Update on Novel Targeted Therapy for Pleural Organization and Fibrosis.

Pleural injury and subsequent loculation is characterized by acute injury, sustained inflammation and, when severe, pathologic tissue reorganization. While fibrin deposition is a normal part of the injury response, disordered fibrin turnover can promote pleural loculation and, when unresolved, fibrosis of the affected area. Within this review, we present a brief discussion of the current IPFT therapies, including scuPA, for the treatment of pathologic fibrin deposition and empyema. We also discuss endogenously expressed PAI-1 and how it may affect the efficacy of IPFT therapies. We further delineate the role of pleural mesothelial cells in the progression of pleural injury and subsequent pleural remodeling resulting from matrix deposition. We also describe how pleural mesothelial cells promote pleural fibrosis as myofibroblasts via mesomesenchymal transition. Finally, we discuss novel therapeutic targets which focus on blocking and/or reversing the myofibroblast differentiation of pleural mesothelial cells for the treatment of pleural fibrosis.

Experience harvesting costal cartilage under IV sedation.

IMPORTANCE: While numerous techniques for costal cartilage harvesting have been described, one consistency in the published literature is that the procedure is performed under general anesthesia. This is the first report to offer IV sedation as a safe alternative to general inhalational anesthesia in cases involving costal cartilage harvesting. OBJECTIVE: To determine the feasibility and safety of costal cartilage harvest with IV sedation. DESIGN: A retrospective chart review was performed of 116 rhinoplasty patients who underwent harvest of costal cartilage grafts under IV sedation from 2005 to 2019. SETTING: Private practice of senior author (AF) at Lasky Clinical Surgical Center. PARTICIPANTS: Consecutive patients who underwent cosmetic and/or functional rhinoplasty. MAIN OUTCOME & MEASURES: The number of cases involving a pneumothorax, size of the pleural injury, radiographic findings, repair technique and treatment for pneumothorax were all recorded. RESULTS: There were 7 cases involving a pleural tear (size range 3-8 mm) during costal cartilage harvest and each of these was repaired intra-operatively. All 7 patients remained clinically stable in recovery room on 2 L of oxygen. Although clinically stable, one patient had radiologic evidence of a pneumothorax of 50%, and thus she was transferred to a hospital for placement of a Heimlich tube with overnight observation. CONCLUSIONS AND RELEVANCE: Although plenural tears can be attributed to surgical technique rather than the type of anesthesia, these cases do provide valuable insight to the fact that successful management of such complications can be accomplished without the need for general anesthesia.

Massive subcutaneous emphysema mimicking anaphylaxis - pathological and radiological correlations.

This report details the pathological and radiological findings in a rare case of massive subcutaneous emphysema. A 74-year-old male presented with sudden onset dyspnea and facial swelling following a fall. His symptoms were refractory to treatments for anaphylaxis, which was suspected clinically, and he quickly succumbed. Autopsy, including post mortem CT scan revealed the underlying etiology to be multiple rib fractures with rupture of the parietal pleura, bilateral pneumothoraxes and massive subcutaneous emphysema involving the face, torso and upper limbs. Multiple frothy air bubbles were observed throughout the mediastinal adipose tissues on internal examination. Our findings echo those of rare previous reports and show how subcutaneous emphysema may, in rare circumstances, mimic anaphylaxis.

[Occurrence of a lethal outcome due to iatrogenic damage of an intercostal vessel during a pleural puncture procedure]. / Nastuplenie letal'nogo iskhoda vsledstvie iatrogennogo povrezhdeniia vetvi mezhrebernoi arterii pri provedenii plevral'noi punktsii.

A rare case of a lethal outcome due to iatrogenic damage to the intercostal vessel, a collateral branch of the posterior intercostal artery, is described. The little-known features of the topography of this vessel (location on the upper edge of the underlying rib), which requires further study in the context of variable anatomy, are given. The risks associated with deviations from the traditionally recommended sites of pleural puncture (below the eighth intercostal space to the scapular line) are substantiated. An analysis of the characteristics of bleeding arising from the intercostal vessels (from two ends, under high pressure, etc.) is given, which implies the extreme importance of a timely diagnosis. Differing points of view on the legal assessment of malpractice when care is delivered by a series of doctors, and the legal necessity of determining the 'point of no return' (the latest moment after the onset of bleeding, in which medical aid can still prevent an unfavorable outcome), are considered. An opinion is expressed on the need for the active participation (initiative) of an expert in the provision of expertise.

