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Background: Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor., Methods: Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours., Results: Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets., Conclusion: This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed., Trial Registration Number: NCT02264418., Competing Interests: Competing interests: PB reports personal fees from Orion Pharma, during the conduct of the study, personal fees from Bristol-Myers Squibb, MSD, Pfizer, Novartis, EUSA, Oncorena, TILT Biotherapeutics, Faron Pharmaceuticals, Ipsen and Herantis Pharma, outside the submitted work, and stock ownership: TILT Biotherapeutics and Terveystalo. At the time of the study PB was employed by Helsinki University Hospital. CM reports consultant/advisory fees from Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion, outside the submitted work, he is also principal/sub-Investigator of clinical trials for Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor. KJP reports personal fees from MSD, BMS, Roche Pfizer, Varian and Ipsen, outside the submitted work, and stock ownership: Faron Pharmaceuticals. At the time of the study KJP was employed part time (6 months) by Orion Pharma. AA reports personal fees from Orion Pharma and Amcure, outside the submitted work. AI reports research grants and personal fees from Ipsen, Novartis, Bayer, Bristol-Myers Squibb, Epizyme, Immune Design, Daiichi Sankyo and MSD outside the submitted work. GC reports personal fees from Roche, Seattle Genetics, Daichii Sankyo, AstraZeneca and Lilly, and other from Roche and Pfizer outside the submitted work. UL reports personal fee from Bayer and Pfizer outside the submitted work, and research grants from Roche, BMS, Pfizer and GSK. H-TA is an employee of HCAHealthcare UK/Sarah Cannon and reports receiving speaker bureau honoraria from Pierre Fabre, Guardant, BeiGene, and Roche outside the submitted work. PH, CG, TI and MVJM were employed by Orion. JAR reports personal fees and other from Novartis, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals Inc., Pfizer and Bayer, personal fees from Eli Lilly, Orion Pharmaceuticals, Peptomyc, Roche Pharmceuticals, Ellipses Pharma, Certera, and Ionctura SA, and other from European Journal of Cancer, VHIO/ Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline, ESMO, Department of Defense, Merck Sharp & Dohme, Lousiania State University, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, WIN Consortium, Janssen, Tocagen, Symphogen, BioAlta, GenMab, CytomX, Kelun-Biotech, Takea-Millenium, and Ipsen outside the submitted work., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Objective: To test various indicators for comparing the outcomes of diabetic foot care., Design: All 396,317 patients treated with hypoglycaemic medication in Finland were followed up based on nationwide registers on hospital discharges and causes of death during 1997-2007., Materials and Methods: The crude and standardized incidences of lower extremity amputations (LEAs), the minor-major ratio of the first LEA and 2-year survival with a preserved leg after the first minor LEA were used as indicators for regional and temporal variation in diabetic foot care., Results: A total of 13,469 LEAs were recorded in 1997-2007. The standardized population-corrected rate of first major LEA per 100,000 person-years declined from 10.0 (95% CI 9.6-10.5) to 7.3 (6.9-7.6) (p < .001), while the minor-major LEA ratio progressed from 0.86 (0.80-0.92) to 1.35 (1.26-1.46) (p < .001). By using these indicators, variation was observed between the university hospital catchment areas. Nationwide, the 2-year survival with a preserved leg after the first minor LEA increased statistically insignificantly from 50.8% (47.3-54.6%) to 55.4% (51.9-59.0%) (p = .08)., Conclusions: The standardized, population-corrected incidence of major LEA, the minor-major LEA ratio, and major-amputation-free survival proved useful as indicators in comparing the outcomes of diabetic foot care., (Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: This retrospective matched case-control study evaluated the consequences of multidrug-resistant Pseudomonas aeruginosa (MDR Pa) in critical leg ischemia (CLI) patients treated with infrainguinal bypass surgery (IBS)., Methods: An outbreak of MDR Pa occurred on our vascular surgical ward during a 13-month period. Bacteria cultures positive for MDR Pa were obtained from 129 patients, and 64 CLI patients treated with IBS formed the study group. A control group of 64 was retrospectively matched from MDR Pa-negative patients treated with IBS in the same unit according to sex, age, presence of diabetes, Fontaine class, graft material, and site of the distal anastomosis. The most frequent sites of initial positive MDR Pa culture were the incisional wound in 30 (47%) and ischemic ulcer in 23 (36%). Median time between the positive MDR Pa-culture and IBS was 14 days (range, 56 days pre-IBS to 246 days post-IBS). Graft patency, survival, leg salvage, and amputation-free survival were assessed., Results: One-year amputation-free survival (+/- standard error) was 52% +/- 6% in the MDR Pa group vs 75% +/- 5% in the control group (P = .02). Five-year amputation-free survival was 29% +/- 6% in the MDR Pa group and 32% +/- 6% in the control group (P = .144). For MDR Pa and control groups, the 1-year survival was 69% +/- 6% and 82% +/- 5% (P = .063), respectively, and 5-year survival was 36% +/- 6% and 36% +/- 6% (P = .302), respectively. For the MDR Pa and control groups, leg salvage was 79% +/- 5% and 92% +/- 4% at 1 year (P = .078) and 73% +/- 7% and 87% +/- 5% at 5 years (P = .126), respectively. The overall secondary patency rate at 1 year was 72% +/- 7% in the MDR Pa group vs 81% +/- 6% in the control group (P = .149). Local wound surgery was more frequent in MDR Pa patients than in controls (P = .002)., Conclusions: The MDR Pa outbreak was associated with a decreased short-term amputation-free survival after IBS for CLI in patients with positive MDR Pa culture. The potential risks of MDR Pa should be seriously considered whenever a positive culture is obtained in a vascular patient with CLI.

