Diaphragm and Lung Transplantation.

Mutual interactions between the diaphragm and lung transplantation (LTx) are known to exist. Before LTx, many factors can exert notable impact on the diaphragmatic function, such as the underlying respiratory disease, the comorbidities, and the chronic treatments of the patient. In the post-LTx setting, even the surgical procedure itself can cause a stressful trauma to the diaphragm, potentially leading to morphological and functional alterations. Conversely, the diaphragm can significantly influence various aspects of the LTx process, ranging from graft-to-chest cavity size matching to the long-term postoperative respiratory performance of the recipient. Despite this, there are still no standard criteria for evaluating, defining, and managing diaphragmatic dysfunction in the context of LTx to date. This deficiency hampers the accurate assessment of those factors which affect the diaphragm and its reciprocal influence on LTx outcomes. The objective of this narrative review is to delve into the complex role the diaphragm plays in the different stages of LTx and into the modifications of this muscle following surgery.

Pulmonary Lobectomy for Early-Stage Lung Cancer with Uniportal versus Three-Portal Video-Assisted Thoracic Surgery: Results from a Single-Centre Randomized Clinical Trial.

Video-assisted thoracic surgery (VATS) is a consolidated approach; however, there is no consensus on the number of ports leading to less postoperative pain. We compared early postoperative pain after uniportal and three-portal VATS lobectomy for early-stage NSCLC. In this randomized clinical trial, patients undergoing VATS lobectomy were randomly assigned to receive uniportal (U-VATS Group) or three-portal (T-VATS Group) VATS. The inclusion criteria were age ≤ 80 years and ASA < 4. The exclusion criteria were clinical T3, previous thoracic surgery, induction therapy, chest radiotherapy, connective tissue or vascular diseases, major organ failure, and analgesics or corticosteroids use. The postoperative analgesia protocol was based on NRS. Pain was measured as analgesic consumption; the secondary endpoints were intra- and postoperative complications, conversion rate, surgical time, dissected lymph nodes, hospital stay, and respiratory function. Out of 302 eligible patients, 120 were included; demographics were distributed homogeneously. The mean cumulative morphine consumption (CMC) in the U-VATS Group after 7 days was lower than in the T-VATS Group (77.4 mg vs. 90.1 mg, p = 0.003). Intraoperative variables and postoperative complications were comparable. The 30-day intercostal neuralgia rate was lower in the U-VATS Group, without reaching statistical significance. Patients undergoing U-VATS showed a lower analgesic consumption compared with the T-VATS Group; analgesic consumption was moderate in both groups.

Hemodynamic failure and graft dysfunction after lung transplant: A possible clinical continuum with immediate and long-term consequences.

INTRODUCTION: The postoperative hemodynamic management after lung transplant (LUTX) is guided by limited evidence. We aimed to describe and evaluate risk factors and outcomes of postoperative vasoactive support of LUTX recipients. METHODS: In a single-center retrospective analysis of consecutive adult LUTX, two cohorts were identified: (1) patients needing prolonged vasoactive support (>12 h from ICU admission) (VASO+); (2) or not (VASO-). Postoperative hemodynamic characteristics were thoroughly analyzed. Risk factors and outcomes of VASO+ versus VASO- cohorts were assessed by multivariate logistic regression and propensity score matching. RESULTS: One hundred and thirty-eight patients were included (86 (62%) VASO+ versus 52 (38%) VASO-). Vasopressors (epinephrine, norepinephrine, dopamine) were used in the first postoperative days (vasoactive inotropic score at 12 h: 6 [4-12]), while inodilators (dobutamine, levosimendan) later. Length of vasoactive support was 3 [2-4] days. Independent predictors of vasoactive use were: LUTX indication different from cystic fibrosis (p = .003), higher Oto score (p = .020), longer cold ischemia time (p = .031), but not preoperative cardiac catheterization. VASO+ patients showed concomitant hemodynamic and graft impairment, with longer mechanical ventilation (p = .010), higher primary graft dysfunction (PGD) grade at 72 h (PGD grade > 0 65% vs. 31%, p = .004, OR 4.2 [1.54-11.2]), longer ICU (p < .001) and hospital stay (p = .013). Levosimendan as a second-line inodilator appeared safe. CONCLUSIONS: Vasoactive support is frequently necessary after LUTX, especially in recipients of grafts of lesser quality. Postoperative hemodynamic dysfunction requiring vasopressor support and graft dysfunction may represent a clinical continuum with immediate and long-term consequences. Further studies may elucidate if this represents a possible treatable condition.

