Computational Fluid Dynamics (CFD) Analysis of Subject-specific Bronchial Tree Models in Lung Cancer Patients.

Lung resection is the only potentially curative treatment for lung cancer. The inevitable partial removal of functional lung tissue along with the tumoral mass requires a careful and structured pre-operative condition of patients. In particular, the postoperative residual functionality of the lung needs to be predicted. Clinically, this is assessed through algorithms based on pulmonary function tests (PFTs). However, these approaches neglect the local airway segment's functionality and provide a globally averaged evaluation. CFD was demonstrated to provide patient-specific, quantitative, and local information on flow dynamics and regional ventilation in the bronchial tree. This study aims to apply CFD to characterize the flow dynamics in 12 patients affected by lung cancer and evaluate the effects of the tumoral masses on flow parameters and lobar flow distribution. Patient-specific airway models were reconstructed from CT images, and the tumoral masses were manually segmented. Measurements of lungs and tumor volumes were collected. A peripherality index was defined to describe tumor distance from the parenchyma. CFD simulations were performed in Fluent®, and the results were analyzed in terms of flow parameters and lobar volume flow rate (VFR). The predicted postoperative forced expiratory volume in 1s (ppoFEV1) was estimated and compared to the current clinical algorithm. The patients under analysis showed relatively small tumoral masses located close to the lung parenchyma. CFD results did not highlight lobar alterations of flow parameters, whereas the flow to the lung affected by the tumor was found to be significantly lower (p=0.026) than the contralateral lung. The estimation ppoFEV1 obtained through the results of the simulations showed a high correlation (ρ=0.993, p<0.001) with the clinical formula.Clinical Relevance- The proposed study establishes the efficacy and applicability of CFD for the pre-operative characterization of patients undergoing lobectomy surgery. This technique can provide additional information on local functionality and flow dynamics to support patients' operability.

A spectroscopic and molecular dynamics study on the aggregation process of a long-acting lipidated therapeutic peptide: the case of semaglutide.

The aggregation properties of semaglutide, a lipidated peptide drug agonist of the Glucagon-like peptide 1 receptor recently approved for the treatment of type 2 diabetes, have been investigated by spectroscopic techniques (UV-Vis absorption, steady-state and time-resolved fluorescence, and electronic circular dichroism) and molecular dynamics simulations. We show that in the micromolar concentration region, in aqueous solution, semaglutide is present as monomeric and dimeric species, with a characteristic monomer-to-dimer transition occurring at around 20 µM. The lipid chain stabilizes a globular morphology of the monomer and dimer species, giving rise to a locally well-defined polar outer surface where the lipid and peptide portions are packed to each other. At very long times, these peptide clusters nucleate the growth of larger aggregates characterized by blue luminescence and a ß-sheet arrangement of the peptide chains. The understanding of the oligomerization and aggregation potential of peptide candidates is key for the development of long acting and stable drugs.

Lung Allocation Score System: First Italian Experience.

BACKGROUND: Lung transplantation is an established therapeutic option for patients with end-stage pulmonary disease. In May 2005, the lung allocation score (LAS) was introduced in the United States to maximize the benefit to the recipient population and reduce waiting list mortality. The LAS has been applied in a region of Italy since March 2016 on a provisional basis. The aims of the study were describing waiting list characteristics and short-term outcomes after lung transplantation before and after LAS introduction. METHODS: All the patients who received transplants between January 1, 2011, and March 15, 2017, were included in our retrospective study. The study population was divided into 2 cohorts (historical cohort and post-LAS cohort) and a comparison among the main perioperative data was performed. RESULTS: The historical cohort consisted of 415 patients on the waiting list with 91 deaths and 199 lung transplants; the post-LAS cohort consisted of 134 patients with 10 deaths on the waiting list and 51 transplants. Median waiting time and mortality on the list decreased from 223 to 106 days (P = .03) and from 11.2% to 7.5% (P > .05), respectively. The transplantation rate increased from 25% to 38% (P = .001) and the probability to receive a transplant in the first year in the post-LAS era increased significantly (P = .004). CONCLUSIONS: The results of the introduction of the LAS system in our region are encouraging and have not shown any adverse short-term effects. The regional coordination decided to prolong the experimental application of LAS in order to accumulate more data and to evaluate medium-term outcomes.

