Validated Prognostic Scores to Predict Outcomes in ECLS-Bridged Patients to Lung Transplantation.

Selection of patients who may benefit from extracorporeal life support (ECLS) as a bridge to lung transplant (LTx) is crucial. The aim was to assess if validated prognostic scores could help in selecting patients who may benefit from ECLS-bridging predicting their outcomes. Clinical data of patients successfully ECLS-bridged to LTx from 2009 to 2021 were collected from two European centers. For each patient, we calculated Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score III (SAPS III), Acute Physiology and Chronic Health Evaluation II (APACHE II), before placing ECLS support, and then correlated with outcome. Median values of SOFA, SAPS III, and APACHE II were 5 (IQR 3-9), 57 (IQR 47.5-65), and 21 (IQR 15-26). In-hospital, 30 and 90 days mortality were 21%, 14%, and 22%. SOFA, SAPS III, and APACHE II were analyzed as predictors of in-hospital, 30 and 90 days mortality (SOFA C-Index: 0.67, 0.78, 0.72; SAPS III C-index: 0.48, 0.45, 0.51; APACHE II C-Index: 0.49, 0.45, 0.52). For SOFA, the score with the best performance, a value ≥9 was identified to be the optimal cut-off for the prediction of the outcomes of interest. SOFA may be considered an adequate predictor in these patients, helping clinical decision-making. More specific and simplified scores for this population are necessary.

A strategy to analyse activity-based profiling of tyrosine kinase substrates in OCT-embedded lung cancer tissue.

The use of optimal cutting temperature (OCT) medium has served to improve the long-term preservation of surgical tissue specimens. Unfortunately, the presence of polymers in OCT has been found to generate signal interference in proteomic-based techniques. Indeed the presence of OCT medium in tissue lysates precludes the analysis of activity based proteomic profiles obtained from lung adenocarcinoma (LuAdCa) resection specimens. In order to probe this question further tissue lysates were prepared from 47 lung non-neoplastic and tumour, node, metastasis (TNM) stage 1 LuAdCa resection specimens embedded with or without OCT, and data of activity based multiplex profiles of protein tyrosine kinase peptide substrates were obtained. We found that changes in overall phosphorylation level coincided with the use of OCT and subsequently developed an OCT per peptide median correcting strategy by performing median centering on the values of each peptide. Application of this post-analytical strategy not only can identify changes in kinase activity but can also assist in identifying novel targets for therapeutic intervention against LuAdCa.

Ex vivo treatment with inhaled N-acetylcysteine in porcine lung transplantation.

BACKGROUND: We have shown the beneficial effects of N-acetylcysteine (NAC) on posttransplant lung function, when both donor and recipient were pretreated intravenously. However, systemic treatment of multiorgan donors may not be clinically relevant. Thus, we hypothesized that ex vivo treatment of donors with nebulized NAC would be adequate to prevent from ischemia-reperfusion injury after lung transplantation. METHODS: Lungs were retrieved from domestic pigs and stored at 4°C for 24 h followed by 2 h of ex vivo lung perfusion (EVLP) to administer 50 mg/kg of NAC via nebulization in the NAC group (n = 6). The control group received nebulized saline (n = 5). Left lungs were transplanted and isolated at 1 h of reperfusion by occluding the right main bronchus and pulmonary artery, followed by 5 h of observation. Physiological data during EVLP and after reperfusion were recorded. Inflammatory response, markers of oxidative stress, and microscopic lung injury were analyzed. RESULTS: There was a trend toward better oxygenation throughout reperfusion period in the treatment group, which was accompanied by inhibited inflammatory response related to reduction in myeloperoxidase activity during EVLP and nuclear factor-κB activation at the end of reperfusion. CONCLUSIONS: Ex vivo treatment of donor lungs with inhaled NAC reduced inflammatory response via its antioxidant activity in experimental porcine lung transplantation.

Orthostatic Hypotension and Antihypertensive Treatment in Lung Transplant Recipients: A Cross-Sectional Study.

