The impact and relevance of techniques and fluids on lung injury in machine perfusion of lungs.

Primary graft dysfunction (PGD) is a common complication after lung transplantation. A plethora of contributing factors are known and assessment of donor lung function prior to organ retrieval is mandatory for determination of lung quality. Specialized centers increasingly perform ex vivo lung perfusion (EVLP) to further assess lung functionality and improve and extend lung preservation with the aim to increase lung utilization. EVLP can be performed following different protocols. The impact of the individual EVLP parameters on PGD development, organ function and postoperative outcome remains to be fully investigated. The variables relate to the engineering and function of the respective perfusion devices, such as the type of pump used, functional, like ventilation modes or physiological (e.g. perfusion solutions). This review reflects on the individual technical and fluid components relevant to EVLP and their respective impact on inflammatory response and outcome. We discuss key components of EVLP protocols and options for further improvement of EVLP in regard to PGD. This review offers an overview of available options for centers establishing an EVLP program and for researchers looking for ways to adapt existing protocols.

Sarcopenia and Mediastinal Adipose Tissue as a Prognostic Marker for Short- and Long-Term Outcomes after Primary Surgical Treatment for Lung Cancer.

Surgical resection remains the gold standard of treatment for early-stage lung cancer. Several risk models exist to predict postoperative morbidity and mortality. Psoas muscle sarcopenia has already successfully been used for morbidity prediction in lung transplantation and is not yet included in the available risk scores for pulmonary resections. We hypothesized that the skeletal muscle index and mediastinal adipose tissue might also have an impact on postoperative outcomes after primary surgery for primary lung cancer. The institutional database was queried for patients with primary lung cancer who were treated with primary lobectomy or segmentectomy between February 2009 and November 2018. In total, 311 patients were included for analysis. Patients receiving neo-/adjuvant chemotherapy or with a positive nodal status were excluded to rule out any morbidity or mortality due to (neo-)adjuvant treatment. Sarcopenia was defined as a skeletal muscle index of <34.4 cm2/m2 for women and <45.4 cm2/m2 for men. Mediastinal adipose tissue was defined with a radiodensity of -150 to -30 Hounsfield units. Sarcopenia was diagnosed in 78 (25.1%) of the 311 patients. Male patients were significantly more likely to suffer from sarcopenia (31.5% vs. 18.1%, p = 0.009). Comorbidities, lung function, tumour histology, pathologic tumour staging, mediastinal adipose tissue and age did not differ between groups with or without sarcopenia. Sarcopenic patients had a significantly longer length of stay, with 13.0 days vs. 9.5 (p = 0.003), and a higher rate of any postoperative complications (59.0% vs. 44.6%, p = 0.036). There was no difference in recurrence rate. Five-year overall survival was significantly better in the patient cohort without sarcopenia (75.6% vs. 64.5%, p = 0.044). Mediastinal adipose tissue showed no significant impact on length of stay, postoperative complications, recurrence rate, morbidity or survival. Sarcopenia, quantified with the skeletal muscle index, is shown to be a risk factor for postoperative morbidity and reduced survival in primary lung cancer. Efforts should be taken to pre-emptively screen for sarcopenia and start countermeasures (e.g., physical prehabilitation, protein-rich nutrition, etc.) during the preoperative workup phase.

Whole stromal fibroblast signature is linked to specific chemokine and immune infiltration patterns and to improved survival in NSCLC.

Cancer associated fibroblasts (CAF) are known to orchestrate multiple components of the tumor microenvironment, whereas the influence of the whole stromal-fibroblast compartment is less understood. Here, an extended stromal fibroblast signature was investigated to define its impact on immune cell infiltration. The lung cancer adenocarcinoma (LUAD) data set of the cancer genome atlas (TCGA) was used to test whole stroma signatures and cancer-associated fibroblast signatures for their impact on prognosis. 3D cell cultures of the NSCLC cancer cell line A549 together with the fibroblast cell line SV80 were used in combination with infiltrating peripheral blood mononuclear cells (PBMC) for in-vitro investigations. Immune cell infiltration was assessed via flow cytometry, chemokines were analyzed by immunoassays and RNA microarrays. Results were confirmed in specimens from NSCLC patients by flow cytometry or immunohistochemistry as well as in the TCGA data set. The TCGA analyses correlated the whole stromal-fibroblast signature with an improved outcome, whereas no effect was found for the CAF signatures. In 3D microtumors, the presence of fibroblasts induced infiltration of B cells and CD69+CD4+ T cells, which was linked to an increased expression of CCL13 and CXCL16. The stroma/lymphocyte interaction was confirmed in NSCLC patients, as stroma-rich tumors displayed an elevated B cell count and survival in the local cohort and the TCGA data set. A whole stromal fibroblast signature was associated with an improved clinical outcome in lung adenocarcinoma and in vitro and in vivo experiments suggest that this signature increases B and T cell recruitment via induction of chemokines.