Lung Transplant From Donor With Tracheal Bronchus: Case Report and Literature Review.

Donor lung abnormalities are quite rare; one of them is the presence of bronchial anomalies, whose incidence range is from 0.1% to 0.5%. The upper right tracheal bronchus is one of the most frequent anatomic variations. We present a case of successful double lung transplant in a young female patient affected by cystic fibrosis from a donor with upper right tracheal bronchus, emerging 2 rings before the tracheal carina. During implantation of the left lung, we performed a double apical segmentectomy on back table; therefore, the right lung was implanted with the standard technique. Four cases of graft transplant characterized by the presence of tracheal bronchus are reported in the scientific literature; the authors report 4 different technical solutions to tackle the problem of anatomic anomaly. We report the first case of graft segmentectomy at back table suggesting a simple, safe, and time-sparing procedure. In conclusion, provided that the team has sufficient skill in reductive surgery at the back table and the anthropometric data are permissive, we stress the opportunity to downsize the graft in order to minimize anastomotic risks and save time.

Lung Transplantation as Successful Treatment of End-stage Idiopathic Pleuroparenchymal Fibroelastosis: A Case Report.

Pleuroparenchymal fibroelastosis (PPFE) is a rare condition, characterized by predominantly upper-lobe pleural and subjacent parenchymal fibrosis, the latter being intra-alveolar with accompanying elastosis of the alveolar walls that leads a clinical progression to respiratory failure. This condition may not be as rare as it seems to be, because nowadays the increasing awareness among specialists is raising the number of new diagnoses. Limited data are available about the prognosis, both for secondary and idiopathic forms. Nevertheless, the idiopathic form seems to be rapidly progressive and no treatment can control the disease, which is why management is challenging. Since the disease was characterized, PPFE cases have been reported in the literature, but most have been secondary rather than idiopathic. Of these, few have successfully undergone lung transplantation as a treatment of end-stage respiratory failure. We here report a successful case of a 38-year-old man affected by idiopathic PPFE who underwent bilateral lung transplantation after extracorporeal membrane oxygenation bridging for an abrupt transition to critical clinical conditions. After a complex postoperative course and a first year characterized by acute rejection, the patient is alive at 5 years with a good quality of life. Our experience confirms that lung transplantation would be a valuable treatment option in case of end-stage idiopathic PPFE cases.

Lobar Lung Transplantation From Deceased Donor: Monocentric Experience.

INTRODUCTION: Lung transplantation is considered a therapeutic option in selected patients affected by end-stage pulmonary disease. The mortality on the waiting list is mainly attributed to the shortage of the donor pool available for transplantation. There are various strategies to overcome this shortage; one of them is lobar transplantation. METHODS: The aim of the current study was to analyze the outcome of lobar lung transplantation from deceased donors in our Lung Transplant Center. Overall survival, perioperative mortality and morbidity, problem on bronchial anastomosis, and chronic rejection were prospectively recorded in a 5-year time-frame. RESULTS: From November 2010 to October 2015, we performed 100 lung transplantations; 6 of which (6%) were lobar transplantations from deceased donors. Three recipients were on an emergency list due to preoperative extracorporeal support. The causes of lobectomy leading to lobar transplantation were: size mismatch (3), iatrogenic vascular damage (2), and chronic atelectasis (1). One patient died 5 months after surgery for sepsis; and 5 patients were alive at the study end (median follow-up: 17.5 months). Prevalence of grade 3 primary graft dysfunction at 72 hours was 50%. One patient developed bronchial stenosis. No cases of chronic rejection were recorded. CONCLUSIONS: Lobar transplantation can be considered a valid tool to overcome the donor pool shortage in selected cases; such a technique has proved particularly useful in critically ill patients who were scheduled in an emergency transplant program.

Lung Transplantation From Donors After Previous Cardiac Surgery: Ideal Graft in Marginal Donor?

