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Gastroparesis is a debilitating and difficult to manage problem that has been reported in 20% to 90% of lung and heart-lung transplant recipients. The primary objective was to evaluate the safety and clinical effectiveness of per-oral endoscopic pyloromyotomy in relieving gastroparesis after lung transplant. Secondary objectives evaluated the effect of per-oral endoscopic pyloromyotomy on gastroesophageal reflux and allograft function.Fifty-two lung transplant recipients underwent per-oral endoscopic pyloromyotomy for refractory gastroparesis. Gastroparesis was assessed by a pre-per-oral endoscopic pyloromyotomy and post-per-oral endoscopic pyloromyotomy radionuclide gastric emptying test and Gastroparesis Cardinal Symptom Index. Secondary outcomes included 90-day complications, gastroesophageal reflux as measured by pH testing, and longitudinal spirometry measurements.Median time from lung transplant to per-oral endoscopic pyloromyotomy was 10.5 months. Twenty-eight patients had prior pyloric botulinum injection with either no improvement or relapse of symptoms. Post-per-oral endoscopic pyloromyotomy gastric emptying tests were available for 32 patients and showed a decrease in median gastric retention at 4 hours from 63.5% pre-per-oral endoscopic pyloromyotomy to 5.5% post-per-oral endoscopic pyloromyotomy (P .0001). Complete normalization of gastric emptying time was noted in 19 patients. Gastroparesis Cardinal Symptom Index score significantly improved after per-oral endoscopic pyloromyotomy (median, 23-3.5; P .0001). Post-per-oral endoscopic pyloromyotomy pH testing showed improved or stable DeMeester score in all patients except 1. Graft function (forced expiratory volume in 1 second) remained stable 1 year after per-oral endoscopic pyloromyotomy.The improvements in symptom score and radionuclide imaging observed in this uncontrolled study suggest that per-oral endoscopic pyloromyotomy is an effective strategy in the lung transplant population and can be performed with minimal morbidity.

Lung transplantation (LTx) has evolved to represent the therapy of choice for many patients with end-stage lung diseases. Appropriate candidate selection for LTx is an important determinant of a positive outcome from transplantation. Posttransplantation survival has steadily improved, but long-term survival continues to be a challenge with a median survival of 5.8 years. Similarly, combined heart-lung transplantation and simultaneous liver-lung transplantation has been performed successfully in select patients who are not expected to survive either organ transplant alone. Moreover, LTx has been performed in patients who develop end-stage pulmonary complications following hematopoietic stem cell transplantation.

Bacteriophage therapy (BT) uses bacteriophages to treat pathogenic bacteria and is an emerging strategy against multidrug-resistant (MDR) infections. Experience in solid organ transplant is limited. We describe BT in 3 lung transplant recipients (LTR) with life-threatening MDR infections caused by Pseudomonas aeruginosa (n=2) and Burkholderia dolosa (n=1). For each patient, lytic bacteriophages were selected against their bacterial isolates. BT was administered for variable durations under emergency Investigational New Drug applications and with patient informed consent. Safety was assessed using clinical/laboratory parameters and observed clinical improvements described, as appropriate. All patients received concurrent antibiotics. Two ventilator-dependent LTR with large airway complications and refractory MDR P.aeruginosa pneumonia received BT. Both responded clinically and were discharged from the hospital off ventilator support. A third patient had recurrent B. dolosa infection following transplant. Following BT initiation, consolidative opacities improved and ventilator weaning was begun. However, infection relapsed on BT and the patient died. No BT-related adverse events were identified in the 3 cases. BT was well tolerated and associated with clinical improvement in LTRs with MDR bacterial infection not responsive to antibiotics alone. BT may be a viable adjunct to antibiotics for patients with MDR infections.