Using machine learning surrogate modeling for faster QSP VP cohort generation.

Virtual patients (VPs) are widely used within quantitative systems pharmacology (QSP) modeling to explore the impact of variability and uncertainty on clinical responses. In one method of generating VPs, parameters are sampled randomly from a distribution, and possible VPs are accepted or rejected based on constraints on model output behavior. This approach works but can be inefficient (i.e., the vast majority of model runs typically do not result in valid VPs). Machine learning surrogate models offer an opportunity to improve the efficiency of VP creation significantly. In this approach, surrogate models are trained using the full QSP model and subsequently used to rapidly pre-screen for parameter combinations that result in feasible VPs. The overwhelming majority of parameter combinations pre-vetted using the surrogate models result in valid VPs when tested in the original QSP model. This tutorial presents this novel workflow and demonstrates how a surrogate model software application can be used to select and optimize the surrogate models in a case study. We then discuss the relative efficiency of the methods and scalability of the proposed method.

Risk factors, complications and costs of prolonged air leak after video-assisted thoracoscopic surgery for primary lung cancer.

Background: Prolonged air leak (PAL) represents a common complication after lung resection. This study aims to analyze the risk factors for the development of a PAL, its impact on the postoperative outcome and to estimate additional treatment costs. Methods: A single center database was queried for all patients scheduled for video-assisted thoracoscopic surgery for primary lung cancer. In total, 957 patients between 2009 and 2021 were analyzed. Exclusion criteria was pneumonectomy. Collected data included demographics and perioperative data (e.g., duration of surgery, postoperative infections, air leak duration etc.). PAL was defined as an air leak lasting for 5 days or longer. The PAL cohort included 103 patients, the non-PAL included 854 patients. Univariate analysis and binomial logistic regression were performed. Cost calculation was performed using available data from prior publications to estimate treatment costs. Results: Male sex, chronic obstructive pulmonary disease (COPD) and low body mass index (BMI) showed to be risk factors for the development of postoperative PAL (P<0.001). Using these risk factors, a risk prediction score for PAL has been established. A subgroup analysis showed a significantly higher rate of sarcopenia in patients with PAL (P<0.001). The mean duration until removal of chest drains and length of stay (LOS) was significantly longer in the PAL cohort (14.2 vs. 4.4 days, P<0.001; 19.8 vs. 9.3 days, P<0.001). Also, the duration of the operation was longer in PAL patients (179.1 vs. 161.2 minutes, P=0.001). Patients with PAL had an elevated risk for postoperative infections [odds ratio (OR) 3.211, 31.1% vs. 12.3%, P<0.001]. As a result of a prolonged LOS, estimated treatment costs were significantly higher for PAL, ranging from 2,888.2 to 12,342.8 € depending on available cost bases compared to the non-PAL cohort, which ranged from 1,370.5 to 5,856.8 € (P<0.001). Conclusions: PAL is a frequent complication that prolongs the LOS after thoracic surgery and, according to the literature, results in elevated readmission rates, leading to excess health care costs. Risk factors for PAL are well established. Preoperative treatment of sarcopenia and dismal nutritional status might alter the risk. As measures to prevent PAL are otherwise limited, guidelines for effective management of PAL need to be established.

Interstitial Pulmonary Fibrosis and Extensive Dendriform Ossification with Persistent Viral Load: A Rare Presentation of Post-COVID-19 Condition in Need of Lung Transplantation.