OBJECTIVES: Lung transplant is the ultimate treatment of many end-stage lung diseases. Calcineurin inhibitors, crucial in immunosuppression for lung transplant recipients, are linked to secondary hypertension, necessitating antihypertensive treatment. In addition, lung transplant recipients frequently experience orthostatic hypotension, occasionally stemming from autonomic dysfunction, but also commonly attributed as a negative side effect of antihypertensive treatment. Our study aimed to evaluate the frequency of orthostatic blood pressure irregularities and investigate the involvement of antihypertensive treatment as a potential risk factor in the occurrence among lung transplant recipients. MATERIALS AND METHODS: Fifty-six consecutive lung transplant recipients, both inpatient and outpatient, at the University Hospital Zurich (Switzerland) were monitored from 1999 to 2013. Transplant recipients underwent a Schellong test (an active standing test). Our evaluation encompassed their initial traits, such as the existence of supine hypertension. We computed the odds ratio for the comparison of the likelihood of experiencing orthostatic hypotension while using a minimum of 1 type of antihypertensive medication versus absence of antihypertensive drugs. RESULTS: Of the lung transplant recipients, 25% showed a positive Schellong test. Within this group, 64% had supine hypertension, and 29% displayed symptoms of orthostatic hypotension. Among the patients, 71% were using at least 1 type of antihypertensive medication. The odds ratio for showing orthostatic hypotension while taking at least 1 type of antihypertensive drug versus the absence of antihypertensive medications was 1.64 (95% exact CI, 0.39-6.90) with P = .50. This finding remained consistent regardless of age, sex, inpatient or outpatient status, and the duration since transplant. CONCLUSIONS: Orthostatic blood pressure dysregulation is prevalent among lung transplant recipients, frequently without noticeable symptoms. In our cohort, the use of antihypertensive medications did not elevate the risk of orthostatic hypotension.

Risk factors influencing postoperative pleural empyema in patients with pleural mesothelioma: a retrospective single-centre analysis.

OBJECTIVES: Postoperative empyema is a severe, potentially lethal complication also present, but poorly studied in patients undergoing surgery for pleural mesothelioma. We aimed to analyse which perioperative characteristics might be associated with an increased risk for postoperative empyema. METHODS: From September 1999 to February 2023 a retrospective analysis of consecutive patients undergoing surgery for pleural mesothelioma at the University Hospital of Zurich was performed. Uni- and multivariable logistic regression was used to identify associated risk factors of postoperative empyema after surgery. RESULTS: A total of 400 PM patients were included in the analysis, of which n = 50 patients developed empyema after surgery (12.5%). Baseline demographics were comparable between patients with (Eyes) and without empyema (Eno). 39% (n = 156) patients underwent extrapleural pneumonectomy (EPP), of whom 22% (n = 35) developed postoperative pleural empyema; 6% (n = 15) of the remaining 244 patients undergoing pleurectomy and decortication (n = 46), extended pleurectomy and decortication (n = 114), partial pleurectomy (n = 54) or explorative thoracotomy (n = 30) resulted in postoperative empyema. In multivariable logistic regression analysis, EPP (odds ratio 2.8, 95% confidence interval 1.5-5.4, P = 0.002) emerged as the only risk factor associated with postoperative empyema when controlled for smoking status. Median overall survival was significantly worse for Eyes (16 months, interquartile range 5-27 months) than for Eno (18 months, interquartile range 8-35 months). CONCLUSIONS: Patients undergoing EPP had a significantly higher risk of developing postoperative pleural empyema compared to patients undergoing other surgery types. Survival of patients with empyema was significantly shorter.

Reconditioning of an injured lung graft with intrabronchial surfactant instillation in an ex vivo lung perfusion system followed by transplantation.

