Identification of a short sequence motif in the influenza A virus pathogenicity factor PB1-F2 required for inhibition of human NLRP3.

Influenza A virus infection activates the NLRP3 inflammasome, a multiprotein signaling complex responsible for the proteolytic activation and release of the proinflammatory cytokine IL-1ß from monocytes and macrophages. Some influenza A virus (IAV) strains encode a short 90-amino acid peptide (PB1-F2) on an alternative open reading frame of segment 2, with immunomodulatory activity. We recently demonstrated that contemporary IAV PB1-F2 inhibits the activation of NLRP3, potentially by NEK7-dependent activation. PB1-F2 binds to NLRP3 with its C-terminal 50 amino acids, but the exact binding motif was unknown. On the NLRP3 side, the interface is formed through the leucine-rich-repeat (LRR) domain, potentially in conjunction with the pyrin domain. Here, we took advantage of PB1-F2 sequences from IAV strains with either weak or strong NLRP3 interaction. Sequence comparison and structure prediction using Alphafold2 identified a short four amino acid sequence motif (TQGS) in PB1-F2 that defines NLRP3-LRR binding. Conversion of this motif to that of the non-binding PB1-F2 suffices to lose inhibition of NLRP3 dependent IL-1ß release. The TQGS motif further alters the subcellular localization of PB1-F2 and its colocalization with NLRP3 LRR and pyrin domain. Structural predictions suggest the establishment of additional hydrogen bonds between the C-terminus of PB1-F2 and the LRR domain of NLRP3, with two hydrogen bonds connecting to threonine and glutamine of the TQGS motif. Phylogenetic data show that the identified NLRP3 interaction motif in PB1-F2 is widely conserved among recent IAV-infecting humans. Our data explain at a molecular level the specificity of NLRP3 inhibition by influenza A virus. IMPORTANCE: Influenza A virus infection is accompanied by a strong inflammatory response and high fever. The human immune system facilitates the swift clearance of the virus with this response. An essential signal protein in the proinflammatory host response is IL-1b. It is released from inflammatory macrophages, and its production and secretion depend on the function of NLRP3. We had previously shown that influenza A virus blocks NLRP3 activation by the expression of a viral inhibitor, PB1-F2. Here, we demonstrate how this short peptide binds to NLRP3 and provide evidence that a four amino acid stretch in PB1-F2 is necessary and sufficient to mediate this binding. Our data identify a new virus-host interface required to block one signaling path of the innate host response against influenza A virus.

An Optimized Method to Culture Human Primary Lung Tumor Cell Spheroids.

Lung cancer is the leading cause of cancer mortality worldwide, with a median survival rate at 5 years of less than 20%. While molecular mapping aids in selecting appropriate therapies, it cannot predict personalized treatment response and long-term efficacy. For addressing these challenges, there is a great need for functional tests. Within this context, we developed patient-derived spheroids (PDS) from tumor and adjacent normal tissue to biomimic the respective tissue for assessing the personalized drug treatment response in vitro. Surgically resected lung specimens were used to generate spheroids using a two-step culture procedure. Flow cytometry and immune staining enabled the characterization of different cell populations resulting from the lung samples. PDS phenotype, cell proliferation and apoptosis were evaluated. Differential gene expression between tumor and adjacent normal tissue was analyzed via RT-qPCR. PDS drug sensitivity was assessed using a cell metabolic assay in response to two chemotherapeutic drug combinations. Cellular and molecular analysis revealed the proportion of epithelial cells, fibroblasts, and immune cells in the patients' tissue samples. Subsequently, PDS models from tumor and normal lung were successfully established using the expanded epithelial cells. As a proof of concept, an analysis of the drug treatment using PDS of lung adenoid cystic carcinoma exhibited a dose-dependent effect in response to cisplatin/etoposide and cisplatin/paclitaxel. Our spheroid model of both tumor and non-tumor lung cells holds great promise for enhancing the treatment efficacy in the cancer patients.