The incidence, presentation, and predisposing factors of post-acute sequelae of COVID-19 (PASC) are currently poorly understood. Lung explants may provide a rare insight into terminal SARS-CoV-2-associated lung damage and its pathophysiology. A 62-year-old man presented with progressively worsening respiratory symptoms after recovering from mild COVID-19 3 months earlier. No underlying pulmonary comorbidities were reported. A chest CT revealed bilateral extensive ground-glass and reticular opacities, suspicious of pulmonary fibrosis. Despite initial high-dose glucocorticoid therapy, the interstitial lung disease progressed, and after exhausting all viable therapeutic options, bilateral lung transplantation was successfully conducted. Histological analysis revealed extensive end-stage interstitial fibrosis with diffuse dendriform ossification and bronchiolar and transitional cell metaplasia. Signs of interstitial remodeling such as an increased interstitial collagen deposition, a pathological accumulation of CD163+/CD206+ M2-polarized macrophages with an increased expression of phosphorylated ERK, and an increased density of CD105+ newly formed capillaries were observed. qRT-PCR and immunohistochemistry for SARS-CoV-2 N-protein in the endothelium of medium-sized vessels confirmed a persistence of SARS-CoV-2. Our findings highlight a highly unusual presentation of SARS-CoV-2-associated lung fibrosis, implying that incomplete viral clearance in the vascular compartment may play a vital pathophysiological role in the development of PASC.

External validation of risk prediction scores in patients undergoing anatomic video-assisted thoracoscopic resection.

BACKGROUND: EuroLung Risk scores were established to predict postoperative morbidity and mortality in patients undergoing anatomic lung resections. We aimed to perform an external validation of the EuroLung scores, which were calculated from data of the European Society of Thoracic Surgeons database, in our video-assisted thoracoscopic surgery cohort. METHODS: All available EuroLung scores were calculated for 718 patients scheduled for anatomic video-assisted thoracoscopic surgery resections between 2009 and 2019. Morbidity and mortality according to the definitions of the EuroLung scores were analyzed in a prospectively maintained database. RESULTS: Overall observed complication rate was 10.45%. Scores showed weak individual correlation (η = 0.155-0.174). The EuroLung1 app score showed the biggest area under the receiver operative characteristic (ROC) curve with 0.660. Binary logistic regression analysis showed that predicted postoperative forced expiratory volume in 1 s was associated with increased complications in both EuroLung1 and parsimonious EuroLung1 scores. Thirty-day mortality was 0.7% (predicted 1.10-1.40%) and was associated with predicted postoperative forced expiratory volume in 1 s for both EuroLung2 and parsimonious EuroLung2 scores. The EuroLung2 (2016) showed the biggest area under the ROC curve with 0.673. Only a very weak eta correlation between predicted and observed mortality was found for both aggregate EuroLung2, EuroLung2 (2016), EuroLung2 (2019), and parsimonious EuroLung2 (2016) (η = 0.025/0.015/0.011/0.009). CONCLUSION: EuroLung scores help to estimate postoperative morbidity. However, even with the highest aggregate EuroLung scores possible only 50% suffer from postoperative morbidity. Although calibration of the scores was acceptable, discrimination between predicted and observed events was poor. Therefore, individual correlation between predicted and observed events is weak. Therefore, EuroLung scores may be best used to compare institutional quality of care to the European Society of Thoracic Surgeons database but should not be used to preclude patients from surgical treatment.

Analysis of Pain Management after Anatomic VATS Resection in Austrian Thoracic Surgery Units.

BACKGROUND: Postoperative pain influences rehabilitation, postoperative complications and quality of life. Despite its impact, there are no uniform treatment guidelines. Different centers seem to use various strategies. This study aims to analyze pain management regimens used after anatomic VATS resections in Austrian thoracic surgery units, with a special interest in opioid usage and strategies to avoid opioids. METHODS: A questionnaire was designed to assess the use of regional anesthesia, postoperative pain medication and characteristics of individual pain management regimens. The questionnaire was sent to all thoracic surgery units in Austria, with nine out of twelve departments returning them. RESULTS: All departments use regional anesthesia during the procedure. Four out of nine centers use epidural analgesia or an intercostal catheter for postoperative regional anesthesia in at least 50% of patients. Two departments follow an opioid restrictive regimen, five depend on the visual analogue scale (VAS) and two administer opioids on a fixed schedule. Three out of nine departments use NSAIDs on a fixed schedule. The most used medication is metamizole (eight out of nine centers; six on a fixed schedule, two depending on VAS) followed by piritramide (six out of nine centers; none as a fixed prescription). CONCLUSIONS: This study reflects the heterogeneity in postoperative pain treatment after VATS anatomic lung resections. All departments use some form of regional anesthesia in the perioperative period; prolonged regional anesthesia is not utilized uniformly to reduce opioid consumption, as suggested in enhanced recovery after surgery programs. More evidence is needed to optimize and standardize postoperative pain treatment.