Lung transplantation is a limited by donor pool shortage. Despite the efforts to extend the graft acceptability with recurrent donor criteria reformulations, previous cardiothoracic surgery is still considered a contraindication. A donor who underwent cardiac surgery could potentially provide an ideal lung but high intraoperative risks and intrinsic technical challenges are expected during the graft harvesting. The purpose of this study is to present our dedicated protocol and four clinical cases of successful lung procurements from donors who had a previous major cardiac surgery. One donor had ascending aortic root (AAR) substitution, another had mitral valve substitution, and two had coronary artery bypass surgery. The others' eligibility criteria for organ allocation, such as ABO compatibility, PaO2/FiO2 ratio, absence of aspiration, or sepsis were respected. In one of the cases with previous coronary bypass grafting, the donor had a veno-arterial extracorporeal membrane oxygenation support. Consequently, the grafts required an ex vivo lung perfusion evaluation. We report the technical details of procurement and postoperative courses of recipients. All procurements were uneventful, without lung damage or waste of abdominal organs related to catastrophic intraoperative events. All recipients had a successful clinical outcome. We believe that successful transplantation is achievable even in a complicated setting, such as cases involving donors with previous cardiac surgery frequently are. Facing lung donor shortage, we strongly support any effort to avoid the loss of possible acceptable lungs. In particular, previous major cardiac surgery does not strictly imply a poor quality of lungs as well as unsustainable graft procurement.

Lung Allocation Score: A Single-Center Simulation.

BACKGROUND: The lung allocation score (LAS) was introduced in the United States in May 2005 with the main goal of reducing the waiting list mortality of patients with end-stage lung diseases, but also to enhance the lung transplant benefit and improve the management of urgent candidates. Several papers have reported that LAS resulted in a reduction of the waiting list mortality but no significant survival benefit was noted. METHODS: We evaluate the usefulness of LAS as a predictor for lung transplantation outcome in 123 patients listed for lung transplantation in an Italian center. Primary endpoints were waiting list mortality and posttransplant mortality at 1 year; secondary endpoints included perioperative circulatory support, cardiopulmonary bypass, primary graft dysfunction, and long-term survival after transplantation. RESULTS: We observed the absence of correlation between LAS and waiting list mortality. The LAS did not affect the long-term survival in our population. CONCLUSIONS: High LAS was predictive of primary graft dysfunction of grade 3 in the first 72 hours after transplantation.

Successful Transplantation of Lungs From an Uncontrolled Donor After Circulatory Death Preserved In Situ by Alveolar Recruitment Maneuvers and Assessed by Ex Vivo Lung Perfusion.

We developed a protocol to procure lungs from uncontrolled donors after circulatory determination of death (NCT02061462). Subjects with cardiovascular collapse, treated on scene by a resuscitation team and transferred to the emergency room, are considered potential donors once declared dead. Exclusion criteria include unwitnessed collapse, no-flow period of >15 min and low flow >60 min. After death, lung preservation with recruitment maneuvers, continuous positive airway pressure, and protective mechanical ventilation is applied to the donor. After procurement, ex vivo lung perfusion (EVLP) is performed. From November 2014, 10 subjects were considered potential donors; one of these underwent the full process of procurement, EVLP, and transplantation. The donor was a 46-year-old male who died because of thoracic aortic dissection. Lungs were procured 4 h and 48 min after death, and deemed suitable for transplantation after EVLP. Lungs were then offered to a rapidly deteriorating recipient with cystic fibrosis (lung allocation score [LAS] 46) who consented to the transplant in this experimental setting. Six months after transplantation, the recipient is in good condition (forced expiratory volume in 1 s 85%) with no signs of rejection. This protocol allowed procurement of lungs from an uncontrolled donor after circulatory determination of death following an extended period of warm ischemia.

Molecular dynamics methods to predict peptide locations in membranes: LAH4 as a stringent test case.