Inhibition of Glycogen Synthase Kinase 3ß Blocks Mesomesenchymal Transition and Attenuates Streptococcus pneumonia-Mediated Pleural Injury in Mice.

Pleural loculation affects about 30,000 patients annually in the United States and in severe cases can resolve with restrictive lung disease and pleural fibrosis. Pleural mesothelial cells contribute to pleural rind formation by undergoing mesothelial mesenchymal transition (MesoMT), whereby they acquire a profibrotic phenotype characterized by increased expression of α-smooth muscle actin and collagen 1. Components of the fibrinolytic pathway (urokinase plasminogen activator and plasmin) are elaborated in pleural injury and strongly induce MesoMT in vitro. These same stimuli enhance glycogen synthase kinase (GSK)-3ß activity through increased phosphorylation of Tyr-216 in pleural mesothelial cells and GSK-3ß mobilization from the cytoplasm to the nucleus. GSK-3ß down-regulation blocked induction of MesoMT. Likewise, GSK-3ß inhibitor 9ING41 blocked induction of MesoMT and reversed established MesoMT. Similar results were demonstrated in a mouse model of Streptococcus pneumoniae-induced empyema. Intraperitoneal administration of 9ING41, after the induction of pleural injury, attenuated injury progression and improved lung function (lung volume and compliance; P < 0.05 compared with untreated and vehicle controls). MesoMT marker α-smooth muscle actin was reduced in 9ING41-treated mice. Pleural thickening was also notably reduced in 9ING41-treated mice (P < 0.05). Collectively, these studies identify GSK-3ß as a newly identified target for amelioration of empyema-related pleural fibrosis and provide a strong rationale for further investigation of GSK-3ß signaling in the control of MesoMT and pleural injury.

CT-guided core needle biopsy of mediastinal nodes through a transpulmonary approach: retrospective analysis of the procedures conducted over six years.

PURPOSE: To retrospectively evaluate the diagnostic performance and complications of a CT-guided core needle cutting biopsy of mediastinal nodes through a transpulmonary approach. MATERIALS AND METHODS: From January 2009 to December 2014, we used a coaxial positioning system and an 18G cutting-type biopsy device to perform CT-guided percutaneous transpulmonary needle biopsies of mediastinal nodes for 127 patients. The diagnostic performance, complication rate, influencing factors, distribution of mediastinal nodes and pathological diagnoses were investigated. RESULTS: Among 127 patients, pathologic analyses showed that all of the biopsies were technically successful. The sensitivity, specificity, positive predictive value, and negative predictive value were all 100%. As for complications, the ratios for pneumothorax and hemoptysis were 33.9% and 4.7%, respectively. Multivariate analyses revealed that the distance from the pleura to the target lesion (P = 0.008) and the numbers of visceral pleura injuries (P = 0.006) were the two most significant risk factors for pneumothorax, and that the distance from the pleura to the target lesion (P = 0.004) was the most significant risk factor for hemoptysis. CONCLUSIONS: CT-guided core needle cutting biopsy of mediastinal nodes through a transpulmonary approach is a safe and efficient diagnostic method. KEY POINTS: • CT-guided core needle biopsy is an accurate technique for diagnosing mediastinal nodes. • The rates of complications are similar to those for pulmonary lesion biopsy. • Pneumothorax risk factors include distance from pleura to target lesion and number of visceral pleura. • Distance from pleura to target lesion is the risk factor for hemoptysis. • CT-guided core needle biopsy is an important diagnostic method for mediastinal nodes.

[A mysterious pleural lesion: A case report]. / Une mystérieuse lésion pleurale : observation anatomoclinique.

A computed tomography scanner first, then a magnetic resonance imaging were performed for chest pain in a 24-year-old woman allowed to find out a 5-cm long and 2-cm large right pleural tumour close to the rachis (T9 and T10) and spindle-shaped. This patient was a smoker and reported a fall down the stairs a few weeks ago. A scan-guided biopsy was decided and microscopic examination revealed a fibrous tissue in which were entrapped regular and non-suspicious alveolar glands. After elimination of differential diagnosis, the most probable hypothesis was that this lesion was due to the traumatism reported by the patient.

Foreign Glass Bodies in Pleura and Pancreas: Systematic Review for Entry Hypotheses and Treatment Options in an Unresolved Case.