Lung Transplantation From Controlled and Uncontrolled Donation After Circulatory Death (DCD) Donors With Long Ischemic Times Managed by Simple Normothermic Ventilation and Ex-Vivo Lung Perfusion Assessment.

Donation after cardiac death (DCD) donors are still subject of studies. In this prospective cohort trial, we compared outcomes after lung transplantation (LT) of subjects receiving lungs from DCD donors with those of subjects receiving lungs from donation after brain death (DBD) donors (ClinicalTrial.gov: NCT02061462). Lungs from DCD donors were preserved in-vivo through normothermic ventilation, as per our protocol. We enrolled candidates for bilateral LT ≥14 years. Candidates for multi-organ or re-LT, donors aged ≥65 years, DCD category I or IV donors were excluded. We recorded clinical data on donors and recipients. Primary endpoint was 30-day mortality. Secondary endpoints were: duration of mechanical ventilation (MV), intensive care unit (ICU) length of stay, severe primary graft dysfunction (PGD3) and chronic lung allograft dysfunction (CLAD). 121 patients (110 DBD Group, 11 DCD Group) were enrolled. 30-day mortality and CLAD prevalence were nil in the DCD Group. DCD Group patients required longer MV (DCD Group: 2 days, DBD Group: 1 day, p = 0.011). ICU length of stay and PGD3 rate were higher in DCD Group but did not significantly differ. LT with DCD grafts procured with our protocols appears safe, despite prolonged ischemia times.

State of the art and new perspectives in surgical treatment of lung cancer: a narrative review.

Background and Objective: Lung cancer is the leading cause of cancer-related deaths worldwide, and its incidence has increased over the past two decades. The standard care for stage I, stage II, and selected cases of stage IIIA non-small cell lung cancer (NSCLC) is surgical resection; in some cases, patients may be offered adjuvant systemic therapy after surgical resection. Patients with lung cancer presenting with distant metastases belong to stage IV: in this setting, some carefully selected patients may benefit from surgery within a multimodality approach. Methods: We performed a comprehensive, non-systematic review of the latest literature to define the present role of surgery in lung cancer treatment. Key Content and Findings: The literature review disclosed a pivotal role of surgery in early stage lung cancer and a complimentary role in locally advanced lung cancer; in very selected cases, surgery might be considered in oligometastatic disease. Conclusions: Surgical treatment of lung cancer still plays a pivotal role in early stages of the disease while, in locally advanced stages, it may contribute to improve overall survival in combination with medical treatments and radiotherapy. More recently, an effective role of surgery has been advocated in carefully selected oligometastatic patients with encouraging initial results.

Intraoperative Extra Corporeal Membrane Oxygenator for Lung Cancer Resections Does Not Impact Circulating Tumor Cells.

BACKGROUND: The diagnosis of active neoplastic disease was traditionally judged an absolute contraindication for extracorporeal membrane oxygenator (ECMO) because of the fear of tumor cells being scattered or seeded. The aim of this study is to compare the number of circulating tumor cells (CTCs) before and after surgery in patients receiving lung cancer resection with and without intraoperative ECMO support. METHODS: This is a prospective, non-randomized, two-arms observational study comparing the number of CTCs before and after surgery in patients receiving lung cancer resection with and without intraoperative ECMO support. The ECMO arm includes patients suffering from lung cancer undergoing pulmonary resection with planned intraoperative ECMO support. The non-ECMO arm includes patients suffering from non-early-stage lung cancer undergoing pulmonary resection without planned intraoperative ECMO support. RESULTS: Twenty patients entered the study, eight in the ECMO arm and twelve in the non-ECMO arm. We did not observe any significant difference between the ECMO and non-ECMO groups in terms of postoperative complications (p = 1.00), ICU stay (p = 0.30), hospital stay (p = 0.23), circulating tumor cells' increase or decrease after surgery (p = 0.24), and postoperative C-reactive protein and C-reactive protein increase (p = 0.80). The procedures in the non-ECMO arm were significantly longer than those in the ECMO arm (p = 0.043). CONCLUSIONS: Intraoperative ECMO for lung cancer resections did not impact CTC increase or decrease after the procedure.

Continuous Glucose Monitoring in Preterm Infants: The Role of Nutritional Management in Minimizing Glycemic Variability.