Safety of continuous intraoperative vagus nerve neuromonitoring during thyroid surgery.

BACKGROUND: Continuous intraoperative neuromonitoring has successfully demonstrated to predict impending damage to the recurrent laryngeal nerve, by detecting changes in electromyographic recordings. Despite the apparent benefits associated with continuous intraoperative neuromonitoring, its safety is still a debate. The aim of this study was to investigate the electrophysiological impact of continuous intraoperative neuromonitoring on the vagus nerve. METHODS: In this prospective study, the amplitude of the electromyographic wave of the vagus nerve-recurrent laryngeal nerve axis was measured both proximally and distally to the stimulation electrode placed upon the vagus nerve. Electromyographic signal amplitudes were collected at three distinct events during the operation: during the dissection of the vagus nerve, before application of the continuous stimulation electrode onto the vagus nerve and after its removal. RESULTS: In total, 169 vagus nerves were analysed, among 108 included patients undergoing continuous intraoperative neuromonitoring-enhanced endocrine neck surgeries. Electrode application resulted in a significant overall decrease in measured proximo-distal amplitudes of -10.94 µV (95 per cent c.i. -17.06 to -4.82 µV) (P < 0.005), corresponding to a mean(s.d.) decrease of -1.4(5.4) per cent. Before the removal of the electrode, the measured proximo-distal difference in amplitudes was -18.58 µV (95 per cent c.i. -28.31 to -8.86 µV) (P < 0.005), corresponding to a mean(s.d.) decrease of -2.50(9.59) per cent. Seven nerves suffered a loss of amplitude greater than 20 per cent of the baseline measurement. CONCLUSION: In addition to supporting claims that continuous intraoperative neuromonitoring exposes the vagus nerve to injury, this study shows a mild electrophysiological impact of continuous intraoperative neuromonitoring electrode placement on the vagus nerve-recurrent laryngeal nerve axis. However, the small observed differences are negligible and were not associated with a clinically relevant outcome, making continuous intraoperative neuromonitoring a safe adjunct in selected thyroid surgeries.

Influenza A virus exploits transferrin receptor recycling to enter host cells.

Influenza A virus (IAV) enters host cells mostly through clathrin-dependent receptor-mediated endocytosis. A single bona fide entry receptor protein supporting this entry mechanism remains elusive. Here we performed proximity ligation of biotin to host cell surface proteins in the vicinity of attached trimeric hemagglutinin-HRP and characterized biotinylated targets using mass spectrometry. This approach identified transferrin receptor 1 (TfR1) as a candidate entry protein. Genetic gain-of-function and loss-of-function experiments, as well as in vitro and in vivo chemical inhibition, confirmed the functional involvement of TfR1 in IAV entry. Recycling deficient mutants of TfR1 do not support entry, indicating that TfR1 recycling is essential for this function. The binding of virions to TfR1 via sialic acids confirmed its role as a directly acting entry factor, but unexpectedly even headless TfR1 promoted IAV particle uptake in trans. TIRF microscopy localized the entering virus-like particles in the vicinity of TfR1. Our data identify TfR1 recycling as a revolving door mechanism exploited by IAV to enter host cells.

Local control and short-term outcomes after video-assisted thoracoscopic surgery segmentectomy versus lobectomy for pT1c pN0 non-small-cell lung cancer.