Background: Besides being a known lymphangiogenic activator, vascular endothelial growth factor (VEGF)-C may express angiogenic potential by proteolytic cleavage and activation of endothelial cells. We assessed myocardial collateral formation and functional changes after adenovirus-mediated VEGF-C gene transfer in an ischemic porcine model., Methods: Fifteen Landrace piglets underwent Ameroid-induced gradual occlusion of the left circumflex artery (LCx) and consequent progressive myocardial ischemia. Three weeks after Ameroid placement, the animals underwent gated 99mTc SPECT during rest and stress, in vivo angiography and 18FDG PET. Pigs were randomized to intramyocardial injections of adenoviruses encoding vascular endothelial growth factor (VEGF-C; n = 7) or control beta-galactosidase (LacZ; n = 5). Four weeks later, the examinations were repeated and histology was analyzed., Results: Angiography showed significant progression of LCx stenosis in both groups during the treatment period. Left ventricular wall thickening (LVWT) at the LCx area in gated 99mTc SPECT remained unchanged in the VEGF-C group, indicating that VEGF-C prevented progression of myocardial ischemia, whereas LVWT deteriorated in the LacZ group (p = 0.042). Semi-quantitative assessment of 18FDG PET suggests more reduction in ischemia in the adVEGF-C group than in controls (p = 0.052). Angiography showed significant clustering of collaterals in the adVEGF-C gene transfer area compared that in LacZ (p = 0.004). von Willebrand factor staining revealed a significantly (p = 0.03) greater number of microvessels in the adVEGF-C-treated myocardium., Conclusions: This appears to be the first large-animal study in which, during progressive ischemia, functional and metabolic benefits of intramyocardial VEGF-C gene transfer were apparent. VEGF-C-induced collateral formation occurred at the site of gene transfer. The angiogenic potency of VEGF-C deserves further study as a therapeutic option.

Background: Obliterative bronchiolitis (OB) is the major cause of morbidity and mortality after lung transplantation. One initiating event in the development of obliteration of the airway lumen is epithelial injury. In our model of chronic rejection, initial ischemic injury and denudation of the epithelium occurs in the isografts, with eventual re-epithelialization and partial patency of the airway lumen. In contrast, allografts do not recover epithelium, and the airway lumen becomes obliterated. We hypothesized that because integrin alphaVbeta6 is expressed in healing epithelium, integrin alphaVbeta6 expression would be greatly increased in isografts, but not in allografts., Methods: Using a rat tracheal allograft rejection model as a source of 4- to 5-microm tissue sections, we compared integrin staining in allografts vs isografts from animals at post-transplant Days 7, 14, 28, and 60. We analyzed the sections using immunohistochemistry after incubation with a specific monoclonal antibody E7P6 against integrin alphaVbeta6. Negative control slides were processed identically, except that primary antibody was omitted., Results: The sections from healing, re-epithelializing isografts showed intense staining when using the antibody recognizing integrin alphaVbeta6, compared with the allografts studied. Days 7 and 14 isografts had increased epithelial expression of alphaVbeta6. As the isograft epithelium recovered, the intensity diminished at Days 28 and 60. In allografts, at Days 7 to 60, we detected only a comparatively low-level of expression in injured epithelium., Conclusions: Integrin alphaVbeta6 is readily detectable in healing isografts. Integrin alphaVbeta6 may be crucial in maintaining a viable epithelial cell layer, which is related to slowed progression of airway obliteration in OB.