Determining the structure of membrane-active peptides inside lipid bilayers is essential to understand their mechanism of action. Molecular dynamics simulations can easily provide atomistic details, but need experimental validation. We assessed the reliability of self-assembling (or "minimum-bias") and potential of mean force (PMF) approaches, using all-atom (AA) and coarse-grained (CG) force-fields. The LAH4 peptide was selected as a stringent test case, since it is known to attain different orientations depending on the protonation state of its four histidine residues. In all simulations the histidine side-chains inserted in the membrane when neutral, while they interacted with phospholipid headgroups in their charged state. This led to transmembrane orientations for neutral-His LAH4 in all minimum-bias AA simulations and in most CG trajectories. By contrast, the charged-His peptide stabilized membrane defects in AA simulations, whereas it was located at the membrane surface in some CG trajectories, and interacted with both lipid leaflets in others. This behavior is consistent with the higher antimicrobial activity and membrane-permeabilizing behavior of the charged-His LAH4. In addition, good agreement with solid-state NMR orientational data was observed in AA simulations. PMF calculations correctly predicted a higher membrane affinity for the neutral-His peptide. Interestingly, the structures and relative populations of PMF local free-energy minima corresponded to those determined in the less computationally demanding minimum-bias simulations. These data provide an indication about the possible membrane-perturbation mechanism of the charged-His LAH4 peptide: by interacting with lipid headgroups of both leaflets through its cationic side-chains, it could favor membrane defects and facilitate translocation across the bilayer.

Clinical risk factors for primary graft dysfunction in a low-volume lung transplantation center.

Primary graft dysfunction (PGD) is a severe acute lung injury syndrome following lung transplantation. Previous studies of clinical risk factors, including a multicenter prospective cohort trial, have identified a number of recipient, donor, and operative variables related to Grade 3 PGD. The aim of this study was to validate these risk factors in a lung transplantation center with a low volume of procedures. We conducted a retrospective cohort study of 45 consecutive lung transplantations performed between January 2011 and September 2013. PGD was defined according to the International Society for Heart and Lung Transplantation grading scale. Risk factors were evaluated independently and the significant confounders entered into multivariable logistic regression models. The overall incidence of Grade 3 PGD was 35.5% at T24, 17.7% at T48, and 15.5% at T72. The following risk factors were associated with Grade 3 PGD at the indicated time points: recipient female gender at T24 (P=.034), mixed diagnoses at T72 (P=.047), ECMO bridge-to-lung transplantation at T24 (P=.0004) and at T48 (P=.038), donor causes of death different from stroke and trauma at T24 (P=.019) and T72 (P=.014), blood transfusions during surgery at T24 (P=.001), intraoperative venoarterial ECMO T24 (P<.0001). Multivariate analysis at T24 identified recipient female gender and intraoperative venoarterial ECMO as risk factors (P=.010 and P=.018, respectively). This study demonstrated that risk factors for severe PGD in a low-volume center were similar to international reports in prevalence and type. ECMO bridge-to-lung transplantation emerged as a risk factor previously underestimated.

Graft downsizing during ex vivo lung perfusion: case report and technical notes.

Among patients with respiratory insufficiency awaiting lung transplantation, small adult patients have a lower opportunity of receiving size-matched pulmonary grafts, because of the shortage of donors, particularly those of small size. Reducing the size of an oversized graft is one of the methods to increase the donor pool; similarly, ex vivo lung perfusion is an emerging technique aimed toward the same purpose. We describe how we combined the 2 techniques (lobar transplantation plus contralateral nonanatomic graft reduction during ex vivo lung perfusion) to overcome graft shortage in a clinical case. For the 1st time, this case report demonstrates that surgical manipulation during ex vivo lung perfusion does not affect the functional improvement in a lung previously judged to be not suitable for transplantation. The 6-month follow-up results are similar to those of standard bilateral lung transplantation.

Fibrils or globules? Tuning the morphology of peptide aggregates from helical building blocks.

The aggregation propensity of helical oligopeptides formed exclusively by the conformationally constrained α-aminoisobutyric acid (Aib or U in a three- or single-letter code, respectively) was studied in methanol and methanol/water solutions by spectroscopic methods (UV-vis absorption, steady-state and time-resolved fluorescence, and FT-IR absorption) and atomic force microscopy (AFM) imaging. The peptides investigated have the general formula UnN, where n = 6, 12, and 15 and N stands for a naphthyl chromophore introduced with the dual aim to serve as a spectroscopic probe and to analyze the effect of an extended aromatic group on the aggregation process. Experiments showed that the aggregation propensity in (70/30)v/v and (50/50)v/v methanol/water solutions increases with increasing the length of the peptide chain, i.e., U6N < U12N < U15N. When the peptides are immobilized on mica as a dried film, the interplay of aromatic-aromatic and interhelix interactions, the latter becoming more and more important with the elongation of the peptide chain, governs the morphology of the resulting mesoscopic aggregates. AFM imaging revealed the formation of globular or fibrillar structures, the predominance of which is controlled by the helix length of the peptide building block.