OBJECTIVES: The aim of this study was to compare short-term outcomes and local control in pT1c pN0 non-small-cell lung cancer that were intentionally treated by video-assisted thoracoscopic surgery (VATS) lobectomy or segmentectomy. METHODS: Multicentre retrospective study of consecutive patients undergoing VATS lobectomy (VL) or VATS segmentectomy (VS) for pT1c pN0 non-small-cell lung cancer from January 2014 to October 2021. Patients' characteristics, postoperative outcomes and survival were compared. RESULTS: In total, 162 patients underwent VL (n = 81) or VS (n = 81). Except for age [median (interquartile range) 68 (60-73) vs 71 (65-76) years; P = 0.034] and past medical history of cancer (32% vs 48%; P = 0.038), there was no difference between VL and VS in terms of demographics and comorbidities. Overall 30-day postoperative morbidity was similar in both groups (34% vs 30%; P = 0.5). The median time for chest tube removal [3 (1-5) vs 2 (1-3) days; P = 0.002] and median postoperative length of stay [6 (4-9) vs 5 (3-7) days; P = 0.039] were in favour of the VS group. Significantly larger tumour size (mean ± standard deviation 25.1 ± 3.1 vs 23.6 ± 3.1 mm; P = 0.001) and an increased number of lymph nodes removal [median (interquartile range) 14 (9-23) vs 10 (6-15); P < 0.001] were found in the VL group. During the follow-up [median (interquartile range) 31 (14-48) months], no statistical difference was found for local and distant recurrence in VL groups (12.3%) and VS group (6.1%) (P = 0.183). Overall survival (80% vs 80%) was comparable between both groups (P = 0.166). CONCLUSIONS: Despite a short follow-up, our preliminary data shows that local control is comparable for VL and VS.

Near-infrared fluorescent imaging techniques for the detection and preservation of parathyroid glands during endocrine surgery.

Objectives: In over 30% of all thyroid surgeries, complications arise from transient and definitive hypoparathyroidism, underscoring the need for real-time identification and preservation of parathyroid glands (PGs). Here, we evaluate the promising intraoperative optical technologies available for the identification, preservation, and functional assessment of PGs to enhance endocrine surgery. Methods: We performed a review of the literature to identify published studies on fluorescence imaging in thyroid and parathyroid surgery. Results: Fluorescence imaging is a well-demonstrated approach for both in vivo and in vitro localization of specific cells or tissues, and is gaining popularity as a technique to detect PGs during endocrine surgery. Autofluorescence (AF) imaging and indocyanine green (ICG) angiography are two emerging optical techniques to improve outcomes in thyroid and parathyroid surgeries. Near-infrared-guided technology has significantly contributed to the localization of PGs, through the detection of glandular AF. Perfusion through the PGs can be visualized with ICG, which can also reveal the blood supply after dissection. Conclusions: Near infrared AF and ICG angiography, providing a valuable spatial and anatomical information, can decrease the incidence of complications in thyroid surgery.

Expert consensus on indocyanine green fluorescence imaging for thoracoscopic lung resection (The Version 2022).

The use of the white-light thoracoscopy is hampered by the low contrast between oncologic margins and surrounding normal parenchyma. As a result, many patients with in situ or micro-infiltrating adenocarcinoma have to undergo lobectomy due to a lack of tactile and visual feedback in the resection of solitary pulmonary nodules. Near-infrared (NIR) guided indocyanine green (ICG) fluorescence imaging technique has been widely investigated due to its unique capability in addressing the current challenges; however, there is no special consensus on the evidence and recommendations for its preoperative and intraoperative applications. This manuscript will describe the development process of a consensus on ICG fluorescence-guided thoracoscopic resection of pulmonary lesions and make recommendations that can be applied in a greater number of centers. Specifically, an expert panel of thoracic surgeons and radiographers was formed. Based on the quality of evidence and strength of recommendations, the consensus was developed in conjunction with the Chinese Guidelines on Video-assisted Thoracoscopy, and the National Comprehensive Cancer Network (NCCN) guidelines on the management of pulmonary lesions. Each of the statements was discussed and agreed upon with a unanimous consensus amongst the panel. A total of 6 consensus statements were developed. Fluorescence-guided thoracoscopy has unique advantages in the visualization of pulmonary nodules, and recognition and resection of the anterior plane of the pulmonary segment. The expert panel agrees that fluorescence-guided thoracoscopic surgery has the potential to become a routine operation for the treatment of pulmonary lesions.