BACKGROUND: Foreign bodies within the pleura and pancreas are infrequent, and the approaches to their treatment still a subject of debate. There is limited knowledge particularly regarding glass foreign bodies. METHODS: We present a case involving large glass splinters in the pleura and pancreas, with an unknown entry point. In addition, a systematic review was conducted to explore entry hypotheses and management options. RESULTS: In addition to our case, our review uncovered eight incidents of intrapleural glass, and another eight cases of glass in other intrathoracic areas. The fragments entered the body through impalement (81%), migrated through the diaphragm after impalement (6%), or caused transesophageal perforation (19%) following ingestion. Eight instances of glass inside the abdominal cavity were documented, with seven resulting from impalement injuries and one from transintestinal migration. There were no recorded instances of glass being discovered within the pancreas. Among the 41 nonglass intrapancreatic foreign bodies found, sewing needles (34%) and fish bones (46%) were the most common; following ingestion, they had migrated through either a transgastric or transduodenal perforation. In all these cases, how the foreign bodies were introduced was often poorly recalled by the patient. Many nonglass foreign bodies tend to become encapsulated by fibrous tissue, rendering them inert, though this is less common with glass. Glass has been reported to migrate through various tissues and cavities, sometimes with a significant delay spanning even decades. There are cases of intrapleural migration of glass causing hemothorax, pneumothorax, and heart and major blood vessels injury. For intrapleural glass fragment management, thoracoscopy proved to be effective in 5 reported cases, in addition to our patient. Most intrapancreatic nonglass foreign bodies tend to trigger pancreatitis and abscess formation, necessitating management ranging from laparoscopic procedures to subtotal pancreatectomy. There have been only four documented cases of intrapancreatic needles that remained asymptomatic with conservative management. There is no direct guidance from the existing literature regarding management of intrapancreatic glass foreign bodies. Consequently, our patient is under observation with regular follow-ups and has remained asymptomatic for the past 2 years. CONCLUSIONS: Glass foreign bodies in the pleura are rare, and our report of an intrapancreatic glass fragment is the first of its kind. Impalement is the most likely method of introduction. As glass has significant migration and an ensuing complication potential, preventive removal of intrapleural loose glass should be considered. However, intrapancreatic glass fragment management remains uncertain.

Intrapleural adenoviral delivery of human plasminogen activator inhibitor-1 exacerbates tetracycline-induced pleural injury in rabbits.

Elevated concentrations of plasminogen activator inhibitor-1 (PAI-1) are associated with pleural injury, but its effects on pleural organization remain unclear. A method of adenovirus-mediated delivery of genes of interest (expressed under a cytomegalovirus promoter) to rabbit pleura was developed and used with lacZ and human (h) PAI-1. Histology, ß-galactosidase staining, Western blotting, enzymatic and immunohistochemical analyses of pleural fluids (PFs), lavages, and pleural mesothelial cells were used to evaluate the efficiency and effects of transduction. Transduction was selective and limited to the pleural mesothelial monolayer. The intrapleural expression of both genes was transient, with their peak expression at 4 to 5 days. On Day 5, hPAI-1 (40-80 and 200-400 nM of active and total hPAI-1 in lavages, respectively) caused no overt pleural injury, effusions, or fibrosis. The adenovirus-mediated delivery of hPAI-1 with subsequent tetracycline-induced pleural injury resulted in a significant exacerbation of the pleural fibrosis observed on Day 5 (P = 0.029 and P = 0.021 versus vehicle and adenoviral control samples, respectively). Intrapleural fibrinolytic therapy (IPFT) with plasminogen activators was effective in both animals overexpressing hPAI-1 and control animals with tetracycline injury alone. An increase in intrapleural active PAI-1 (from 10-15 nM in control animals to 20-40 nM in hPAI-1-overexpressing animals) resulted in the increased formation of PAI-1/plasminogen activator complexes in vivo. The decrease in intrapleural plasminogen-activating activity observed at 10 to 40 minutes after IPFT correlates linearly with the initial concentration of active PAI-1. Therefore, active PAI-1 in PFs affects the outcome of IPFT, and may be both a biomarker of pleural injury and a molecular target for its treatment.

Active α-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with tetracycline-induced pleural injury and in human pleural fluids.