BACKGROUND: We tested whether an injured lung graft from category-3 donation after cardiac death donor could be reconditioned with an ex vivo lung perfusion (EVLP) system by intrabronchial diluted surfactant lavage before transplantation. METHODS: In a pig model, cardiac arrest was induced by deconnecting from the ventilator. Left lung injury was done by intrabronchial instillation of 1 mL/kg pepsin + HCl. After retrieval, the heart-lung block was stored at 4°C for 2 h. In the treated group, transplantation was performed after reconditioning with intrabronchial diluted surfactant lavage in EVLP system. RESULTS: During EVLP, surfactant group showed better oxygenation and lower pulmonary vascular resistance. After transplantation, better oxygenation, lower mean pulmonary artery pressure, and lower lung edema were observed in surfactant group. Lower blood IL-1 beta and IL-6 cytokine levels were measured in the surfactant group. In bronchoalveolar lavage, the percentage of neutrophils, IL-1 beta and IL-6 cytokine levels, amount of protein, and neutrophil infiltration in the lung tissue at the end of the experiment were significantly lower in the surfactant group. CONCLUSIONS: Our data demonstrate the feasibility of reconditioning and transplantation of an acutely damaged lung graft due to aspiration from a category-3 DCD donor. Implementation of an EVLP system is an efficacious tool to recondition and assess a questionable graft before transplantation.

Surgical management of lung cancer during the COVID-19 pandemic - a narrative review and single-centre report.

The coronavirus disease 2019 (COVID-19) pandemic has had a severe impact on oncological and thoracic surgical practice worldwide. In many hospitals, the care of COVID-19 patients required a reduction of elective surgery, to avoid viral transmission within the hospital, and to save and preserve personnel and material resources. Cancer patients are more susceptible to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and are at an increased risk of a severe course of disease. In many patients with lung cancer, this risk is further increased owing to comorbidities, older age and a pre-existing lung disease. Surgical resection is an important part of the treatment in patients with early stage or locally advanced non-small cell lung cancer, but the treatment of these patients during the COVID-19 pandemic becomes a challenging balance between the risk of patient exposure to SARS-CoV-2 and the need to provide timely and adequate cancer treatment despite limited hospital capacities. This manuscript aims to provide an overview of the surgical treatment of lung cancer patients during the COVID-19 pandemic including the triage and prioritisation as well as the surgical approach, and our own experience with cancer surgery during the first pandemic wave. We furthermore aim to highlight the risk and potential consequences of delayed lung cancer treatment due to the deferral of surgery, screening appointments and follow-up visits. With much attention being diverted to COVID-19, it is important to retain awareness of cancer patients, maintain oncological surgery and avoid treatment delay during the pandemic.

Survival outcomes in a prospective randomized multicenter Phase III trial comparing patients undergoing anatomical segmentectomy versus standard lobectomy for non-small cell lung cancer up to 2 cm.

OBJECTIVES: The oncological equivalence of anatomical segmentectomy for early stage non-small cell lung cancer (NSCLC) is still controversial. Primary aim of this study was survival outcomes in combination with improved quality of life after segmentectomy compared with lobectomy in patients with pathological stage Ia NSCLC (up to 2 cm, 7th edition) MATERIALS AND METHODS: We conducted a prospective, randomized, multicenter phase III trial to confirm the non-inferiority of segmentectomy to lobectomy in regard to prognosis (trial No. DRKS00004897). Patients were randomized to undergo either segmentectomy or lobectomy and followed up for 5-years survival and tumor recurrence. The 5-year hazard ratio comparing lobectomy with segmentectomy was required to remain above 0.5. RESULTS: Between October 2013 and June 2016, 108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled; 54 were assigned to lobectomy and 54 (1 drop-out) to segmentectomy. In-hospital and 90 days mortality was 0% in both groups. Overall survival at 5 years was 86.52% in the lobectomy compared to 78.21% in the segmentectomy group (HR = 0.61, (95% CI 0.23-1.66), p-value of non-inferiority test, p-ni = 0.687). Disease free survival was 77.29% for the lobectomy and 77.96% for the segmentectomy patients (HR = 1.50, (95% CI 0.60-3.76), p-ni = 0.019). At a median follow-up of 5 years, no differences were noted in either the locoregional or distant recurrent disease in both groups (9.4% vs 7.4%, p-ni = 0.506). CONCLUSION: Overall survival, locoregional and distant recurrences was not significantly difference for patients undergoing either segmentectomy or lobectomy for stage Ia NSCLC. The targeted non-inferiority of segmentectomy to lobectomy could not be proven for primary endpoint overall survival, but was significant for the secondary endpoint of disease free survival.