Effectiveness of rib fixation compared to pain medication alone on pain control in patients with uncomplicated rib fractures: study protocol of a pragmatic multicenter randomized controlled trial-the PAROS study (Pain After Rib OSteosynthesis).

BACKGROUND: Persistent pain and disability following rib fractures result in a large psycho-socio-economic impact for health-care system. Benefits of rib osteosynthesis are well documented in patients with flail chest that necessitates invasive ventilation. In patients with uncomplicated and simple rib fractures, indication for rib osteosynthesis is not clear. The aim of this trial is to compare pain at 2 months after rib osteosynthesis versus medical therapy. METHODS: This trial is a pragmatic multicenter, randomized, superiority, controlled, two-arm, not-blinded, trial that compares pain evolution between rib fixation and standard pain medication versus standard pain medication alone in patients with uncomplicated rib fractures. The study takes place in three hospitals of Thoracic Surgery of Western Switzerland. Primary outcome is pain measured by the brief pain inventory (BPI) questionnaire at 2 months post-surgery. The study includes follow-up assessments at 1, 2, 3, 6, and 12 months after discharge. To be able to detect at least 2 point-difference on the BPI between both groups (standard deviation 2) with 90% power and two-sided 5% type I error, 46 patients per group are required. Adjusting for 10% drop-outs leads to 51 patients per group. DISCUSSION: Uncomplicated rib fractures have a significant medico-economic impact. Surgical treatment with rib fixation could result in better clinical recovery of patients with uncomplicated rib fractures. These improved outcomes could include less acute and chronic pain, improved pulmonary function and quality of life, and shorter return to work. Finally, surgical treatment could then result in less financial costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04745520 . Registered on 8 February 2021.

Contralateral Pneumonectomy 27 Years After Right Single-Lung Transplantation for Emphysema: A Case Report.

BACKGROUND Following single-lung transplantation, native lung inflation can progressively develop in patients with emphysema. CASE REPORT A 74-year-old female patient presented with worsening dyspnea during daily activities. She underwent a right single-lung transplantation for emphysema 27 years ago. Despite recurrent episodes of acute rejection of the grafted lung, the patient had satisfactory recovery of physical fitness during that period and did not report any serious complications or respiratory symptoms. Her recent dyspnea was due to hyperinflation of the native emphysematous lung with mediastinal shift, reduction of venous blood return, and compression of the grafted lung. Although surgical lung volume reduction had resulted in temporary functional improvement 2 years ago, a completion contralateral pneumonectomy was deemed necessary to allow re-expansion of the grafted lung. After anesthesia induction and placement of a double-lumen tube, selective ventilation of the left emphysematous native lung confirmed the absence of gas exchange based on near-zero end-expiratory carbon dioxide fraction. During selective ventilation of the grafted lung, satisfactory gas exchange was achieved and pneumonectomy proceeded uneventfully under minimally-invasive thoracotomy. Immediately after anesthesia emergence and tracheal extubation, the patient experienced respiratory improvement. Continuous thoracic epidural blockade allowed pain-free mobilization and respiratory therapy to facilitate re-expansion of the grafted lung. CONCLUSIONS After single-lung transplantation in COPD patients, native lung hyperinflation is a well-described rare complication. Lung volume reduction including pneumonectomy can be considered a valuable treatment option.

Operative Planning of Chest Wall Reconstructions Illustrated by a Large Defect in a Child.