Vitamin D deficiency is common in patients with cystic fibrosis (CF), and guidelines recommend 25-hydroxyvitamin D (25OHD) levels ≥ 30 ng/mL. This threshold was selected because serum parathyroid hormone (PTH) rises in healthy individuals when the 25OHD level falls below 30 ng/mL. PTH levels50 pg/mL are associated with an increased risk of bone loss. However, the relationship between 25OHD and PTH has not been studied in CF. We sought to determine the appropriate goal 25OHD level in patients with CF by identifying the level below which the risk of PTH50 pg/mL begins to increase.Levels of 25OHD and PTH in 216 individuals with CF were collected prospectively. Individuals with 25OHD30 ng/mL were treated with vitamin D2, and levels were reevaluated.Mean 25OHD level was 25.7 ± 12.4 ng/mL, and mean PTH level was 46.7 ± 25.9 pg/mL. In 63% of individuals, 25OHD level was30 ng/mL, and in 38.0% it was ≤ 20 ng/mL. Low 25OHD levels were significantly associated with elevated PTH levels, with a mean PTH of 53.1 ± 29.8 pg/mL for 25OHD level 0 to 19 ng/mL; 51.1 ± 30.7 pg/mL for 25OHD level 20 to 29 ng/mL; 38.4 ± 16.4 pg/mL for 25OHD level 30 to 39 ng/mL; and 37.2 ± 16.4 pg/mL for 25OHD level ≥ 40 ng/mL (P = .006). We assessed the sensitivity of different 25OHD thresholds to identify individuals meeting the goal of a PTH level50 pg/mL to reduce the risk of bone loss. To obtain 90% sensitivity, a 25OHD level ≥ 35 ng/mL was required. Strikingly, 23% of individuals with 25OHD levels 30 to 34 ng/mL still had a PTH level50 pg/mL. This decreased to 14% for 25OHD level ≥ 35 ng/mL.Inadequate serum 25OHD levels are common in adults with CF and are associated with elevated PTH levels. Aiming to maintain 25-OHD levels ≥ 35 ng/mL in individuals with CF decreases the risk of having a PTH level associated with secondary hyperparathyroidism and bone loss.

Purpose: The standard of care in Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC) is chemotherapy and radiation; however, Radiation-Induced Lung Injury (RILI), which may be prevented by the anti-inflammatory and anti-oxidant properties of Flaxseed (FS), impedes its maximum benefit. Materials and Methods: Patients with LA-NSCLC requiring definitive RT were randomized to one FS or control muffin daily from start to 2 weeks after RT. Blood and urine were collected to quantify plasma FS metabolites, Enterodione (ED) and Enterolactone (EL), and urinary oxidative stress biomarkers, 8, 12-iso-iPF2a-VI (isoprostane) and 8-oxo-7,8-dihydro-2’deoxyguanosine (8-oxo-dGuo). Tolerability was defined as consuming ≥ 75% of the intended muffins and no ≥ grade 3 gastrointestinal toxicities. Results: Fourteen patients (control,7; FS,7) were enrolled. The tolerability rates were 42.9 versus 71.4% (p=0.59) for FS and control, respectively. Mean percentages of intended number of muffins consumed were 37% versus 73% (p=0.12). ED and EL increased at onset of FS and decreased with discontinuation, confirming bioavailability. Isoprostane and 8-oxo-dGuo were detectable. There was a trend towards decreased rates of pneumonitis in FS. Conclusions: This is the first study to report FS bioavailability and quantify oxidative stress markers in NSCLC patients. FS in the administered muffin formulation did not meet tolerability criteria. Given the promising mechanism of FS as a radioprotectant, further investigations should focus on the optimal method for administration of FS.