Lymphovascular invasion is an independent prognostic factor for survival in pathologically proven N2 non-small cell lung cancer.

BACKGROUND: We aimed to analyse the nodal spread of our non-small cell lung cancer pN2 cohort according to tumour location, the possible implications of an unusual spreading pattern, and other factors influencing postoperative survival after anatomical lung resection. METHODS: In this retrospective observational study, clinical data was collected for 124 consecutive non-small cell lung cancer (NSCLC) patients with a pathological N2 (stage IIIA or B) undergoing anatomical lung resection at our institution between 2001 and 2010. Cox regression was used to analyse independent predictors of 5-year overall survival and recurrence-free survival. RESULTS: A total of 105 patients were included in the final analysis. Tumour location in the right upper lobe and middle lobe  was significantly more often associated with involvement of lymph node stations 2 and 4 than NSCLC in the right lower lobe (station 2: right upper vs right lower lobe, p = 0.001 and middle vs right lower lobe, p = 0.038; station 4: right upper vs right lower lobe, p<0.001 and middle vs right lower lobe, p = 0.056), while tumours in the right upper lobe showed significantly less involvement of stations 7 and 8 compared with right lower lobe tumours (station 7 p <0.001, station 8 p = 0.004). Left sided tumours in the upper lobe had significantly more involvement of station 5 compared to lower lobe tumours (p = 0.009). However, atypical lymphatic nodal zone involvement did not emerge as a significant predictor of survival. Lymphovascular invasion was the only independent prognostic factor for 5-year overall survival (hazard ratio [HR] 2.10, p = 0.015) and recurrence-free survival (HR 1.68, p = 0.049) when controlled for adjuvant therapy. CONCLUSION: Lymphovascular invasion was identified as the only independent prognostic factor for 5-year overall survival and recurrence-free survival in our pathologically proven N2 NSCLC cohort when controlled for adjuvant therapy. This study extends the current evidence of an adverse prognostic effect of lymphovascular invasion on a stage III population, confirms the adverse prognostic effect of lymphovascular invasion detected by immunohistochemistry, and thereby reveals another subgroup within the pN2 population with worse prognosis regarding 5-year overall survival and recurrence-free survival.  .

Long-Term Outcomes of Cadaveric Lobar Lung Transplantation: An Important Surgical Option.

BACKGROUND: Cadaveric lobar lung transplantation (L-LTx) is developed to overcome donor-recipient size mismatch. Controversial short- and long-term outcomes following L-LTx have been reported compared to full-sized lung transplantation (F-LTx). This study reports long-term outcomes after L-LTx. METHODS: We reviewed patients undergoing lung transplantation (LTx) between 2000 and 2016. The decision to perform L-LTx was made based mainly on donor-recipient height discrepancy and visual assessment of donor lungs. Predicted donor-recipient total lung capacity (TLC) ratio was calculated more recently. Primary outcome was overall survival. RESULTS: In all, 370 bilateral LTx were performed during the study period, among those 250 (67%) underwent F-LTx and 120 (32%) underwent L-LTx, respectively. One- and 5-year survival rates were 85% vs. 90% and 53% vs. 63% for L-LTx and F-LTx, respectively (p = 0.16). Chronic lung allograft dysfunction (CLAD)-free survival at 5 years was 48% in L-LTx vs. 51% in F-LTx recipients (p = 0.89), respectively. Age, intraoperative extracorporeal membrane oxygenation (ECMO) use, intensive care unit (ICU) stay, and postoperative renal replacement therapy (RRT) were significant prognostic factors for survival using multivariate analysis. CONCLUSIONS: Overall survival and CLAD-free survival following L-LTx were comparable to F-LTx. Given the ongoing donor organ shortage, cadaveric L-LTx remains as an important resource in LTx.