High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity with diverse immune cell infiltration patterns, which has been linked to therapy sensitivity and resistance. However, full understanding of how immune cell phenotypes vary across different patient subgroups is lacking. Here, we dissect the NSCLC tumor microenvironment at high resolution by integrating 1,283,972 single cells from 556 samples and 318 patients across 29 datasets, including our dataset capturing cells with low mRNA content. We stratify patients into immune-deserted, B cell, T cell, and myeloid cell subtypes. Using bulk samples with genomic and clinical information, we identify cellular components associated with tumor histology and genotypes. We then focus on the analysis of tissue-resident neutrophils (TRNs) and uncover distinct subpopulations that acquire new functional properties in the tissue microenvironment, providing evidence for the plasticity of TRNs. Finally, we show that a TRN-derived gene signature is associated with anti-programmed cell death ligand 1 (PD-L1) treatment failure.

A Delphi Consensus report from the "Prolonged Air Leak: A Survey" study group on prevention and management of postoperative air leaks after minimally invasive anatomical resections.

OBJECTIVES: This study reports the results of an international expert consensus process evaluating the assessment of intraoperative air leaks (IAL) and treatment of postoperative prolonged air leaks (PAL) utilizing a Delphi process, with the aim of helping standardization and improving practice. METHODS: A panel of 45 questions was developed and submitted to an international working group of experts in minimally invasive lung cancer surgery. Modified Delphi methodology was used to review responses, including 3 rounds of voting. The consensus was defined a priori as >50% agreement among the experts. Clinical practice standards were graded as recommended or highly recommended if 50-74% or >75% of the experts reached an agreement, respectively. RESULTS: A total of 32 experts from 18 countries completed the questionnaires in all 3 rounds. Respondents agreed that PAL are defined as >5 days and that current risk models are rarely used. The consensus was reached in 33/45 issues (73.3%). IAL were classified as mild (<100 ml/min; 81%), moderate (100-400 ml/min; 71%) and severe (>400 ml/min; 74%). If mild IAL are detected, 68% do not treat; if moderate, consensus was not; if severe, 90% favoured treatment. CONCLUSIONS: This expert consensus working group reached an agreement on the majority of issues regarding the detection and management of IAL and PAL. In the absence of prospective, randomized evidence supporting most of these clinical decisions, this document may serve as a guideline to reduce practice variation.

Clinical relevance of lung transplantation for COVID-19 ARDS: a nationwide study.

BACKGROUND: Although the number of lung transplantations (LTx) performed worldwide for COVID-19 induced acute respiratory distress syndrome (ARDS) is still low, there is general agreement that this treatment can save a subgroup of most severly ill patients with irreversible lung damage. However, the true proportion of patients eligible for LTx, the overall outcome and the impact of LTx to the pandemic are unknown. METHODS: A retrospective analysis was performed using a nationwide registry of hospitalised patients with confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-Cov-2) infection admitted between January 1, 2020 and May 30, 2021 in Austria. Patients referred to one of the two Austrian LTx centers were analyzed and grouped into patients accepted and rejected for LTx. Detailed outcome analysis was performed for all patients who received a LTx for post-COVID-19 ARDS and compared to patients who underwent LTx for other indications. RESULTS: Between January 1, 2020 and May 30, 2021, 39.485 patients were hospitalised for COVID-19 in Austria. 2323 required mechanical ventilation, 183 received extra-corporeal membrane oxygenation (ECMO) support. 106 patients with severe COVID-19 ARDS were referred for LTx. Of these, 19 (18%) underwent LTx. 30-day mortality after LTx was 0% for COVID-19 ARDS transplant recipients. With a median follow-up of 134 (47-450) days, 14/19 patients are alive. CONCLUSIONS: Early referral of ECMO patients to a LTx center is pivotal in order to select patients eligible for LTx. Transplantation offers excellent midterm outcomes and should be incorporated in the treatment algorithm of post-COVID-19 ARDS.