Unlabelled: Goblet cells are important in the maintenance of the epithelial cell population in the airway, defense against injury and storage and release of mucins, which can protect the surface epithelial layer. In our rat tracheal model of acute rejection, there is injury and loss of respiratory epithelium in allografts. This loss of epithelium is associated with obliteration of the airway lumen. In small bowel allografts, studies have shown that the loss of goblet cells is an important histologic feature of rejection. The aims of this study were: (i) to examine for the first time the close time-course of goblet cell proliferation in acute rejection; and (ii) to compare the isograft vs. allograft morphometric changes associated with epithelial damage., Methods: Heterotopically transplanted rat tracheas (n = 45) were harvested at days 3,5,7, 10 and 12. Hematoxylin & eosin (H & E), Alcian blue and PAS staining was completed. Computerized image analysis was used to assess epithelial coverage. The mean number of PAS-positive goblet cells counted at 40x/field was determined, and 10 fields were counted per tracheal section. RESULTS There was a significant decrease in the number of goblet cells in the allografts between days 5 and 12 (p < 0.006). In the isografts, there was a gradual increase from day 3 to 10 (p < 0.05), then a sharp fall from day 10 to 12 (p < 0.03). In isografts from day 7 to 10, the goblet cell number increased, while the percentage respiratory epithelium remained the same. The percentage respiratory epithelial coverage and the number of goblet cells showed a direct correlation in the allografts (r2 = 0.57)., Conclusions: Our study shows, for the first time, that goblet cell proliferation occurs in the epithelial repair phase in isografts, whereas in allografts the goblet cells are lost and do not recover.

Objective: to evaluate the frequency of potential oral foci of infection in patients scheduled for elective abdominal aortic surgery., Design: prospective clinical study., Materials: oral health and dentures of 50 patients (33 males and 17 females, mean age 65 years) were examined before aortic surgery., Chief Outcome Measures: radiographic and clinical examination with special emphasis on identifying acute and chronic oral and ontogenic conditions which may contribute to aortic prosthesis infection., Results: eighty-two per cent of the patients had some oral infection foci. The mean number of remaining teeth in the cohort was 9.3, and 21% of these were potential infectious foci (62% in the patients). Twenty-six per cent of the patients suffered from oral Candida infection. Seventy-four per cent of the patients had total or partial dentures, 45% of which were ill-fitting and needed repair., Conclusions: oral infectious foci occur frequently in patients needing aortic surgery. Untreated foci may contribute to aortic prosthesis infection. Preoperative oral evaluation and elimination of intraoral infection is recommended for patients scheduled for abdominal aortic repair., (Copyright 2000 Harcourt Publishers Ltd.)

Background: In our swine model of obliterative bronchiolitis preventing obliteration by the standard immunosuppression with cyclosporine, methylprednisolone, and azathioprine was not successful. The purpose of this study was to test the ability of a new immunosuppressive regimen to prevent alloimmune reaction and obliteration of the allografts. This regimen includes the novel macrolide SDZ RAD, i.e., 40-O-(2hydroxyethyl)-rapamycin., Methods: Donor lung allografts of 1 cm3 were implanted sub-cutaneously into 11 random-bred non-related domestic pigs receiving daily oral cyclosporine (10 mg/kg) and methylprednisolone (20 mg). In addition, the animals received either oral azathioprine (2 mg/kg) (Group 1) or oral SDZ RAD (1.5 mg/kg) (Group 2). Histologic alterations were graded from 0 to 3 based on repeatedly removed implants during a follow-up period of 3 months., Results: Total epithelial destruction and permanent luminal obliteration occurred within 37 days in Group 1. After an initial grade of 2.3+/-0.3 destruction, epithelial recovery was evident in Group 2 (P < 0.01), and the bronchi stayed patent. Cartilaginous destruction was milder in Group 2 (P < 0.05) than in Group 1, but chondrocytic proliferation was more intense (P < 0.05). Alveolar tissue and native structures of the bronchial wall were destroyed in Group 1, but preserved in Group 2 with total recovery after a mild-grade initial necrosis., Conclusions: Unlike the standard triple therapy, SDZ RAD combined with cyclosporine and methylprednisolone preserves the pulmonary allografts and prevents epithelial destruction and subsequent luminal obliteration. This suggests that this regimen might efficiently suppress obliterative bronchiolitis and improve long-term results in lung transplant recipients.