Membrane thickness and the mechanism of action of the short peptaibol trichogin GA IV.

Trichogin GA IV (GAIV) is an antimicrobial peptide of the peptaibol family, like the extensively studied alamethicin (Alm). GAIV acts by perturbing membrane permeability. Previous data have shown that pore formation is related to GAIV aggregation and insertion in the hydrophobic core of the membrane. This behavior is similar to that of Alm and in agreement with a barrel-stave mechanism, in which transmembrane oriented peptides aggregate to form a channel. However, while the 19-amino acid long Alm has a length comparable to the membrane thickness, GAIV comprises only 10 amino acids, and its helix is about half the normal bilayer thickness. Here, we report the results of neutron reflectivity measurements, showing that GAIV inserts in the hydrophobic region of the membrane, causing a significant thinning of the bilayer. Molecular dynamics simulations of GAIV/membrane systems were also performed. For these studies we developed a novel approach for constructing the initial configuration, by embedding the short peptide in the hydrophobic core of the bilayer. These calculations indicated that in the transmembrane orientation GAIV interacts strongly with the polar phospholipid headgroups, drawing them towards its N- and C-termini, inducing membrane thinning and becoming able to span the bilayer. Finally, vesicle leakage experiments demonstrated that GAIV activity is significantly higher with thinner membranes, becoming similar to that of Alm when the bilayer thickness is comparable to its size. Overall, these data indicate that a barrel-stave mechanism of pore formation might be possible for GAIV and for similarly short peptaibols despite their relatively small size.

Extracorporeal lung perfusion and ventilation to improve donor lung function and increase the number of organs available for transplantation.

INTRODUCTION: Ex vivo lung perfusion (EVLP) has been validated as a valuable technique to increase the pool of organs available for lung transplantation. MATERIAL AND METHODS: After a preclinical experience, we obtained permission from the Ethics Committee of our institution to transplant lungs after EVLP reconditioning. ABO compatibility, size match, and donor arterial oxygen pressure (PaO(2))/fraction of inspired oxygen (FiO(2)) ≤ 300 mm Hg were considered to be inclusion criteria, whereas the presence of chest trauma and lung contusion, evidence of gastric content aspiration, pneumonia, sepsis, or systemic disease were exclusion criteria. We only considered subjects on an extra corporeal membrane oxygenation (ECMO) bridge to transplantation with rapid functional deterioration. Using Steen solution with packed red blood cells oxygenated with 21% O(2), 5% to 7% CO(2) was delivered, targeted with a blood flow of approximately 40% predicted cardiac output. Once normothermic, the lungs were ventilated with a tidal volume of 7 mL/kg a PEEP of 5 cmH(2)O and a respiratory rate of 7 bpm. Lungs were considered to be suitable for transplantation if well oxygenated [P(v-a) O(2) > 350 mm Hg on FiO(2) 100%], in the absence of deterioration of pulmonary vascular resistance and lung mechanics over the perfusion time. RESULTS: From March to September 2011, six lung transplantations were performed, including two with EVLP. The functional outcomes were similar between groups: at T72 posttransplantation, the median PaO(2)/FiO(2) were 306 mm Hg (range, 282 to 331 mm Hg) and 323 mm Hg (range, 270 to 396 mm Hg) (P = 1, EVLP versus conventional). Intensive care unit ICU and hospital length of stay were similar (P = .533 and P = .663, respectively) with no mortality at 60 days in both groups. EVLP donors were older (49 ± 6 y versus 21 ± 7 y, P < .05), less well oxygenated (184 ± 6 mm Hg versus 570 ± 30, P < .05), displaying higher Oto scores (9.5 ± 0.7 versus 1.7 ± 1.5, P < .05). CONCLUSIONS: The first 6 months of the EVLP program allowed us to increase the number of organs available for transplantation with short-term outcomes comparable to conventional transplantations.