Glycemic variability (GV) is common in preterm infants. In the premature population, GV is a risk factor for morbidity and mortality. Both hypo- and hyperglycemia can impair neurodevelopment. We investigated the impact of continuous versus intermittent tube enteral feeding on GV. In our prospective observational study, 20 preterm infants with a gestational age ≤ 34 weeks at either continuous or intermittent bolus full enteral feeding. For five days, continuous glucose monitoring (CGM) was utilized, which was achieved through the subcutaneous insertion of a sensor. A total of 27,532 measurements of blood glucose were taken. The mean amplitude of glycemic excursions did not differ between the two cohorts statistically. Continuous feeding resulted in higher positive values, increasing the risk of hypo- and hyperglycemia. Subjects who were small for their gestational age had a higher standard deviation during continuous feeding (p = 0.001). Data suggest that intermittent bolus nutrition is better for glycemic control than continuous nutrition. Nutritional management optimization of preterm infants appears to be critical for long-term health. In the future, CGM may provide a better understanding of the optimal glucose targets for various clinical conditions, allowing for a more personalized approach to management.

Lung Transplant for ARDS after COVID-19: Long-Term Outcomes and Considerations about Detrimental Issues.

During the first outbreak of COVID-19 in Italy, based on the only few cases reported from a Chinese centre at the time, we performed lung transplantation in two patients with irreversible acute respiratory distress syndrome (ARDS) after COVID-19 at our centre. After two years, we report the outcomes of these cases and some considerations. The first patient, an 18-year-old male, is in excellent conditions twenty-four months after surgery. The second patient was a 48-year-old man; his airways were colonized by carbapenemase-producing klebsiella pneumoniae at the time of lung transplantation, and he had previously suffered from delirium and hallucinations in the intensive care unit. His postoperative clinical course was complicated by dysexecutive behaviour and then septic shock; he died 62 days after surgery. The recently reported experience of different transplantation centres has led to the inclusion of irreversible acute respiratory distress syndrome (ARDS) after COVID-19 among the indications for lung transplantation in carefully selected patients. Our results confirm the feasibility and the good long-term outcomes of lung transplantation for COVID-19-associated ARDS. Nonetheless, our experience corroborates the need for careful recipient selection: special attention must be paid to the single-organ dysfunction principle, the evaluation of any neuro-psychiatric disorder, and MDR germs colonization, before listing.

Interobserver variability in the evaluation of primary graft dysfunction after lung transplantation: impact of radiological training and analysis of discordant cases.

PURPOSE: Radiologic criteria for the diagnosis of primary graft dysfunction (PGD) after lung transplantation are nonspecific and can lead to misinterpretation. The primary aim of our study was to assess the interobserver agreement in the evaluation of chest X-rays (CXRs) for PGD diagnosis and to establish whether a specific training could have an impact on concordance rates. Secondary aim was to analyze causes of interobserver discordances. MATERIAL AND METHODS: We retrospectively enrolled 164 patients who received bilateral lung transplantation at our institution, between February 2013 and December 2019. Three radiologists independently reviewed postoperative CXRs and classified them as suggestive or not for PGD. Two of the Raters performed a specific training before the beginning of the study. A senior thoracic radiologist subsequently analyzed all discordant cases among the Raters with the best agreement. Statistical analysis to calculate interobserver variability was percent agreement, Cohen's kappa and intraclass correlation coefficient. RESULTS: A total of 473 CXRs were evaluated. A very high concordance among the two trained Raters, 1 and 2, was found (K = 0.90, ICC = 0.90), while a poorer agreement was found in the other two pairings (Raters 1 and 3: K = 0.34, ICC = 0.40; Raters 2 and 3: K = 0.35, ICC = 0.40). The main cause of disagreement (52.4% of discordant cases) between Raters 1 and 2 was the overestimation of peribronchial thickening in the absence of unequivocal bilateral lung opacities or the incorrect assessment of unilateral alterations. CONCLUSION: To properly identify PGD, it is recommended for radiologists to receive an adequate specific training.

Surgical management of superior sulcus tumors: A twenty-year experience of an oncological high volume referral centre.

