Lung Transplantation for Primary Ciliary Dyskinesia and Kartagener Syndrome: A Multicenter Study.

Primary ciliary dyskinesia, with or without situs abnormalities, is a rare lung disease that can lead to an irreversible lung damage that may progress to respiratory failure. Lung transplant can be considered in end-stage disease. This study describes the outcomes of the largest lung transplant population for PCD and for PCD with situs abnormalities, also identified as Kartagener's syndrome. Retrospectively collected data of 36 patients who underwent lung transplantation for PCD from 1995 to 2020 with or without SA as part of the European Society of Thoracic Surgeons Lung Transplantation Working Group on rare diseases. Primary outcomes of interest included survival and freedom from chronic lung allograft dysfunction. Secondary outcomes included primary graft dysfunction within 72 h and the rate of rejection ≥A2 within the first year. Among PCD recipients with and without SA, the mean overall and CLAD-free survival were 5.9 and 5.2 years with no significant differences between groups in terms of time to CLAD (HR: 0.92, 95% CI: 0.27-3.14, p = 0.894) or mortality (HR: 0.45, 95% CI: 0.14-1.43, p = 0.178). Postoperative rates of PGD were comparable between groups; rejection grades ≥A2 on first biopsy or within the first year was more common in patients with SA. This study provides a valuable insight on international practices of lung transplantation in patients with PCD. Lung transplantation is an acceptable treatment option in this population.

Genome-wide expression of the residual lung reacting to experimental Pneumonectomy.

BACKGROUND: Acute or chronic irreversible respiratory failure may occur in patients undergoing pneumonectomy. Aim of this study was to determine transcriptome expression changes after experimental pneumonectomy in swine model. Experimental left pneumonectomy was performed in five pigs under general anaesthesia. Both the resected and the remaining lung, after 60 post-operative completely uneventful days, underwent genome-wide bulk RNA-Sequencing (RNA-Seq). RESULTS: Histological analysis showed dilation of air spaces and rupture of interalveolar septa. In addition, mild inflammation, no fibrosis, radial stretch of the bronchus, strong enlargement of airspaces and thinning of the blood supply were observed. Bioinformatic analyses of bulk RNA-Seq data identified 553 Differentially Expressed Genes (DEGs) at adjusted P-value below 0.001, between pre- and post-pneumonectomy. The top 10 up-regulated DEGs were Edn1, Areg, Havcr2, Gadd45g, Depp1, Cldn4, Atf3, Myc, Gadd45b, Socs3; the top 10 down-regulated DEGs were Obscn, Cdkn2b, ENSSSCG00000015738, Prrt2, Amer1, Flrt3, Efnb2, Tox3, Znf793, Znf365. Leveraging digital cytometry tools, no difference in cellular abundance was found between the two experimental groups, while the analysis of cell type-specific gene expression patterns highlighted a striking predominance of macrophage-specific genes among the DEGs. DAVID-based gene ontology analysis showed a significant enrichment of "Extrinsic apoptotic signaling pathway" (FDR q = 7.60 × 10- 3) and "Response to insulin" (FDR q = 7.60 × 10- 3) genes, along with an enrichment of genes involved as "Negative regulators of DDX58/IFIH1 signaling" (FDR q = 7.50 × 10- 4) found by querying the REACTOME pathway database. Gene network analyses indicated a general dysregulation of gene inter-connections. CONCLUSION: This translational genomics study highlighted the existence both of individual genes, mostly dysregulated in certain cellular populations (e.g., macrophages), and gene-networks involved in pulmonary reaction after left pneumonectomy. Their involvement in lung homeostasis is largely supported by previous studies, carried out both in humans and in other animal models (under homeostatic or disease-related conditions), that adopted candidate-gene approaches. Overall, the present findings represent a preliminary assessment for future, more focused, studies on compensatory lung adaptation, pulmonary regeneration and functional reload.

Pulmonary Hamartoma Associated With Lung Cancer (PHALC Study): Results of a Multicenter Study.