Lung transplantation and posterior reversible encephalopathy syndrome: a case series.

Posterior reversible encephalopathy syndrome is a neurological problem characterized by headache, altered mental status, focal neurological deficits, visual disorders, and seizures. The disorder is related to a number of diseases including calcineurin inhibitor therapy in solid organ transplantation. The incidence of posterior reversible encephalopathy syndrome in lung transplantation patients is unclear; probably the majority of the cases are unreported. The authors have described a case series constituted of four patients presenting posterior reversible encephalopathy syndrome after bilateral lung transplantation. The cases had in common complicated surgery and a posttransplant course characterized by hypertension, hypomagnesemia and acidosis. Invasive mechanical ventilation, calcineurin inhibitor discontinuation, aggressive antihypertensive therapy, and electrolyte regulation led to near complete recovery of symptoms.

Early lung retransplantation in a patient affected by cystic fibrosis correlated with donor cause of death: a case report.

The relationship between donor cause of death and lung transplantation outcomes remains unclear. We report a case of lung transplantation in a young patient affected by cystic fibrosis. Immediately after lung reperfusion a pulmonary hypertension was observed that was intractable with maximal medical therapy requiring surgical resection of the left lower lobe which became congested after a few days. The donor had died from suicidal hanging; the authors attributed the posttransplantation pulmonary hypertension which is an uncommon form of primary graft dysfunction to this cause of death. The patient was treated with early bilateral lung retransplantation which required a long, troublesome hospital stay. In conclusion, the authors warn against the use of lungs from donors who die due to hanging even when the gas exchanges were ideal.

Late lung retransplantation using extracorporeal membrane oxygenation as a bridge: case report.

Lung retransplantation is the only therapeutic option for acute and chronic graft failure, but only a few cases have been described to have been performed with extracorporeal membrane oxygenation (ECMO) support. We describe the successful case of a 46-year-old man treated with right lung transplantation and left lung retransplantation supported by venovenous ECMO. Lung retransplantation is the only therapeutic option to treat severe primary graft dysfunction, major technical problems, and refractory chronic rejection following pulmonary transplantation. Despite a number of comprehensive studies on lung retransplantation, only a few works have addressed the use of extracorporeal membrane oxygenation (ECMO) as a bridge to the surgical reoperation. Herein we have presented a patient treated with pulmonary bilateral retransplantation subsequent to ECMO therapy for progressive deterioration of pulmonary function in single lung transplantation.

Primary pulmonary glomangioma: a coin lesion negative on PET study. Case report and literature review.

Glomus tumor is an uncommon perivascular lesion usually located in the dermis of the extremities. It rarely involves the respiratory tract or the lungs. We present the clinical and pathological features of a 39-year-old man who was evaluated for an incidental radiological finding of a pulmonary nodule. A chest computed tomography (CT) confirmed the presence of an upper left lobe coin lesion. Bronchoscopy and 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) were negative. An intraoperative frozen section examination was interpreted as a neuroendocrine tumor; therefore a left upper lobectomy with lymphadenectomy was performed. An immunohistochemical examination supported the diagnosis of a primary pulmonary glomangioma. The patient was free of disease at the 51-month follow-up. Due to its uncertain behavior we stress the usefulness of typical lung resection, lymph node dissection, and accurate follow-up.

Bridge to lung transplantation by venovenous extracorporeal membrane oxygenation: a lesson learned on the first four cases.

Extracorporeal membrane oxygenation (ECMO) is the only therapeutic option for patients with ventilation-refractory hypercapnia while awaiting lung transplantation. Moreover, there is increasing success using ECMO for definitive respiratory failure in formerly healthy patients. This report describes the use of membrane oxygenation as a bridge to lung transplantation in 2 patients on the waiting list and in 2 previously healthy patients. Our experience showed that coagulation management, critical illness myopathy, and psychological disorders were the most critical problems. One patient died at 2 days after transplantation, 1 at 3 months, and 2 returned to their pretransplantation activities. We concluded that ECMO is an adequate bridge to lung transplantation but, especially in formerly healthy patients, an awake procedure is advisable for a successful outcome.