Objectives: Superior sulcus tumour, which affects the lung's apex, is an uncommon subtype of non-small cell lung cancer (NSCLC). The current study examined the clinical characteristics and management of superior sulcus NSCLC patients in a high-volume referral oncological centre over 22 years. Methods: Retrospective review of 100 surgeries with curative intent for superior sulcus NSCLC over 22 years (July 1998 - December 2020). The surgical approach was defined according to the lesion site and the anatomy of the thoracic inlet. Survival curves, including non-cancer-related deaths, were drawn using the Kaplan-Meier methods, and the log-rank test was used to evaluate differences in survival across groups of patients. Cox proportional hazards regression was used to assess the association between selected clinical and pathologic characteristics on OS. Results: 54 patients received induction treatments. The surgical approach was anterior thoracotomy in 53 patients, Paulson incision in 30, and a combined in 8. The median postoperative length of stay was 11 days (range: 5 - 27 days). Overall 90-day mortality was 6.93%. The median OS was 24.3 months. After a median follow-up of 3 years, 5-year and 10-year OS rates were 33.9% and 26.4%, respectively. A significantly lower 5-year OS was observed in patients with the nodal disease (46.6% in pN0 vs 13.2% in pN+; p = 0.024), without preoperative treatments (41.0% in patients without preoperative treatments versus 17.4%; p = 0.09) and anteriorly located tumour (anterior vs posterior: 17.4% vs 49.1%; p = 0.032). Cox proportional hazards regression showed better survival in the pT1 stage (HR = 4.6; 95% CI: 1.9 - 11.2; p = 0.00076) and in R0 (HR = 4.2; 95% CI: 1.4 - 12.5; p = 0.010). Conclusions: Superior sulcus tumours still represent a life-threatening condition that, while curable in a significant proportion of cases, requires complex procedures with high surgical risks and a multimodality treatment setting. An optimal surgical approach should be planned to maximise resection completeness and survival. Other factors affecting survival are related to tumour staging, emphasising the importance of a meticulous preoperative workup and candidate selection to identify those expected to benefit from a survival benefit.

Management of Pleural Effusion Secondary to Malignant Mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly aggressive pleural tumour which has been epidemiologically linked to occupational exposure to asbestos. MPM is often associated with pleural effusion, which is a common cause of morbidity and whose management remains a clinical challenge. In this review, we analysed the literature regarding the diagnosis and therapeutic options of pleural effusion secondary to mesothelioma. Our aim was to provide a comprehensive view on this subject, and a new algorithm was proposed as a practical aid to clinicians dealing with patients suffering from pleural effusion.

An EBC/Plasma miRNA Signature Discriminates Lung Adenocarcinomas From Pleural Mesothelioma and Healthy Controls.

BACKGROUND: Despite significant improvement in screening programs for cancers of the respiratory district, especially in at-risk subjects, early disease detection is still a major issue. In this scenario, new molecular and non-invasive biomarkers are needed to improve early disease diagnosis. METHODS: We profiled the miRNome in exhaled breath condensate (EBC) and plasma samples from fourteen patients affected by lung AdCa, nine healthy subjects. miRNA signatures were then analyzed in another neoplasia of the respiratory district, i.e. pleural mesothelioma (n = 23) and subjects previously exposed to asbestos were used as controls for this cohort (n = 19). Selected miRNAs were analyzed in purified pulmonary neoplastic or normal epithelial and stromal cell subpopulation from AdCa patients. Finally, the plasmatic miRNA signature was analyzed in a publicly available cohort of NSCLC patients for data validation and in silico analysis was performed with predicted miRNA targets using the multiMiR tool and STRING database. RESULTS: miR-597-5p and miR-1260a are significantly over-expressed in EBC from lung AdCa and are associated with AdCa. Similarly, miR-1260a is also up-regulated in the plasma of AdCa patients together with miR-518f-3p and correlates with presence of lung cancer, whereas let-7f-5p is under-expressed. Analysis of these circulating miRNAs in pleural mesothelioma cases confirmed that up-regulation of miR-518f-3p, -597-5p and -1260a, is specific for lung AdCa. Lastly, quantification of the miRNAs in laser-assisted microdissected lung tissues revealed that miR-518f-3p, 597-5p and miR-1260a are predominantly expressed in tumor epithelial cells. Validation analysis confirmed miR-518f-3p as a possible circulating biomarker of NSCLC. In silico analysis of the potentially modulated biological processes by these three miRNAs, shows that tumor bioenergetics are the most affected pathways. CONCLUSIONS: Overall, our data suggest a 3-miRNAs signature as a non-invasive and accurate biomarker of lung AdCa. This approach could supplement the current screening approaches for early lung cancer diagnosis.

Diagnostic accuracy of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) for mediastinal lymph node staging of lung cancer.

Lung cancer is one of the leading causes of cancer-related mortality around the world. A prompt diagnosis and accurate staging are of the essence in order to establish the appropriate treatment plan. Mediastinal lymph nodes involvement is the most important parameter to define the therapeutic path, and particularly to decide whether a patient can be offered a potentially curative surgery. Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA), together with oesophageal ultrasound (EUS), has a pivotal role in the diagnosis and staging of lung cancer. These procedures have excellent diagnostic performances, can be performed without requiring general anaesthesia, and are far less invasive than mediastinoscopy and video-assisted thoracic surgery (VATS). Moreover, EBUS-TBNA allows to biopsy intrapulmonary lymph nodes. Different studies have been investigated the diagnostic accuracy of EBUS-TBNA for the diagnosis and staging of lung cancer, with always good but heterogeneous results. In some studies, EBUS-TBNA has shown to yield adequate samples for molecular testing and immunocytochemistry too. Rapid on site cytologic evaluation (ROSE) can be used to assess the adequacy of samples during the endoscopic procedure. The aim of this review article is to describe the current evidence on the diagnostic accuracy of EBUS-TBNA for the diagnosis of lung cancer. We also reported our centre's experience and the results of 456 EBUS-TBNA performed between April 2016 and March 2020.