PURPOSE: Pulmonary hamartoma is the most common benign tumor of the lung. We analyzed a 20-year historical series of patients with pulmonary hamartoma undergoing surgical resection, aiming to evaluate the characteristics, the outcomes, and the association between hamartoma and lung cancer. METHODS: It was a retrospective multicenter study including the data of all consecutive patients with pulmonary hamartoma undergoing surgical resection. The end-points were to evaluate: (i) the characteristics of hamartoma, (ii) outcomes, and (iii) whether hamartoma was a predictive factor for lung cancer development RESULTS: Our study population included 540 patients. Upfront surgical or endoscopic resection was performed in 385 (71%) cases while in the remaining 155 (29%) cases, the lesions were resected 20 ± 3.5 months later due to increase in size. In most cases, lung sparing resection was carried out including enucleation (n = 259; 48%) and wedge resection (n = 230; 43%) while 5 (1%) patients underwent endoscopic resection. Only two patients (0, 2%) had major complications. One patient (0.23%) had recurrence after endoscopic resection, while no cases of malignant degeneration were seen (mean follow-up:103.3 ± 93 months). Seventy-six patients (14%) had associated lung cancer, synchronous in 9 (12%) and metachronous in 67 (88%). Only age > 70-year-old (p = 0.0059) and smokers > 20 cigarettes/day (p < 0.0001) were the significant risk factors for lung cancer. CONCLUSION: PH was a benign tumor, with no evidence of recurrence and/or of malignant degeneration after resection. The association between hamartoma and lung cancer was a spurious phenomenon due to common risk factors.

Analysis of CT features and quantitative texture analysis in patients with thymic tumors: correlation with grading and staging.

OBJECTIVES: To evaluate potential relationship between qualitative CT features, quantitative texture analysis (QTA), histology, WHO staging, Masaoka classification and myasthenic syndrome in patients with thymic tumors. MATERIALS AND METHODS: Sixteen patients affected by histologically proven thymic tumors were retrospectively included in the study population. Clinical information, with special regard to myasthenic syndrome and serological positivity of anti-AchR antibodies, were recorded. Qualitative CT evaluation included the following parameters: (a) location; (b) tumor edges; (c) necrosis; (d) pleural effusion; (e) metastases; (f) chest wall infiltration; (g) tumor margins. QTA included evaluation of "Mean" (M), "Standard Deviation" (SD), "Kurtosis" (K), "Skewness" (S), "Entropy" (E), "Shape from Texture" (TX_sigma) and "average of positive pixels" (MPP). Pearson-Rho test was used to evaluate the relationship of continuous non-dichotomic parameters, whereas Mann-Whitney test was used for dichotomic parameters. RESULTS: Histological evaluation demonstrated thymoma in 12 cases and thymic carcinoma in 4 cases. Tumor necrosis was significantly correlated with QTA Mean (p = 0.0253), MPP (p = 0.0417), S (p = 0.0488) and K (p = 0.0178). WHO staging was correlated with Mean (p = 0.0193), SD (p = 0.0191) and MPP (p = 0.0195). Masaoka classification was correlated with Mean (p = 0.0322), MPP (p = 0.0315), skewness (p = 0.0433) and Kurtosis (p = 0.0083). Myasthenic syndrome was significantly associated with Mean (p = 0.0211) and MPP (p = 0.0261), whereas tumor size was correlated with Mean (p = 0.0241), entropy (p = 0.0177), MPP (p = 0.0468), skewness (p = 0.009) and Kurtosis (p = 0.006). CONCLUSION: Our study demonstrates significant relationship between radiomics parameters, histology, grading and clinical manifestations of thymic tumors.

Establishment and long-term culture of human cystic fibrosis endothelial cells.