Rescue Blanket as a Provisional Seal for Penetrating Chest Wounds in a New Ex Vivo Porcine Model.

BACKGROUND: Open pneumothorax after a penetrating thorax trauma is a life-threatening disease with high mortality. An emergency application of a chest seal (CS) allowing the release of trapped air is the optimum initial therapy until surgical chest drainage is available. METHODS: In a newly developed experimental porcine model of open pneumothorax, we tested 3 different materials regarding their applicability for acute treatment of sucking chest wounds in prehospital emergency care, namely a commonly used rescue blanket (RB), plastic foil from a gauze package (packing material), and a commercial CS. RESULTS: An ex vivo open pneumothorax model using a porcine chest wall and a vacuum-assisted drainage system was successfully established. RB segments sized 70 × 100 mm achieved significantly higher rates of successful sealing than plastic foils from a gauze package sized 100 × 100 mm when the devices were applied to the moistened chest wall and fixed on 3 sides (5/5 [100%] vs 0/5 [0%], respectively; P = .002). Loosely fixed RBs efficiently released injected air (10/10 [100%]) and consequently sealed the wound in all cases (10/10). CONCLUSIONS: RBs, applied wet, are appropriate CSs with good occlusive and adherence properties. Fixation on 2 sides of the dressing is sufficient to allow trapped air to exit while providing appropriate sealing of the chest wound. RBs were superior to plastic foils from a gauze package and were seen to function as a potent makeshift CS when no commercial CS is available.

A spark of hope: histopathological and functional recovery after critical COVID-19.

BACKGROUND: There are substantial concerns about fibrotic and vascular pulmonary sequelae after coronavirus disease 2019 (COVID-19) associated acute respiratory distress syndrome (ARDS).AQ1 Histopathology reports of lung biopsies from COVID-19 survivors are scarce. CASE: We herein report results of functional and histopathological studies in a 70 year-old man undergoing a co-incidental tumor lobectomy six months after long-term mechanical ventilation for COVID-19 pneumonia. CONCLUSION: Despite several unfavorable risk factors, this case presentation shows a completed pulmonary recovery process within a few months.

Qualitative Risk Analysis for Contents of Dry Toilets Used to Produce Novel Recycling Fertilizers.

Human excreta are a sustainable, economical source of nutrients, and can be used to produce recycling fertilizer for horticulture by collecting and processing the contents of dry toilets. Herein, we discuss the key categories of risk associated with the main groups of materials commonly found in dry toilets. The study was part of the development of a German product standard for marketable and quality-assured recycling fertilizers from human excreta for use in horticulture. Particular attention is paid to ensuring that the fertilizer is epidemiologically and environmentally harmless and that the quality of the recycling fertilizer is adequate in terms of low pollution and nutrient availability. In sum, the risk of transmissible human pathogens lies within the human excreta, particularly feces; plant materials added during composting are of particular phytosanitary relevance; pharmaceutical residues in excrements and chemical additives are potential sources of pollutants; non-biodegradable contaminants can cause pollution and injury; and the horticultural risks involve mainly the ammonia emission potential and in some cases the salinity effects of urine. These risks can be reduced significantly (i) with education of users around proper operation of dry toilets and the consequences of adding inappropriate waste, (ii) with facilitation of proper use with general waste bins and clear instructions, and importantly (iii) by using modern sanitization and cleaning processes and testing for harmful substances under the guidance of local laws and regulations, ensuring safe and high-quality fertilizers. In conclusion, the benefits of using dry toilet contents to produce fertilizers for use in horticulture are unquestionable. Our analysis highlights the need to support recycling optimization and awareness for the purpose of a sustainable circular economy and to minimize the risk of harm to humans and the environment overall.

Delay to surgical treatment in lung cancer patients and its impact on survival in a video-assisted thoracoscopic lobectomy cohort.