Reconstruction of large chest wall defects is challenging. Here we discuss the process of decision-making in planning chest wall reconstruction, considering the requirements of tumor removal, stabilization of the chest wall, and soft tissue coverage, illustrated by a case of a hemi-chest wall defect in a child. Ewing sarcoma measuring 10 × 9 × 13 cm was resected in a 9-year-old boy, followed by stabilization using a Gore-Tex patch. Due to extension of the oncologic resection far into the superomedial quadrant of the chest, tension-free coverage with a classical latissimus-dorsi flap could not be achieved. Integrating the serratus-anterior muscle into the flap creating a chimeric latissimus-dorsi/serratus-anterior flap allowed for excellent soft tissue coverage of the foreign body. As the skin could be preserved, careful incision planning was necessary to allow for best possible exposure during oncologic resection and flap harvest, while ensuring skin vascularization impaired by underlying tumor resection. Two vertical skin incisions were chosen, one presternal and a second in the mid-axillary fold delineating a large bipedicled skin flap. Postoperative recovery was excellent. Solid skin vascularization and adequate soft tissue coverage of the alloplastic material allowed for the patient to receive two cycles of postoperative radiotherapy without developing wound dehiscence. Careful interdisciplinary planning of skin incisions allowed for good exposure for tumor resection and flap harvest while preserving skin vascularization. Choosing a chimeric latissimus-dorsi/serratus-anterior flap provided larger coverage than a classical latissimus-dorsi flap with minimal additional donor site morbidity. Taken together, we here present a pragmatic solution to a complex problem.

Performance of prolonged air leak scoring systems in patients undergoing video-assisted thoracoscopic surgery segmentectomy.

OBJECTIVES: We assessed the accuracy of 3 validated lobectomy scoring systems to predict prolonged air leak (PAL) in patients undergoing video-assisted thoracoscopic surgery (VATS) segmentectomy. METHODS: We reviewed all consecutive patients who had a VATS segmentectomy between January 2016 and October 2020. We determined PALs on postoperative day 5. These findings were correlated with the calculated Brunelli (gender, age, body mass index [BMI], forced expiratory volume in 1 s < 80 and pleural adhesion), Epithor (gender, location, dyspnoea score, BMI, type of resection and pleural adhesion) and European Society of Thoracic Surgeons (ESTS) (gender, BMI and forced expiratory volume in 1 s) scores of each patient. RESULTS: A total of 453 patients (mean age: 66.5 years, female/male sex ratio: 226/227) underwent a VATS segmentectomy for malignant (n = 400) and non-malignant (n = 53) disease. Postoperative cardiopulmonary complications and in-hospital mortality rates were 19.6% and 0.4%, respectively. Median chest tube drainage duration and hospital stay were 2 (interquartile range: 1-4) and 4 (interquartile range: 3-7) days, respectively. On day 5, the prevalence of PAL was 14.1%. The ESTS, Brunelli and Epithor scores for the treated population were, respectively, class A (6.8%), class B (3.2%), class C (10.8%) and class D (28.2%); very low and low (0%), moderate (5%), high (6.3%) and very high (21%); and class A (7%), class B (13.2%), class C (24%) and class D (27.8%). All scores correlated with PAL (p ≤ 0.001). The areas under the receiver operating characteristic (ROC) curve were 0.686, 0.680 and 0.644, respectively. CONCLUSIONS: All 3 scoring systems were correlated with PAL > 5 days following the VATS segmentectomies. ESTS scores seem easier to introduce in clinical practice, but validation by a multicentre cohort is mandatory.

Is the indocyanine green score an accurate predictor of postoperative parathyroid hormone level?