Intrapleural processing of prourokinase (scuPA) in tetracycline (TCN)-induced pleural injury in rabbits was evaluated to better understand the mechanisms governing successful scuPA-based intrapleural fibrinolytic therapy (IPFT), capable of clearing pleural adhesions in this model. Pleural fluid (PF) was withdrawn 0-80 min and 24 h after IPFT with scuPA (0-0.5 mg/kg), and activities of free urokinase (uPA), plasminogen activator inhibitor-1 (PAI-1), and uPA complexed with α-macroglobulin (αM) were assessed. Similar analyses were performed using PFs from patients with empyema, parapneumonic, and malignant pleural effusions. The peak of uPA activity (5-40 min) reciprocally correlated with the dose of intrapleural scuPA. Endogenous active PAI-1 (10-20 nM) decreased the rate of intrapleural scuPA activation. The slow step of intrapleural inactivation of free uPA (t1/2(ß) = 40 ± 10 min) was dose independent and 6.7-fold slower than in blood. Up to 260 ± 70 nM of αM/uPA formed in vivo [second order association rate (kass) = 580 ± 60 M(-1)·s(-1)]. αM/uPA and products of its degradation contributed to durable intrapleural plasminogen activation up to 24 h after IPFT. Active PAI-1, active α2M, and α2M/uPA found in empyema, pneumonia, and malignant PFs demonstrate the capacity to support similar mechanisms in humans. Intrapleural scuPA processing differs from that in the bloodstream and includes 1) dose-dependent control of scuPA activation by endogenous active PAI-1; 2) two-step inactivation of free uPA with simultaneous formation of αM/uPA; and 3) slow intrapleural degradation of αM/uPA releasing active free uPA. This mechanism offers potential clinically relevant advantages that may enhance the bioavailability of intrapleural scuPA and may mitigate the risk of bleeding complications.

Plasminogen-plasmin system in the pathogenesis and treatment of lung and pleural injury.

Lung and pleural injuries are characterized by inflammation, fibrinous transitional matrix deposition, and ultimate scarification. The accumulation of extravascular fibrin is due to concurrently increased local coagulation and decreased fibrinolysis, the latter mainly as a result of increased plasminogen activator inhibitor-1 (PAI-1) expression. Therapeutic targeting of disordered fibrin turnover has long been used for the treatment of pleural disease. Intrapleural fibrinolytic therapy has been found to be variably effective in clinical trials, which likely reflects empiric dosing that does not account for the wide variation in pleural fluid PAI-1 levels in individual patients. The incidence of empyema is increasing, providing a strong rationale to identify more effective, nonsurgical treatment to improve pleural drainage and patient outcomes. Therapeutics designed to resist inhibition by PAI-1 are in development for the treatment of pleural loculation and impaired drainage. The efficacy and safety of these strategies remains to be proven in clinical trial testing. Fibrinolytic therapy administered via the airway has also been proposed for the treatment of acute lung injury, but this approach has not been rigorously validated and is not part of routine clinical management at this time. Challenges to airway delivery of fibrinolysins relate to bioavailability, distribution, and dosing of the interventional agents.

Left hemothorax: an unusual complication of delayed right ventricular perforation by a permanent pacemaker lead.

Cardiac ventricle perforation by a pacemaker (PM) lead is an uncommon complication of PM implantation. We report a patient with a delayed right ventricular perforation from a permanent PM lead which presented as a left hemothorax.

Dying transfixing his own heart: a rare case of suicide by stabbing.

A 22-year-old man was found dead in his room, lying on his bed, with a kitchen knife embedded in his thorax. The external examination revealed only 1 deep incised horizontal wound in the third left intercostal space beside the sternum. There were no hesitation marks or defense injuries. On both flexor sides of the wrists, the forearms, and the arms and on the right and the left side of the neck, there were several old transversal cut scars. At the autopsy, once the single-edged knife was removed, and after a median sternotomy, the penetration depth of the stab wound revealed an incision of the left pleura, the pericardium, and the transfixed heart, from the anterior to the posterior side, ending on the seventh thoracic vertebra. Toxicological screening resulted as negative. Death occurred as a result of hemorrhagic shock after deep myocardial injuries. A psychiatric history of paranoid schizophrenia; the old scars, which were marks of previous attempted suicides; and the position of the weapon suggested that it was a suicide caused by a single strong stab wound in the cardiac region. This unusual manner of self-stabbing with a single stab to the heart without hesitation wounds was important to exclude other causes of death.

Pleural damage during capsulectomy and exchange of long-standing breast implants in Poland syndrome: a cautionary tale.