Endothelial cell (EC) dysfunction has been reported in cystic fibrosis (CF) patients. Thus, the availability of CF EC is paramount to uncover mechanisms of endothelial dysfunction in CF. Using collagenase digestion, we isolated cells from small fragments of pulmonary artery dissected from non-CF lobes or explanted CF lungs. These cells were a heterogeneous mixture, containing variable percentages of EC. To obtain virtually pure pulmonary artery endothelial cells (PAEC), we developed an easy, inexpensive, and reliable method, based on the differential adhesion time of pulmonary artery cells collected after collagenase digestion. With this method, we obtained up to 95% pure non-CF and CF-PAEC. Moreover, we also succeed at immortalizing both PAEC and CF-PAEC, which remained viable and with unchanged phenotype and proliferation rate over the 30th passage. These cells recapitulated cystic fibrosis transmembrane conductance regulator expression and functions of the parental cells. Thus, we isolated for the first time endothelial cells from CF patients, providing a valuable tool to define the emerging role of EC in CF lung and vascular disease.

Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation.

BACKGROUND: Thymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors (TETs). A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA (miRNAs) differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation. METHODS: mRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma (TC1889) cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid (VPA). RESULTS: Starting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib. CONCLUSIONS: Altogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.

Mechanisms of endothelial cell dysfunction in cystic fibrosis.

Although cystic fibrosis (CF) patients exhibit signs of endothelial perturbation, the functions of the cystic fibrosis conductance regulator (CFTR) in vascular endothelial cells (EC) are poorly defined. We sought to uncover biological activities of endothelial CFTR, relevant for vascular homeostasis and inflammation. We examined cells from human umbilical cords (HUVEC) and pulmonary artery isolated from non-cystic fibrosis (PAEC) and CF human lungs (CF-PAEC), under static conditions or physiological shear. CFTR activity, clearly detected in HUVEC and PAEC, was markedly reduced in CF-PAEC. CFTR blockade increased endothelial permeability to macromolecules and reduced trans­endothelial electrical resistance (TEER). Consistent with this, CF-PAEC displayed lower TEER compared to PAEC. Under shear, CFTR blockade reduced VE-cadherin and p120 catenin membrane expression and triggered the formation of paxillin- and vinculin-enriched membrane blebs that evolved in shrinking of the cell body and disruption of cell-cell contacts. These changes were accompanied by enhanced release of microvesicles, which displayed reduced capability to stimulate proliferation in recipient EC. CFTR blockade also suppressed insulin-induced NO generation by EC, likely by inhibiting eNOS and AKT phosphorylation, whereas it enhanced IL-8 release. Remarkably, phosphodiesterase inhibitors in combination with a ß2 adrenergic receptor agonist corrected functional and morphological changes triggered by CFTR dysfunction in EC. Our results uncover regulatory functions of CFTR in EC, suggesting a physiological role of CFTR in the maintenance EC homeostasis and its involvement in pathogenetic aspects of CF. Moreover, our findings open avenues for novel pharmacology to control endothelial dysfunction and its consequences in CF.

Preliminary clinical experience with a dedicated interventional robotic system for CT-guided biopsies of lung lesions: a comparison with the conventional manual technique.

OBJECTIVE: Evaluate the performance of a robotic system for CT-guided lung biopsy in comparison to the conventional manual technique. MATERIALS AND METHODS: One hundred patients referred for CT-guided lung biopsy were randomly assigned to group A (robot-assisted procedure) or group B (conventional procedure). Size, distance from entry point and position in lung of target lesions were evaluated to assess homogeneity differences between the two groups. Procedure duration, dose length product (DLP), precision of needle positioning, diagnostic performance of the biopsy and rate of complications were evaluated to assess the clinical performance of the robotic system as compared to the conventional technique. RESULTS: All biopsies were successfully performed. The size (p = 0.41), distance from entry point (p = 0.86) and position in lung (p = 0.32) of target lesions were similar in both groups (p = 0.05). Procedure duration and radiation dose were significantly reduced in group A as compared to group B (p = 0.001). Precision of needle positioning, diagnostic performance of the biopsy and rate of complications were similar in both groups (p = 0.05). CONCLUSION: Robot-assisted CT-guided lung biopsy can be performed safely and with high diagnostic accuracy, reducing procedure duration and radiation dose in comparison to the conventional manual technique. KEY POINTS: • CT-guided biopsy is the main procedure to obtain diagnosis in lung tumours. • The robotic device facilitates percutaneous needle placement under CT guidance. • Robot-assisted CT-guided lung biopsy reduces procedure duration and radiation dose.