Background: The diagnosis of acute rejection in lung transplantation generally relies on transbronchial biopsies. This invasive procedure may be associated with bronchial bleeding or pneumothorax and may not be feasible in patients with severely compromised lung function. The hypothesis of the current study was that histopathological findings of donor bronchial segments implanted into the subcutaneous tissue of lung allograft recipients would predict lung tissue rejection scores, thus providing the clinician with an alternate source of information., Methods: Unilateral left lung transplantation was performed in 34 cynomolgus monkeys as part of a drug efficacy study. After completion of the transplant procedure, 4 bronchial ring segments of the explanted recipient left lung and 4 bronchial ring segments of the non-transplanted right donor lung were implanted subcutaneously in the abdominal region. Lung allograft rejection was evaluated by open lung biopsies of the allograft performed on postoperative (PO) Day 14 and during sacrifice on PO Day 28. At the time of each biopsy, 2 donor and 2 recipient subcutaneous bronchial rings were explanted. Histologic evaluation of the lung tissue samples was performed according to the working formulation of the International Society for Heart and Lung Transplantation. Bronchial rings were independently evaluated by assessing the degree of airway narrowing; percentage of intact epithelial coverage as well as its specific histology (respiratory ciliated, flattened cuboidal, squamous); presence of lymphocytes, macrophages or spindle cells; and presence of peribronchial inflammation, luminal fibrosis, lymphocytic bronchitis or luminal mucous. Statistical analysis was performed by logistic regression., Results: In the recipient bronchial rings, there was no evidence of airway narrowing. There was 98% epithelial coverage, 71% that were respiratory ciliated cells, and there was no inflammation. Donor bronchial rings showed no airway narrowing for monkeys with grade A0 to A2 rejection in tissue biopsies and a maximum narrowing (41.2%) with A4 rejection. Epithelial cell coverage was approximately 100% with grade A0-A2 and 44+/-11% with A4 rejection. Lymphocytic bronchitis was most severe in A4 rejection and minimal in A0 to A2 rejection. By logistic regression analysis, independent predictors of a likelihood of rejection were the degree of airway obliteration, the percentage of epithelial cell coverage, the degree of lymphocytic bronchitis and the product of respiratory and flattened cuboidal cell coverage., Conclusions: The current data show that histologic alterations of subcutaneously implanted donor bronchial rings correlate with lung tissue biopsy scores based on the ISHLT working formulation. Because subcutaneous bronchial rings can be explanted under local anesthesia, they may provide useful information for the diagnosis of acute allograft rejection in patients with impaired lung function, patients that obtaining lung tissue samples may not be feasible.

Background: We studied a heterotopic large-animal model with obliterative airway lesions caused by allograft rejection., Methods: Lung fragments (1 cm3) with airways (LB), and 1 to 2 mm diameter bronchi alone (B) were implanted subcutaneously in 11 domestic piglets weighing 20 kg. Six animals each received 40 implants from nonrelated donors without immunosuppression (group A). Another 5 animals had autograft implants (group U). The implants were harvested consecutively for histologic analysis over 3 months in group A and 6 months in group U., Results: In group U, the initial ischemia caused mild to moderate epithelial damage with moderate metaplasia but with a return to normal ciliary epithelium within 1 month. Transient mild luminal obliteration with granulation tissue and mononuclear cells was observed during the first weeks, but after 4 weeks the lumen was patent and filled with mucus. In the bronchial wall, moderate fibrosis developed in LB implants, whereas mild fibrosis was seen in B implants. In group A, the epithelium was totally absent by 2 weeks, and mild inflammation, fibrosis, and destruction of the cartilage with pericartilaginous mononuclear accumulation were observed in the bronchial wall. Small airways were gradually obliterated between days 7 and 21, initially by granulation tissue and mononuclear cells and later by progressive fibrosis., Conclusions: In this model, autografted airway implants stayed patent for at least 6 months, whereas total luminal obliteration histologically resembling obliterative bronchiolitis developed in allografts within 21 days. Because small airways, including bronchioli, can be transplanted with the use of this model, it may be useful for research into the causes of airway obliteration, which may be relevant to the pathogenesis of obliterative bronchiolitis in lung recipients.