Implementing CT tumor volume and CT pleural thickness into future staging systems for malignant pleural mesothelioma.

OBJECTIVES: Tumor thickness and tumor volume measured by computed tomography (CT) were suggested as valuable prognosticator for patients' survival diagnosed with malignant pleural mesothelioma (MPM). The purpose was to assess the accuracy of CT scan based preoperatively measured tumor volume and thickness compared to actual tumor weight of resected MPM specimen and pathologically assessed tumor thickness, as well as an analysis of their impact on overall survival (OS). METHODS: Between 09/2013-08/2018, 74 patients were treated with induction chemotherapy followed by (extended) pleurectomy/decortication ((E)PD). In 53 patients, correlations were made between CT-measured volume and -tumor thickness (cTV and cTT) and actual tumor weight (pTW) based on the available values. Further cTV and pT/IMIG stage were correlated using Pearson correlation. Overall survival (OS) was calculated with Kaplan Meier analysis and tested with log rank test. For correlation with OS Kaplan-Meier curves were made and log rank test was performed for all measurements dichotomized at the median. RESULTS: Median pathological tumor volume (pTV) and pTW were 530 ml [130 ml - 1000 ml] and 485 mg [95 g - 982 g] respectively. Median (IQR) cTV was 77.2 ml (35.0-238.0), median cTT was 9.0 mm (6.2-13.7). Significant association was found between cTV and pTV (R = 0.47, p < 0.001) and between cTT and IMIG stage (p = 0,001) at univariate analysis. Multivariate regression analysis revealed, that only cTV correlates with pTV. Median follow-up time was 36.3 months with 30 patients dead at the time of the analysis. Median OS was 23.7 months. 1-year and 3-year survival were 90 and 26% respectively and only the cTV remained statistically associated with OS. CONCLUSION: Preoperatively assessed CT tumor volume and actual tumor volume showed a significant correlation. CT tumor volume may predict pathological tumor volume as a reflection of tumor burden, which supports the integration of CT tumor volume into future staging systems.

Preselection of robust radiomic features does not improve outcome modelling in non-small cell lung cancer based on clinical routine FDG-PET imaging.

BACKGROUND: Radiomics is a promising tool for identifying imaging-based biomarkers. Radiomics-based models are often trained on single-institution datasets; however, multi-centre imaging datasets are preferred for external generalizability owing to the influence of inter-institutional scanning differences and acquisition settings. The study aim was to determine the value of preselection of robust radiomic features in routine clinical positron emission tomography (PET) images to predict clinical outcomes in locally advanced non-small cell lung cancer (NSCLC). METHODS: A total of 1404 primary tumour radiomic features were extracted from pre-treatment [18F]fluorodeoxyglucose (FDG)-PET scans of stage IIIA/N2 or IIIB NSCLC patients using a training cohort (n = 79; prospective Swiss multi-centre randomized phase III trial SAKK 16/00; 16 centres) and an internal validation cohort (n = 31; single centre). Robustness studies investigating delineation variation, attenuation correction and motion were performed (intraclass correlation coefficient threshold > 0.9). Two 12-/24-month event-free survival (EFS) and overall survival (OS) logistic regression models were trained using standardized imaging: (1) with robust features alone and (2) with all available features. Models were then validated using fivefold cross-validation, and validation on a separate single-centre dataset. Model performance was assessed using area under the receiver operating characteristic curve (AUC). RESULTS: Robustness studies identified 179 stable features (13%), with 25% stable features for 3D versus 4D acquisition, 31% for attenuation correction and 78% for delineation. Univariable analysis found no significant robust features predicting 12-/24-month EFS and 12-month OS (p value > 0.076). Prognostic models without robust preselection performed well for 12-month EFS in training (AUC = 0.73) and validation (AUC = 0.74). Patient stratification into two risk groups based on 12-month EFS was significant for training (p value = 0.02) and validation cohorts (p value = 0.03). CONCLUSIONS: A PET-based radiomics model using a standardized, multi-centre dataset to predict EFS in locally advanced NSCLC was successfully established and validated with good performance. Prediction models with robust feature preselection were unsuccessful, indicating the need for a standardized imaging protocol.