Extended-criteria uncontrolled DCD donor for a fragile recipient: A case report about a challenging yet successful lung transplantation.

INTRODUCTION: Lung donation after circulatory death (DCD) has proved to be an effective strategy for expanding the donor pool, but is still considered challenging. We report a successful case of lung procurement from an extended-criteria uncontrolled DCD. PRESENTATION OF CASE: We evaluated the lungs of an uncontrolled DCD from a hospital without extracorporeal membrane oxygenation (ECMO) program. The donor was a non-smoker 20-year old male with a history of cardiomyopathy, cardiocirculatory arrests, and Lennox-Gastaut syndrome. Cardiac arrest occurred in a swimming pool, and bronchoscopy showed signs of inhalation. We employed our usual normothermic in-situ open-ventilated lung approach. After retrieval, lungs were stored on ice, then evaluated with ex-vivo lung perfusion (EVLP) and judged suitable for transplantation. The recipient was a 26-year old female with cystic fibrosis on long-term oxygen therapy, on the waitlist for up to 21 months due to her anthropomorphic characteristics. She required central VA-ECMO support during bilateral lung transplantation. Primary graft dysfunction (PGD) within the first 72 h reached grade 3; post-operative peripheral VV-ECMO support was discontinued two days after surgery. The patient was discharged 28 days after surgery; she is alive two years after transplantation with no signs of rejection nor anastomotic complications. DISCUSSION: Despite the spreading use of lungs from controlled DCD, perplexities remain on uncontrolled DCD, namely: severe PDG, postoperative mortality, airway complications. CONCLUSION: Our case report suggests that good results can be achieved with uncontrolled DCD despite the presence of relative contraindications: inhalation of water, prolonged ischemic times and recipient in poor conditions.

The European experience.

Traditionally, pulmonary lobectomy has always been considered as the gold standard for the treatment of early stage non-small cell lung cancer (NSCLC); limited resections have been proposed in case of "compromised" patients, with relevant comorbidities. In the last years, the interest in anatomical segmentectomies among surgeons has been progressively growing, even for patients fit for lobectomy, in selected cases. In this article we debate the current trends in the treatment of early stage NSCLC around Europe.

Bronchoalveolar Lavage-microRNAs Are Potential Novel Biomarkers of Outcome After Lung Transplantation.

Primary graft dysfunction, infections, and acute rejection (AR) worsen lung transplantation (LTx) outcome and patient survival. Despite significant efforts, reliable biomarkers of acute lung allograft dysfunction are lacking. To address this issue, we profiled the bronchoalveolar lavage (BAL) miRNome in LTx patients. METHODS: BAL-microRNAs (miRNAs) from 16 patients were collected 7 days (T0), 15 days (T1), and 3 months (T2) after bilateral LTx and profiled on low-density array. Unsupervised and supervised analyses were used to identify miRNAs associated with clinical features, pneumonia, or AR. Prognostic markers were identified using the Cox model. Targeted signaling pathways were predicted in silico. A second series of 11 patients were used to validate AR-associated miRNAs. RESULTS: Variation in BAL-miRNAs was associated with acute lung allograft dysfunction. Increased levels of miR-23b-3p at T2 were detected in patients with pneumonia, whereas let-7f-5p, miR-146b-3p, miR-22-5p, miR-29c-5p, miR-362-5p, and miR-452-5p were upregulated at T2 in patients with AR. miR-148b-5p and miR-744-3p distinguished LTx patients with AR in both cohorts. Low miR-148b-5p and high miR-744-3p expression levels were significantly associated with a shorter time to AR either within the first year after LTx or during follow-up. Combination of the 2 miRNAs identified LTx patients with higher AR risk independently of clinical variables. CONCLUSIONS: Our data provide new insights into the roles of BAL-miRNAs in regulating the pulmonary environment after transplantation and suggest that these miRNAs could serve as biomarkers of early- or mid-stage events. If validated, these findings could pave the way to a personalized clinical approach in LTx patients.

Next generation sequencing panel in undifferentiated autoinflammatory diseases identifies patients with colchicine-responder recurrent fevers.

OBJECTIVES: The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID. METHODS: We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes. RESULTS: Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%. CONCLUSION: Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.