BACKGROUND: Hypoparathyroidism is common after total thyroidectomy, primarily due to inadvertent disruption of the parathyroid gland blood supply during thyroid dissection. Indocyanine green helps determine the degree of vascularization and correlates with parathyroid gland vitality. It is difficult to determine how the indocyanine green score affects postoperative parathyroid hormone levels because all 4 parathyroid glands must be evaluated during surgery. We determined whether there is a correlation between intraoperative indocyanine green score and postoperative serum parathyroid hormone levels. METHODS: We retrospectively studied patients who underwent total thyroidectomy where we could identify all 4 parathyroid glands and establish a global indocyanine green score. Each parathyroid gland was scored from 0 to 2 depending on indocyanine green uptake. The global indocyanine green score was the sum of the individual scores for each gland. The scores were then correlated to parathyroid hormone and calcium levels on days 1 and 10 after surgery. RESULTS: We included 83 patients, 11 of whom presented with postoperative transient hypoparathyroidism; all but one had an indocyanine green score lower than 4 of 8. There was a significant correlation between the global indocyanine green score and postoperative parathyroid hormone level. A global indocyanine green score >3.75 can exclude postoperative hypoparathyroidism with a true negative value of 98%. Indocyanine green angiography is a better diagnostic test to predict a postoperative transient hypoparathyroidism compared with visual perfusion scoring. CONCLUSION: These findings suggest that the indocyanine green score based on intraoperative indocyanine green angiography predicts parathyroid gland function. It is a valuable instrument to predict hypoparathyroidism after total thyroidectomy.

Ventilatory efficiency slope is associated with cardiopulmonary complications after thoracoscopic anatomical lung resection.

OBJECTIVES: The aim of this study was to identify whether steeper V.E/V. CO2 slope was associated with cardiopulmonary complications (CPC) after anatomical resection by video-assisted thoracic surgery. Long-term survival was analysed as secondary outcome. METHODS: We reviewed the files of all consecutive patients who underwent pulmonary anatomical resections by video-assisted thoracic surgery between January 2010 and October 2020 at the Centre for Thoracic Surgery of Western Switzerland. Logistic regression was used to investigate the risk of CPC associated with the V.E/V.CO2 slope and other possible confounders. Survival was analysed with Kaplan-Meier curves. Risk factors associated with survival were analysed with a Cox proportional hazards model. RESULTS: The V.E/V.CO2 slope data were available for 145 patients [F/M: 66/79; mean age (standard deviation): 65.8 (8.9)], which were included in the analysis. Patients underwent anatomical resection [lobectomy (71%) or segmentectomy (29%)] mainly for lung cancer (96%). CPC and all-cause 90-day mortality were 29% and 1%, respectively. The mean (standard deviation) percentage of the predicted V.O2peak was 70% (17). Maximum effort during cardiopulmonary exercise test was reached in only 31% of patients. The V.E/V.CO2 slope (standard deviation) was not different if the maximum effort was reached or not [39 (6) vs 37 (7), P = 0.21]. V.E/V.CO2 slope >35 was associated with an increased risk of CPC (odds ratio 2.9, 95% confidence interval 1.2, 7.2, P = 0.020). V.E/V.CO2 slope >35 was not associated with shorter survival censored for lung cancer-related death. CONCLUSIONS: V . E/V.CO2 slope >35 is significantly associated with postoperative CPC after anatomical resections by video-assisted thoracic surgery. CLINICAL REGISTRATION NUMBER CER-VD (SWITZERLAND): Project ID: 2021-00620.

Optimization of tumor spheroid model in mesothelioma and lung cancers and anti-cancer drug testing in H2052/484 spheroids.

Advanced lung cancers and mesothelioma remain incurable diseases. Despite some promising new therapy strategies, predicting whether an individual patient will be sensitive to a given therapy is challenging. The purpose of this study is to establish and evaluate the efficiency of a three-dimensional spheroid model of human thoracic cancer in predicting the efficacy of drugs. Human mesothelioma and lung tumor spheroids were established from cell lines and primary cells derived from the patient. The growth kinetics and cell viability of microtumors were assessed using spheroid size and intracellular ATP level. The sensitivity of the mesothelioma spheroids to the cisplatin or cisplatin/pemetrexed combination was determined. We determined that studying the kinetics of the spheroid growth for 15 days after seeding 1000 cells/well in a 96-well plate was optimal. Monitoring the growth kinetic and intracellular ATP of spheroids allowed the identification of early changes in spheroid viability. Finally, we validated this model by measuring a dose-dependent reduction in the cell viability of mesothelioma H2052/484 spheroids treated with both first-line treatments, cisplatin and the cisplatin/pemetrexed combination. In conclusion, we have developed a three-dimensional spheroid model of thoracic tumor cells useful for tailoring the medical treatment to the specific characteristics of each patient.