Extended surgical resection in stage III non-small cell lung cancer.

Stage III includes a large variety of clinical situations from chest wall invasion together with intralobar lymph node metastasis to any size of a lung cancer in combination with mediastinal lymph node involvement (N2/N3). Furthermore, the prognosis of patients with lymph node metastasis depends largely on the extent of the disease, which may range from micro-metastasis occasionally found during surgery to bulky and/or multilevel involvement of the mediastinum or extracapsular infiltration. Not surprising the optimal treatment including the role of surgery for stage IIIA (N2) and stage IIIB (T4/N3) non-small cell lung cancer is discussed controversially. Adequate analysis of the clinical stage is key to select the best treatment. In general, patients benefit from surgery, when a radical resection can be achieved with a low morbidity and mortality. A multidisciplinary approach is indicated in most patients, which present with stage III disease at diagnosis. Preferentially patients should be treated in study protocols whenever they are available. Radical surgery including chest wall resection may result in a 5-year survival rate of up to 50% in T3N1 disease. Adjuvant chemotherapy is recommended and radiotherapy is reserved for cases with unclear resection margins. Clinical trials of preoperatively proven N2 patients could show a better outcome when downstaging is achieved after neoadjuvant chemo- or chemoradiotherapy prior to surgery. Patients who may need a pneumonectomy should be selected with caution since some centers experience a high perioperative mortality rate. If unforeseen N2 disease is found during surgery, an adjuvant therapy is recommended. Patients with T4 tumors (infiltration of great vessels, trachea, esophagus, vertebral bodies, etc.) show an increasing 5-year survival from 15 to 35% after radical resection with acceptable perioperative mortality if treated in experienced centers. In stage III non-small cell lung cancer, surgery should be performed within a multimodality approach. Surgery should be recommended when resection is radical including systematic lymph node dissection and mortality and morbidity are low.

Complex sleeve lobectomy has the same surgical outcome when compared with conventional lobectomy in patients with lung cancer.

OBJECTIVES: No significant data are available to assess whether complex sleeve lobectomy (complex-SL) can be considered comparable to conventional lobectomy (CL) in terms of surgical outcome. The purpose of this study was to compare surgical and oncological outcomes of complex-SL with CL in patients with lung cancer. METHODS: Between 2000 and 2015, a total of 568 patients who underwent open CL (defined as resection of only 1 lobe) and 187 patients who underwent SL were analysed. The SL group was divided into 2 subgroups: standard-SL (bronchial SL, n = 106) and complex-SL (n = 81) (defined as bronchial sleeve resection together with another surgical intervention: bronchovascular SL, n = 40; vascular SL, n = 26; atypical bronchoplasty with resection of more than 1 lobe, n = 12; bronchial SL + chest wall resection, n = 3). RESULTS: The complex-SL group had more patients with chronic obstructive pulmonary disease (COPD) (25.9% vs 12.5%, P = 0.001), neoadjuvant treatment (39.5% vs 12.0%, P < 0.001), advanced-stage non-small-cell lung cancer (53.2% vs 33.1%, P = 0.001) and low preoperative forced expiratory volume in 1 s (77.2% vs 84.3%, P = 0.004) than the CL group. The overall surgical mortality (in-hospital or 30-day) was 2.6% (n = 20); it was 2.8% for CL and 2.8% for complex-SL. Postoperative complications occurred in 34.9% of the CL group and 39.5% of the complex-SL group (P = 0.413). The pulmonary complication rate was similar between the groups (24.1% for CL, 27.2% for complex-SL, P = 0.552). The 5-year survival in the CL group was 57.1%, and in the complex-SL group it was 56.2% (P = 0.888). Multivariate analysis showed that TNM stage (P < 0.001) and N status (P < 0.001) were significant and independent negative prognostic factors for survival. CONCLUSIONS: Complex-SL had a comparable outcome to CL, although the complex-SL group had more patients with advanced-stage NSCLC, low preoperative forced expiratory volume in 1 s and COPD.