BACKGROUND Spaceflight missions may require crewmembers to conduct Extravehicular Activities (EVA) for repair, maintenance or scientific purposes. Pre-breathe protocols in preparation for an EVA entail 100% hyperoxia exposure that may last for a few hours (5-8 hours), and may be repeated 2-3 times weekly. Each EVA is associated with additional challenges such as low levels of total body cosmic/galactic radiation exposure that may present a threat to crewmember health and therefore, pose a threat to the success of the mission. We have developed a murine model of combined, hyperoxia and radiation exposure (double-hit) in the context of evaluating countermeasures to oxidative lung damage associated with space flight. In the current study, our objective was to characterize the early and chronic effects of repeated single and double-hit challenge on lung tissue using a novel murine model of repeated exposure to low-level total body radiation and hyperoxia. This is the first study of its kind evaluating lung damage relevant to space exploration in a rodent model. METHODS Mouse cohorts (n=5-15/group) were exposed to repeated: a) normoxia; b) >95% O2 (O2); c) 0.25Gy single fraction gamma radiation (IR); or d) a combination of O2 and IR (O2+IR) given 3 times per week for 4 weeks. Lungs were evaluated for oxidative damage, active TGFβ1 levels, cell apoptosis, inflammation, injury, and fibrosis at 1, 2, 4, 8, 12, 16, and 20 weeks post-initiation of exposure. RESULTS Mouse cohorts exposed to all challenge conditions displayed decreased bodyweight compared to untreated controls at 4 and 8 weeks post-challenge initiation. Chronic oxidative lung damage to lipids (malondialdehyde levels), DNA (TUNEL, cleaved Caspase 3, cleaved PARP positivity) leading to apoptotic cell death and to proteins (nitrotyrosine levels) was elevated all treatment groups. Importantly, significant systemic oxidative stress was also noted at the late phase in mouse plasma, BAL fluid, and urine. Importantly, however, late oxidative damage across all parameters that we measured was significantly higher than controls in all cohorts but was exacerbated by the combined exposure to O2 and IR. Additionally, impaired levels of arterial blood oxygenation were noted in all exposure cohorts. Significant but transient elevation of lung tissue fibrosis (p

Background Wholegrain flaxseed (FS), and its lignan component (FLC) consisting mainly of secoisolariciresinol diglucoside (SDG), have potent lung radioprotective properties while not abrogating the efficacy of radiotherapy. However, while the whole grain was recently shown to also have potent mitigating properties in a thoracic radiation pneumonopathy model, the bioactive component in the grain responsible for the mitigation of lung damage was never identified. Lungs may be exposed to radiation therapeutically for thoracic malignancies or incidentally following detonation of a radiological dispersion device. This could potentially lead to pulmonary inflammation, oxidative tissue injury, and fibrosis. This study aimed to evaluate the radiation mitigating effects of FLC in a mouse model of radiation pneumonopathy. Methods We evaluated FLC-supplemented diets containing SDG lignan levels comparable to those in 10% and 20% whole grain diets. 10% or 20% FLC diets as compared to an isocaloric control diet (0% FLC) were given to mice (C57/BL6) (n=15-30 mice/group) at 24, 48, or 72-hours after single-dose (13.5 Gy) thoracic x-ray treatment (XRT). Mice were evaluated 4 months post-XRT for blood oxygenation, lung inflammation, fibrosis, cytokine and oxidative damage levels, and survival. Results FLC significantly mitigated radiation-related animal death. Specifically, mice fed 0% FLC demonstrated 36.7% survival 4 months post-XRT compared to 60–73.3% survival in mice fed 10%-20% FLC initiated 24–72 hours post-XRT. FLC also mitigated radiation-induced lung fibrosis whereby 10% FLC initiated 24-hours post-XRT significantly decreased fibrosis as compared to mice fed control diet while the corresponding TGF-beta1 levels detected immunohistochemically were also decreased. Additionally, 10-20% FLC initiated at any time point post radiation exposure, mitigated radiation-induced lung injury evidenced by decreased bronchoalveolar lavage (BAL) protein and inflammatory cytokine/chemokine release at 16 weeks post-XRT. Importantly, neutrophilic and overall inflammatory cell infiltrate in airways and levels of nitrotyrosine and malondialdehyde (protein and lipid oxidation, respectively) were also mitigated by the lignan diet. Conclusions Dietary FLC given early post-XRT mitigated radiation effects by decreasing inflammation, lung injury and eventual fibrosis while improving survival. FLC may be a useful agent, mitigating adverse effects of radiation in individuals exposed to incidental radiation, inhaled radioisotopes or even after the initiation of radiation therapy to treat malignancy.