How can we minimize the risks by optimizing patient's condition shortly before thoracic surgery?

The "moderate-to-high-risk" surgical patient is typically older, frail, malnourished, suffering from multiple comorbidities and presenting with unhealthy life style such as smoking, hazardous drinking and sedentarity. Poor aerobic fitness, sarcopenia and "toxic" behaviors are modifiable risk factors for major postoperative complications. The physiological challenge of lung cancer surgery has been likened to running a marathon. Therefore, preoperative patient optimization or " prehabilitation " should become a key component of improved recovery pathways to enhance general health and physiological reserve prior to surgery. During the short preoperative period, the patients are more receptive and motivated to adhere to behavioral interventions (e.g., smoking cessation, weaning from alcohol, balanced food intake and active mobilization) and to follow a structured exercise training program. Sufficient protein intake should be ensured (1.5-2 g/kg/day) and nutritional defects should be corrected to restore muscle mass and strength. Currently, there is strong evidence supporting the effectiveness of various modalities of physical training (endurance training and/or respiratory muscle training) to enhance aerobic fitness and to mitigate the risk of pulmonary complications while reducing the hospital length of stay. Multimodal interventions should be individualized to the patient's condition. These bundle of care are more effective than single or sequential intervention owing to synergistic benefits of education, nutritional support and physical training. An effective prehabilitation program is necessarily patient-centred and coordinated among health care professionals (nurses, primary care physician, physiotherapists, nutritionists) to help the patient regain some control over the disease process and improve the physiological reserve to sustain surgical stress.

Restricted, optimized or liberal fluid strategy in thoracic surgery: A narrative review.

Perioperative fluid balance has a major impact on clinical and functional outcome, regardless of the type of interventions. In thoracic surgery, patients are more vulnerable to intravenous fluid overload and to develop acute respiratory distress syndrome and other complications. New insight has been gained on the mechanisms causing pulmonary complications and the role of the endothelial glycocalix layer to control fluid transfer from the intravascular to the interstitial spaces and to promote tissue blood flow. With the implementation of standardized processes of care, the preoperative fasting period has become shorter, surgical approaches are less invasive and patients are allowed to resume oral intake shortly after surgery. Intraoperatively, body fluid homeostasis and adequate tissue oxygen delivery can be achieved using a normovolemic therapy targeting a "near-zero fluid balance" or a goal-directed hemodynamic therapy to maximize stroke volume and oxygen delivery according to the Franck-Starling relationship. In both fluid strategies, the use of cardiovascular drugs is advocated to counteract the anesthetic-induced vasorelaxation and maintain arterial pressure whereas fluid intake is limited to avoid cumulative fluid balance exceeding 1 liter and body weight gain (~1-1.5 kg). Modern hemodynamic monitors provide valuable physiological parameters to assess patient volume responsiveness and circulatory flow while guiding fluid administration and cardiovascular drug therapy. Given the lack of randomized clinical trials, controversial debate still surrounds the issues of the optimal fluid strategy and the type of fluids (crystalloids versus colloids). To avoid the risk of lung hydrostatic or inflammatory edema and to enhance the postoperative recovery process, fluid administration should be prescribed as any drug, adapted to the patient's requirement and the context of thoracic intervention.

Blood-Based Multi-Cancer Detection Using a Novel Variant Calling Assay (DEEPGENTM): Early Clinical Results.