Objective: Our aim was to evaluate the development of changes on high-resolution CT (HRCT) associated with chronic pulmonary rejection., Materials and Methods: Repeated HRCT examinations were performed 140 times on 13 consecutive lung transplant recipients during a mean observation period of 26 months. The postoperative time interval to the first detection of each chronic change on CT was calculated and compared with the onset of chronic rejection. Bronchiolitis obliterans syndrome (BOS) or the histologic diagnosis of obliterative bronchiolitis was assessed by the published criteria of the International Society for Heart and Lung Transplantation., Results: BOS developed in eight patients, on an average, within 11.6 (+/-5.0) months. Histologic diagnosis was available from five patients. On HRCT, among the first identifiable chronic changes were volume contraction, decreased peripheral vascular and bronchial markings, and thickening of septal lines, all of which appeared between 7 (+/-5.0) and 11 (+/-6.8) months postoperatively. The mean interval for appearance of bronchodilatation was 12.5 (+/-8.7) months. Hyperlucency and mosaic phenomenon were identified, on an average, 16 (+/-6.3) and 21 (+/-7.3) months after transplantation., Conclusion: On radiologic monitoring of lung recipients with HRCT, in addition to bronchodilatation. a special attention should be paid to the early chronic changes, including diminution of peripheral bronchovascular markings, thickening of septal lines, and volume reduction, which usually precede the establishment of the diagnosis of chronic rejection, whereas hyperlucency and mosaic phenomenon usually appear during more advanced BOS.

Decreased exercise capacity is the main factor restricting the daily life of patients with chronic congestive heart failure (CHF). We performed a controlled, randomized study to evaluate the effect of dynamic exercise training of moderate intensity on exercise capacity and gas exchange in patients with CHF. Twenty-seven patients with stable CHF, New York Heart Association (NYHA) functional class II and III, were randomized to training (n = 12) and control (n = 15) groups. During a 3-month period, the training group underwent a supervised physical training program using a bicycle ergometer for 30 min 3 times a week at a load corresponding to 50 to 60% of their peak oxygen consumption. Thereafter, they were advised to continue training at home for the next 3 months. The control group did not change their previous physical activity. A graded maximal exercise test with respiratory gas analysis and an endurance test with constant submaximal workload were performed at baseline and after 3 and 6 months. The exercise endurance increased from 14.7 +/- 2.0 to 27.8 +/- 2.7 min (p < 0.01) and the peak oxygen consumption tended to improve from 19.3 +/- 1.6 to 21.7 +/- 2.3 mL/kg/min (p = 0.09) during the supervised training period. At submaximal workloads, minute ventilation was reduced by 16% per se (p < 0.01) and by 7% in proportion to carbon dioxide production (p < 0.05). Oxygen consumption at the anaerobic threshold increased from 10.5 +/- 0.8 to 12.7 +/- 1.0 mL/kg/min (p < 0.05). The positive training effects were associated with an improvement in the NYHA functional class. The effects of supervised training were preserved during the home-based training period. The results indicate that physical training of moderate intensity significantly improves the exercise capacity and reduces the exaggerated ventilatory response to exercise, particularly at submaximal working levels in patients with CHF. This is associated with alleviation of symptoms.

Background: Chronic rejection is a major long-term complication after lung transplantation. The purpose of our study was to evaluate the role of repeated high-resolution computed tomographic examinations in monitoring the development of bronchiolitis obliterans syndrome after lung transplantation., Methods: A total of 126 high-resolution computed tomographic examination in 13 lung transplant recipients was analyzed. During a mean follow-up period of 23 months, bronchiolitis obliterans syndrome developed in eight of the patients. A scoring system from 0 to 10 based on the number of chronic changes on high-resolution computed tomography was developed, and the score of each patient was compared with decline in the forced expiratory volume in 1 second and maximal forced expiratory flow rate of 50% of the forced vital capacity., Results: The score of chronic changes, measured at 1 year after transplantation, correlated inversely with the values of forced expiratory volume in 1 second and maximal forced expiratory flow rate at 50% of the forced vital capacity (p < 0.05). Stage I bronchiolitis obliterans syndrome was associated with scores of 4 to 6 (mean 5.0), stage 2 with scores of 6 to 9 (mean 7.0), and stage 3 with scores of 6 to 9 (mean 7.7). The sensitivity of high-resolution computed tomography was 93% and its specificity was 92% when five chronic changes were used as a cutoff level., Conclusions: The progress of chronic changes on high-resolution computed tomography occurs concurrently with the development of bronchiolitis obliterans syndrome. High-resolution computed tomography may provide additional morphologic information for noninvasive evaluation of chronic lung rejection.