Correlation between collateral ventilation and interlobar lung fissures.

BACKGROUND: New bronchoscopic techniques for end-stage emphysema treatment are nowadays available; the presence of interlobar collateral ventilation (CV) and interlobar lung fissures (ILF) is crucial for patient selection. OBJECTIVES: Assessment of these variables has been reported previously, but it has never been anatomically validated in vivo. This is the purpose of our study. METHODS: Twenty-one patients undergoing lung resection for lung cancer were prospectively enrolled in this study. At operation, CV was assessed by the Chartis catheter system. ILF completeness at high-resolution computed tomography (HRCT) was retrospectively reviewed. The ILF status at HRCT and at surgery was compared; furthermore, the relationship between CV and ILF status was assessed. RESULTS: At HRCT, ILF were incomplete in 18 cases; at catheter evaluation, CV was present in 11 cases; 15 patients had incomplete ILF at operation. HRCT specificity, sensitivity and accuracy were 33, 93 and 76% compared with ILF status at surgery. HRCT accuracy was 90% on the right and 63% on the left. We demonstrated a high grade of probability of CV presence and incomplete ILF at surgery (odds ratio = 10.0). CONCLUSIONS: There is a correlation between ILF status and CV. Both catheter evaluation of CV and HRCT assessment of ILF show some limitations. However, the cumulative information provided by these techniques allows to reliably assess the anatomical ILF status.

Lung Cancer Surgery in Octogenarians: Implications and Advantages of Artificial Intelligence in the Preoperative Assessment.

The general world population is aging and patients are often diagnosed with early-stage lung cancer at an advanced age. Several studies have shown that age is not itself a contraindication for lung cancer surgery, and therefore, more and more octogenarians with early-stage lung cancer are undergoing surgery with curative intent. However, octogenarians present some peculiarities that make surgical treatment more challenging, so an accurate preoperative selection is mandatory. In recent years, new artificial intelligence techniques have spread worldwide in the diagnosis, treatment, and therapy of lung cancer, with increasing clinical applications. However, there is still no evidence coming out from trials specifically designed to assess the potential of artificial intelligence in the preoperative evaluation of octogenarian patients. The aim of this narrative review is to investigate, through the analysis of the available international literature, the advantages and implications that these tools may have in the preoperative assessment of this particular category of frail patients. In fact, these tools could represent an important support in the decision-making process, especially in octogenarian patients in whom the diagnostic and therapeutic options are often questionable. However, these technologies are still developing, and a strict human-led process is mandatory.

Xanthoma of rib: a case report and review of the literature.

BACKGROUND: Xanthomas are well-circumscribed benign proliferative lesions seen mainly in soft tissues. Usually, they are found in hyperlipidemia and familial hyperlipoproteinemia. Histologically, are characterized by macrophage-like mononuclear cells, multinucleated giant cells and abundant foam cells. The bone involvement, however, is notoriously rare and rib localization is extremely rare. CASE PRESENTATION: A 55-year-old man performed a chest X-ray and a subsequent chest Computed Tomography scan showing a rib lesion that was surgically removed and a diagnosis of rib xanthoma was made. The patient presented an unknown condition of hyperlipidemia. CONCLUSION: Rib xanthoma can be discovered accidentally and can be helpful in identifying an unrecognized condition of hyperlipidemia.

Modified sympathicotomy in patients with refractory ventricular tachycardia and structural heart disease: a single-center experience.