We present 3 patients undergoing revisional implant surgery more than 20 years after congenital breast asymmetry correction. All of them had Poland syndrome. In 2 patients, the parietal pleura was inadvertently damaged during capsulectomy, resulting in a pneumothorax in one patient and implant loss in the other. The loss followed a copious accumulation of fluid around the implant, possibly due to a (persistent) communication with the pleural cavity. In the first case the pneumothorax was successfully treated intraoperatively. The third patient suffered no complications during surgery. Predisposing factors for pleural damage during revisional implant surgery for congenital breast asymmetry are discussed, in addition to the merits of total capsulectomy during implant exchange. It is concluded that surgeons should aim to minimize the possibility of pleural damage during this surgery and should proceed with caution when performing total capsulectomy in at-risk patients.

Intrapleural rupture of a pulmonary arteriovenous fistula.

A 72-year-old white woman was admitted to the hospital for mitral valve replacement with a metallic valve. A few days after surgery, the patient experienced a sudden cardiac arrest and died because of the intrapleural rupture of a pulmonary arteriovenous fistula.

[The surgical treatment of the pleural empyem].

The treatment results of the 286 patients with pleural empyem after thoracic injuries (n=107) and closed trauma of the pleural cavity (n=179) were retrospectively analyzed. The frequency of pleural empyem was 1.39% by injuries and 1.34% by the closed thoracic trauma. 15 (14%) patients of the first group developed the bronchopleural fistula, whereas the complication was observed in 32 (17.9%) patients of the second group. The adequate pleural drainage with intrapleural enzyme therapy in acute inflammation period allowed recovery in 78% and 71.9% of patients, respectively. Early videothoracoscopic sanation of the pleural cavity shortened the recovery time in more then 1.5 times. The chronization of the empyem was more often observed after the closed thoracic trauma - 14.5% rather than 6.5% after the open thoracic injury. The lethality rate by pleural empyem was 14% after the open injuries and 15.6% after the closed trauma.

Sternal plate closure: indications, surgical procedure and follow-up.

OBJECTIVES: Titanium plate osteosynthesis (Synthes) is an alternative option for sternal closure. The indications and time point of application are still debated. This study investigated the application and feasibility of this technique after median sternotomy. METHODS: Forty-one patients (29 M/12F, mean age 63 ± 17 years) received the plate system for complicated sternal conditions. Indications, intraoperative course and postoperative follow-up were assessed. RESULTS: Sternal deformity was present in 5 % (2/41), sternal fractures in 17 % (7/41), bone defect in 12 % (5/41), wire loosening in 39 % (16/41) and pseudoarthrosis in 27 % (11/41). 54 % (22/41) of patients showed concomitant sternal infection. Two intraoperative complications were noted: mammary artery injury (1 patient), pleural injury (1 patient). At discharge the patients reported no pain (90 %, 37/41) or only occasional discomfort (10 %, 4/41). Postoperative complications were subcutaneous hematoma in 12 % (5/41), seroma in 12 % (5/41) and sternal reinfection in 7 % (3/41). 12 % (5/41) showed occasional discomfort and 7 % (3/41) had persistent pain leading to plate removal. CONCLUSION: The Titanium Sternal Fixation System is comfortable and easy to use. It can be used to treat a wide spectrum of indications, especially for pseudoarthrosis, an entity which has not yet received sufficient attention.

Pleural defect repair with an overlapping method using fibrin glue-coated collagen fleece.

PURPOSE: Collagen fleece coated with fibrin glue (TachoComb; CSL Behring, Tokyo, Japan) is a tissue adhesive and sealant used to stop hemorrhage and air leakage. We assessed the efficacy of overlapping methods combined with the use of TachoComb to repair pleural defects. METHODS: Using a beagle animal model, circular and square defects were created on the pulmonary pleura and then repaired with TachoComb patches of varying minimum overlap widths (MOW). The airway pressure at which air leakage from the repaired region occurred (bursting pressure) was measured in a water sealing test. The ability of TachoComb to withstand temporal changes was assessed by repairing a 6-mm circular defect. The bursting pressure was measured at 5 min, 10 min, 3 h, and 24 h after the repair. RESULTS: TachoComb patches with an MOW ≥ 6 mm withstood significantly higher pressures than patches with an MOW ≤ 3 mm for both circular and square defects. The bursting pressure was found to increase over time for up to 3 h after being applied, indicating that adhesion of the TachoComb patch to the pleural tissue improved during the 3-h period. CONCLUSION: Pleural defects repaired using an overlapping method with an MOW of 6 mm were able to withstand airway pressures ≥ 40 cmH(2)O.