This is an early clinical analysis of the DEEPGENTM platform for cancer detection. Newly diagnosed cancer patients and individuals with no known malignancy were included in a prospective open-label case-controlled study (NCT03517332). Plasma cfDNA that was extracted from peripheral blood was sequenced and data were processed using machine-learning algorithms to derive cancer prediction scores. A total of 260 cancer patients and 415 controls were included in the study. Overall, sensitivity for all cancers was 57% (95% CI: 52, 64) at 95% specificity, and 43% (95% CI: 37, 49) at 99% specificity. With 51% sensitivity and 95% specificity for all stage 1 cancers, the stage-specific sensitivities trended to improve with higher stages. Early results from this preliminary clinical, prospective evaluation of the DEEPGENTM liquid biopsy platform suggests the platform offers a clinically relevant ability to differentiate individuals with and without known cancer, even at early stages of cancer.

Stage III N2 non-small cell lung cancer treatment: decision-making among surgeons and radiation oncologists.

BACKGROUND: Stage III N2 non-small cell lung cancer (NSCLC) is a very heterogeneous disease associated with a poor prognosis. A number of therapeutic options are available for patients with Stage III N2 NSCLC, including surgery [with neoadjuvant or adjuvant chemotherapy (CTx)/neoadjuvant chemoradiotherapy (CRT)] or CRT potentially followed by adjuvant immunotherapy. We have no clear evidence demonstrating a significant survival benefit for either of these approaches, the selection between treatments is not always straightforward and can come down to physician and patient preference. The very heterogeneous definition of resectability of N2 disease makes the decision-making process even more complex. METHODS: We evaluated the treatment strategies for preoperatively diagnosed stage III cN2 NSCLC among Swiss thoracic surgeons and radiation oncologists. Treatment strategies were converted into decision trees and analysed for consensus and discrepancies. We analysed factors relevant to decision-making within these recommendations. RESULTS: For resectable "non-bulky" mediastinal lymph node involvement, there was a trend towards surgery. Numerous participants recommend a surgical approach outside existing guidelines as long as the disease was resectable, even in multilevel N2. With increasing extent of mediastinal nodal disease, multimodal treatment based on radiotherapy was more common. CONCLUSIONS: Both, surgery- or radiotherapy-based treatment regimens are feasible options in the management of Stage III N2 NSCLC. The different opinions reflected in the results of this manuscript reinforce the importance of a multidisciplinary setting and the importance of shared decision-making with the patient.

Outcome of parapneumonic empyema managed surgically or by fibrinolysis: a multicenter study.

BACKGROUND: Parapneumonic empyema (PPE) management remains debated. Here we present the outcome of a comparable population with PPE treated over a 4-year period in two Thoracic Surgery University Centers with different approaches: one with an early "surgical" and the other with a "fibrinolytic" approach. METHODS: All operable patients with PPE managed in both centers between January 2014 and January 2018 were reviewed. Patients with persistent pleural effusion/loculations following drainage were managed by a "surgical" approach in one center and by "fibrinolytic" approach in the other. For each patient, we recorded the age, sex, hospital stay, morbidity/mortality and change in pleural opacity on chest X-ray before and at the end of the treatment. RESULTS: During the study period, 66 and 93 patients underwent PPE management in the "surgical" and "fibrinolytic" centers respectively. The population characteristics were comparable. Infection was controlled in all patients. In the "fibrinolytic" group, 20 patients (21.5%) underwent an additional drain placement while 12 patients (12.9%) required surgery to correct PPE. In the "surgical" group, 4 patients (6.1%) developed postoperative arrhythmia while 2 patients (3%) underwent a second surgery to evacuate a hemothorax. Median drainage {3 [2-4] vs. 5 [4-7] days} and hospital {7 [5-10] vs. 11 [7-19] days} durations were significantly lower in the "surgical" compared to the "fibrinolytic" center. Pleural opacity regression with therapy was significantly more important in the "surgical" compared to the "fibrinolytic" group (-22%±18% vs. -16%±17%, P=0.035). CONCLUSIONS: Surgical management of PPE was associated with shorter chest tube and hospital duration and better pleural space control. Prospective randomized studies are mandatory.