In single-lung transplant recipients, the usefulness of spirometric indexes in detecting acute events involving the lung graft is limited due to the bias caused by the native lung. Selective functional monitoring is needed for the proper evaluation of complications after transplantation, but thus far, to our knowledge, no clinically feasible methods for selective graft-function assessment have been presented. In ten single-lung recipients, of whom six had a parenchymal lung disease and four had pulmonary hypertension, the relative ventilation (Vtx), perfusion (Qtx), and ventilation/perfusion ratio of the transplanted lung (V/Qtx) were determined with multidetector 133Xe radiospirometry. Additionally, the fractions of FEV1, FVC, and diffusing capacity for carbon monoxide (Dco) of the transplant (FEV1tx, FVCtx, Dcotx, respectively) were determined by using corresponding radiospirometric parameters for the calculation of their distribution between the lungs. The analysis included seven episodes of acute rejection and nine episodes of infection. The Qtx decreased during acute rejection but did not change during infection (p=0.001). Compared with the figures during infection, the V/Qtx increased during acute rejection significantly (p<0.05) in patients with underlying fibrosis or emphysema, but not in those with pulmonary hypertension. In detection of acute events, the sensitivity of the selective parameters, ie, FEV1tx (86%) and FVCtx (73%), was higher than that of the sum-function parameters, FEV1 (66%) and FVC (40%). Moreover, the sensitivity of Dcotx (80%) was higher than that of Dco (60%) in detecting acute rejection. The findings indicate that, in single-lung recipients with a parenchymal lung disease, the assessment of Qtx, V/Qtx, and Dcotx with a radioactive tracer can help to distinguish acute rejection from infection. The graft-selective parameters, ie, FEV1tx, FVCtx, and Dcotx, tended to be more sensitive than the corresponding sum-function parameters in detecting acute events, thus providing a more accurate functional profile of the single-lung graft.

Background: Staging of bronchiolitis obliterans syndrome is based on the decline of forced expiratory volume in 1 second, a measure of overall ventilatory capacity. A single staging system is applied to all lung recipients, regardless of the bias which can be caused by the native lung after single lung transplantation., Methods: We determined the decline of graft function in single lung recipients by a combination of two methods: 133-Xe radiospirometry and dynamic spirometry. The forced expiratory volume in 1 second fraction of the transplant (FEV1tx) was calculated from the proportion of ventilation of the transplant (Vtx) and forced expiratory volume in 1 second. Eight single lung recipients were followed up for a median observation period of 17 months; bronchiolitis obliterans syndrome developed in four of them., Results: The fractional decline of forced expiratory volume in 1 second of the transplant was significantly greater than the decline of forced expiratory volume in 1 second (p = 0.016) in all patients during the follow-up. In the patients with bronchiolitis obliterans syndrome, the mean decline in forced expiratory volume in 1 second was 1.1 L (39.5%), and in forced expiratory volume in 1 second of the transplant it was 0.9 L (55.8%). The measurement of forced expiratory volume in 1 second of the transplant suggested stage 2a and 3a dysfunction in two grafts in which the assessment of forced expiratory volume in 1 second indicated stage 1a bronchiolitis obliterans syndrome. In one patient, decrease of forced expiratory volume in 1 second of the transplant was suggestive of chronic dysfunction 4 months before it was diagnosed by biopsy and declined lung function., Conclusions: The assessment of forced expiratory volume in 1 second seems to underestimate the severity of chronic dysfunction in single lung grafts. Instead, the determination of forced expiratory volume in 1 second of the transplant with radioactive tracers provides selective information of the graft function, which could be used for clinical evaluation of bronchiolitis obliterans syndrome in single lung recipients.