BACKGROUND: Modified cardiac sympathetic denervation (CSD) with stellate ganglion (SG) sparing is a novel technique for cardiac neuromodulation in patients with refractory ventricular tachycardia (VT). OBJECTIVES: Our aim is to describe the mid- to long-term clinical outcome of the modified CSD with SG sparing in a series of patients with structural heart disease (SHD) and refractory VT. METHODS: All consecutive patients with SHD and refractory VT undergoing modified CSD were enrolled. Baseline clinical characteristics and periprocedural data were collected for all patients. The primary outcome was any recurrence of sustained VT. RESULTS: We enrolled 15 patients (age: 69.2 ± 7.9 years; male 100%) undergoing modified CSD. Left ventricular ejection fraction was 37 ± 11% and all patients had an implantable cardiac defibrillator (ICD); the underlying cardiomyopathy was non-ischemic in 73.3% of them. At least one previous ablation had been attempted in 66.6% of cases. The 73.3% of patients underwent bilateral CSD and the mean effective surgical time was 10.8 ± 2.4 min per side; no major periprocedural complication occurred. After a median follow-up time of 15 months (IQR: 8.5-24.5 months), the primary outcome occurred in 47.6% of cases. All patients experienced a reduction of ICD shocks after CSD (3.1 ICD shocks/patient before vs. 0.3 ICD shocks/patient after CSD; p-value: 0.001). Bilateral CSD and a VT cycle length < 340 ms were associated with better outcomes. CONCLUSIONS: A modified CSD approach with stellate ganglion sparing appears to be safe, fast, and effective in the treatment of patients with SHD and refractory VTs.

Long-term follow-up after bronchoscopic lung volume reduction in patients with emphysema.

Bronchoscopic lung volume reduction (BLVR) is a novel emphysema therapy. We evaluated long-term outcome in patients with heterogeneous emphysema undergoing BLVR with one-way valves. 40 patients undergoing unilateral BLVR entered our study. Pre-operative mean forced expiratory volume in 1 s (FEV(1)) was 0.88 L · s(-1) (23%), total lung capacity was 7.45 L (121%), intrathoracic gas volume was 6 L (174%), residual volume (RV) was 5.2 L (232%), and the 6-min walk test (6MWT) was 286 m. All patients required supplemental oxygen; the Medical Research Council (MRC) dyspnoea score was 3.9. High-resolution computed tomography (HRCT) results were reviewed to assess the presence of interlobar fissures. 33 patients had a follow-up of >12 months (median 32 months). 37.5% of the patients had visible interlobar fissures. 40% of the patients died during follow-up. Three patients were transplanted and one underwent lung volume reduction surgery. Supplemental oxygen, FEV(1), RV, 6MWT and MRC score showed a statistically significant improvement (p ≤ 0.0001, p = 0.004, p = 0.03, p = 0.003 and p<0.0001, respectively). Patients with visible fissures had a functional advantage. BLVR is feasible and safe. Long-term sustained improvements can be achieved. HRCT-visible interlobar fissures are a favourable prognostic factor.

Non-Intubated Thoracic Surgery: Standpoints and Perspectives.

Non-intubated video-assisted thoracic surgery (NI-VATS) combines the advantages of a non-intubated surgery with the benefits of a minimally invasive approach. First, NI-VATS is performed in the case of fragile patients when general anesthesia and/or orotracheal intubation can be foreseen as inconvenient. However, NI-VATS indications have been increasingly extended to different patient conditions, considering the increasingly assessed safety and feasibility of the procedure. Currently, the NI-VATS approach is used worldwide for different thoracic surgery procedures, including the management of malignant pleural effusion, surgical treatment of empyema, anatomical and non-anatomical lung resection, and other indications. In fact, this approach has shown to be less impactful than VATS under general anesthesia, allowing for shortened hospitalization and faster recovery after surgery. Besides, NI-VATS is associated with fewer pulmonary complications, less respiratory distress, and a mild systemic inflammatory reaction. For these reasons, this approach should be considered not only in patients with poor cardiac or respiratory function (general functional reserve), but also in other eligible conditions. We explored the anesthetic and surgical aspects of such an approach, including the management of analgesia, cough reflex, depth of sedation, and intraoperative technical issues to put this approach in perspective.

Cardiac sympathetic denervation for untreatable ventricular tachycardia in structural heart disease. Strengths and pitfalls of evolving surgical techniques.

Cardiac sympathetic denervation (CSD) is a valuable option in the setting of refractory ventricular arrhythmias in patient with structural heart disease. Since the procedure was introduced for non structural heart disease patients the techniques evolved and were modified to be adopted in several settings. In this state-of-the-art article we revised different techniques, their rationale, strengths, and pitfalls.