of one week.

10. The method of any of claims 1 through 9 further comprising determining the target lung volume by:ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION (i) imaging the lung of the subject; (ii) identifying emphysematous lung tissue within the subject comprising a region with most emphysematous lung tissue; and (iii) determining the target volume within the region of most emphysematous lung tissue.

11. The method of claim, wherein the step of imaging comprising imaging by CT scan.

12. The method of claim 3, wherein the intermediate dose of radiation around the periphery of the target volume of lung tissue comprises a decreasing gradient of radiation as the distance form the target volume is increased.

13. A method of treating emphysema in a subject in need thereof comprising administering to the subject stereotactic irradiation to emphysematous tissue within the lung of the subject at a dose sufficient to cause fibrosis within the emphysematous tissue.

14. The method of claim 13, wherein the dose is from about 40 to about 50 Gy.

15. The method of either of claims 13 or 14, wherein the dose is administered a total of about 3 times over a week.

16. The method of any of claims 13 through 15 further comprising analyzing an image of the lung of a subject to identify a target region comprising the emphysematous tissue.

17. The method of claim 16 wherein the image is an image generated by CT scan.

18. A method of treating emphysema and / or hyperinflation of a lung of a subject in need thereof comprising: administering to the subject a biologically effective dose of radiation to the lung tissue of the subject.

19. The method of claim 18, wherein the step of administering comprises administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION 20. The method of any of claims 18 through 19 further comprising analyzing an image of the lung of a subject to identify a target region comprising the emphysematous tissue within the lung tissue of a subject.

21. The method of any of claims 18 through 20 further comprising a step of administering to the subject an intermediate dose of radiation around the periphery of the target volume of lung tissue.

22. The method of any of claims 18 through 21, wherein the subject has a BODE score from about 3 to about 8.

23. The method of claim 22, wherein the BODE score is at or above about 5.

24. The method of any of claims 18 through 23, wherein the target volume of lung tissue in the subject comprises a significant amount of parenchyma.

25. The method of any of claims 18 through 24, wherein the method is free of performing a surgery on the subject.

26. The method of any of claims 18 through 25, wherein the biological effective dose of radiation is from about 35 to about 55 Gy.

27. The method of claim 26, wherein the dose is about 45 Gy.

28. The method of any of claims 18 through 27, wherein the step of administering is performed a total of about three times over a period of one week.

29. The method of any of claims 18 through 28 further comprising determining the target lung volume by: (i) imaging the lung tissue of the subject; (ii) identifying a region of the lung tissue with significant emphysematous lung tissue; and (iii) determining the target volume within the region of significant emphysematous lung tissue.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION 30. The method of claim 29, wherein the step of imaging the lung tissue comprises imaging by CT scan.

31. The method of claim 21, wherein the intermediate dose of radiation around the periphery of the target volume of lung tissue comprises a decreasing gradient of radiation as the distance from the target volume is increased.

32. The method of any of claims 18 through 31, wherein the subject is diagnosed with or has been diagnosed with severe emphysema.

33. The method of any of claims 18 through 32, wherein the subject has been diagnosed or is diagnosed with a significant amount of parenchyma in the lung tissue.

34. A method of improving pulmonary function, exercise capacity and / or dyspnea in a subject in need thereof comprising: administering to the subject a biologically effective dose of radiation to the lung tissue of the subject.

35. The method of claim 34, wherein the biologically effective dose is a dose sufficient to cause fibrosis in a region of lung tissue of the subject comprising emphysematous tissue.

36. The method of claim 34 or 35, wherein the step of administering comprises administering a dose of radiation to a target volume of lung tissue of the subject equal to no more than about 10% of total lung volume of the subject.

37. The method of any of claims 34 through 36 further comprising analyzing an image of the lung of a subject to identify a target region comprising the emphysematous tissue within the lung tissue of a subject.

38. The method of any of claims 34 through 37 further comprising a step of administering to the subject an intermediate dose of radiation around the periphery of the target volume of lung tissue.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION 39. The method of any of claims 34 through 38, wherein the subject has a BODE score from about 3 to about 8.

40. The method of claim 39, wherein the BODE score is at or above about 5.

41. The method of any of claims 34 through 40, wherein the target volume of lung tissue in the subject comprises a significant amount of parenchyma.

42. The method of any of claims 34 through 41, wherein the method is free of performing a surgery on the subject.

43. The method of any of claims 37 through 42, wherein the biological effective dose of radiation is from about 35 to about 55 Gy.

44. The method of claim 43, wherein the dose is about 45 Gy.

45. The method of any of claims 34 through 44, wherein the step of administering is performed a total of about three times over a period of one week.

46. The method of any of claims 34 through 45 further comprising determining the target lung volume by: (i) imaging the lung tissue of the subject; (ii) identifying a region of the lung tissue with significant emphysematous lung tissue; and (iii) determining the target volume within the region of significant emphysematous lung tissue.

47. The method of claim 46, wherein the step of imaging the lung tissue comprises imaging by CT scan.

48. The method of claim 38, wherein the intermediate dose of radiation around the periphery of the target volume of lung tissue comprises a decreasing gradient of radiation as the distance from the target volume is increased.ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION 49. The method of any of claims 34 through 48, wherein the subject is diagnosed with or has been diagnosed with severe emphysema.

50. The method of any of claims 34 through 49, wherein the subject has been diagnosed or is diagnosed with a significant amount of parenchyma in the lung tissue.

51. A method treating emphysema in a subject in need thereof, the method comprising: (a) establishing a volume for reduction in emphysematous lung tissue in the subject; (b) delineating a planning target volume for reduction within the volume for reduction; and (c) irradiating the planning target volume with a dose of radiation.

52. The method of claim 51, wherein the volume is about 10% of total lung volume of the subject and the planning target volume is less than about 30 cc.

53. The method of claim 51 or 52, wherein the dose is about 45 Gy in administered in three fractions.

54. The method of any one of claims 51 through 53, wherein the emphysematous lung tissue includes a region of most emphysematous lung tissue and the planning target volume is within the region of most emphysematous lung tissue.

55. The method of claim 54 further comprising identifying the most emphysematous lung tissue on one or more computed tomography scan images of the subject, manually contouring the images, and editing the images to form the target volume for reduction within the most emphysematous lung tissue.

56. A system comprising: an imaging device; a beam source; a memory storing processor-executable instructions; and a processor configured to execute the processor executable instructions; the processor executable instructions comprising instructions for:ATTORNEY DOCKET NO STFD-010-PCT PCT APPLICATION (a) establishing a volume for reduction in emphysematous lung tissue in the subject, (b) delineating a planning target volume for reduction within the volume; and (c) irradiating the planning target volume with a dose of radiation from the beam source.

57. The system of claim 56, wherein the instructions further comprise defining the target volume as about 10% of total lung volume of the subject and the planning target volume as equal to or less than about 30 cc of total lung volume.

58. The system of claim 56 or 57, wherein the instructions for irradiating comprise instructions for irradiating a dose of about 45 Gy in three fractions.

59. The system of any one of claims 56 thr0ugh 58, wherein instructions comprise determining a region of most emphysematous lung tissue within the emphysematous lung tissue includes and defining the planning target volume within the region of most emphysematous lung tissue.

60. The method of claim 59, wherein the instructions comprise identifying the most emphysematous lung tissue on one or more computed tomography scan images of the subject, contouring the images, and editing the images to form the target volume for reduction within the most emphysematous lung tissue.

Images