Patient pathways from first suspicious imaging until final surgical treatment vary and in some instances cause considerable delay. This study aims to investigate the impact of this delay on survival of lung cancer patients. The institutional database was queried to identify patients with primary lung cancer who were treated with primary surgery. Time intervals were defined as date of first suspicious medical images until date of surgical treatment. All patients received PET-CT staging and tissue confirmation prior to treatment planning in a multidisciplinary tumor board. Patients with unknown date of first contact, follow-up CT-scans of pulmonary nodules, or neoadjuvant therapy were excluded. In total, 287 patients treated between 2009 and 2017 were included for further analysis. Median time between first suspicious medical imaging and surgical therapy was 62 (range 23-120) days and did not differ between male and female patients. Patients were then classified into two groups according to the duration of the medical work-up: group A up to 60 days, and group B from 61 to 120 days. Clinical T and N stages were comparable between the groups. There was no difference in overall survival between the two groups. In the subgroup of cT2 tumors (87 patients), there was a significant survival benefit for patients in group A (p = 0.043), while nodal stages, stage migration, lymphatic vessel invasion, grading and other potentially survival-influencing clinical parameters were comparable between the groups. Delay between diagnosis and treatment of lung cancer may result in dismal outcome. Efforts need to focus on improving and streamlining patient pathways to shorten the delay until surgical treatment to a minimum. Process improvement might be achieved by stringent interdisciplinary work-up and a patient-centered approach.

Intercostal Catheters for Postoperative Pain Management in VATS Reduce Opioid Consumption.

BACKGROUND: Postoperative pain after video-assisted thoracoscopic surgery (VATS) affects patients' recovery, postoperative complications, and length of stay (LOS). Despite its relevance, there are no guidelines on optimal perioperative pain management. This study aims to analyse the effects of an additional intercostal catheter (ICC) in comparison to a single shot intraoperative intercostal nerve block (SSINB). METHODS: All patients receiving an anatomic VATS resection between June 2019 and May 2020 were analysed retrospectively. The ICC cohort included 51 patients, the SSINB cohort included 44 patients. RESULTS: There was no difference in age, gender, comorbidities, or duration of surgery between cohorts. Pain scores on the first postoperative day, after chest drain removal, and highest pain score measured did not differ between groups. The overall amount of opioids (morphine equivalent: 3.034 mg vs. 7.727 mg; p = 0.002) as well as the duration of opioid usage (0.59 days vs. 1.25 days; p = 0.005) was significantly less in the ICC cohort. There was no difference in chest drain duration, postoperative complications, and postoperative LOS. CONCLUSIONS: Pain management with ICC reduces the amount of opioids and number of days with opioids patients require to achieve sufficient analgesia. In conclusion, ICC is an effective regional anaesthesia tool in postoperative pain management in minimally invasive thoracic surgery.

Nerve at risk: anatomical variations of the left recurrent laryngeal nerve and implications for thoracic surgeons.

OBJECTIVES: Recurrent laryngeal nerve (RLN) injury during thoracic surgery may result in life-threatening postoperative complications including recurrent aspiration and pneumonia. Anatomical details of the intrathoracic course are scarce. However, only an in-depth understanding of the anatomy will help reduce nerve injury. The aim of this study was to assess the anatomic variations of the intrathoracic left RLN. METHODS: Left-sided vagal nerves and RLN were dissected in 100 consecutive Caucasian cadavers during routine autopsy. Anatomical details were documented. Available demographic data were assessed for possible correlations. RESULTS: All nerves were identified during dissection. Variant courses were classified in 3 different groups according to the level at which the RLN separated from the vagal nerve: above the aortic arch, level with the aortic arch and below the aortic arch. We found 11% of RLN separating above the aortic arch and crossing the aortic arch at a considerable distance to the vagal nerve. In 48% of the RLN, the nerve split off when it was level with the aortic arch, and 41% of the RLN leave the vagal nerve in a perpendicular direction below the aortic arch. All nerves crossed the ligamentum arteriosum on the posterior side. No gender-specific differences were observed. CONCLUSIONS: Mediastinal lymph node dissection in left-sided lung cancer patients puts the RLN at risk. With more detailed anatomical knowledge about its course, it is possible to avoid risking the nerve. Visualization will help protect the nerve.