Radiomics Feature Activation Maps as a New Tool for Signature Interpretability.

INTRODUCTION: In the field of personalized medicine, radiomics has shown its potential to support treatment decisions. However, the limited feature interpretability hampers its introduction into the clinics. Here, we propose a new methodology to create radiomics feature activation maps, which allows to identify the spatial-anatomical locations responsible for signature activation based on local radiomics. The feasibility of this technique will be studied for histological subtype differentiation (adenocarcinoma versus squamous cell carcinoma) in non-small cell lung cancer (NSCLC) using computed tomography (CT) radiomics. MATERIALS AND METHODS: Pre-treatment CT scans were collected from a multi-centric Swiss trial (training, n=73, IIIA/N2 NSCLC, SAKK 16/00) and an independent cohort (validation, n=32, IIIA/N2/IIIB NSCLC). Based on the gross tumor volume (GTV), four peritumoral region of interests (ROI) were defined: lung_exterior (expansion into the lung), iso_exterior (expansion into lung and soft tissue), gradient (GTV border region), GTV+Rim (GTV and iso_exterior). For each ROI, 154 radiomic features were extracted using an in-house developed software implementation (Z-Rad, Python v2.7.14). Features robust against delineation variability served as an input for a multivariate logistic regression analysis. Model performance was quantified using the area under the receiver operating characteristic curve (AUC) and verified using five-fold cross validation and internal validation. Local radiomic features were extracted from the GTV+Rim ROI using non-overlapping 3x3x3 voxel patches previously marked as GTV or rim. A binary activation map was created for each patient using the median global feature value from the training. The ratios of activated/non-activated patches of GTV and rim regions were compared between histological subtypes (Wilcoxon test). RESULTS: Iso_exterior, gradient, GTV+Rim showed good performances for histological subtype prediction (AUCtraining=0.68-0.72 and AUCvalidation=0.73-0.74) whereas GTV and lung_exterior models failed validation. GTV+Rim model feature activation maps showed that local texture feature distribution differed significantly between histological subtypes in the rim (p=0.0481) but not in the GTV (p=0.461). CONCLUSION: In this exploratory study, radiomics-based prediction of NSCLC histological subtypes was predominantly based on the peritumoral region indicating that radiomics activation maps can be useful for tracing back the spatial location of regions responsible for signature activation.

Comparison of robust to standardized CT radiomics models to predict overall survival for non-small cell lung cancer patients.

BACKGROUND: Radiomics is a promising tool for the identification of new prognostic biomarkers. Radiomic features can be affected by different scanning protocols, often present in retrospective and prospective clinical data. We compared a computed tomography (CT) radiomics model based on a large but highly heterogeneous multicentric image dataset with robust feature pre-selection to a model based on a smaller but standardized image dataset without pre-selection. MATERIALS AND METHODS: Primary tumor radiomics was extracted from pre-treatment CTs of IIIA/N2/IIIB NSCLC patients from a prospective Swiss multicentric randomized trial (npatient  = 124, ninstitution  = 14, SAKK 16/00) and a validation dataset (npatient  = 31, ninstitution  = 1). Four robustness studies investigating inter-observer delineation variation, motion, convolution kernel, and contrast were conducted to identify robust features using an intraclass correlation coefficient threshold >0.9. Two 12-months overall survival (OS) logistic regression models were trained: (a) on the entire multicentric heterogeneous dataset but with robust feature pre-selection (MCR) and (b) on a smaller standardized subset using all features (STD). Both models were validated on the validation dataset acquired with similar reconstruction parameters as the STD dataset. The model performances were compared using the DeLong test. RESULTS: In total, 113 stable features were identified (nshape  = 8, nintensity  = 0, ntexture  = 7, nwavelet  = 98). The convolution kernel had the strongest influence on the feature robustness (<20% stable features). The final models of MCR and STD consisted of one and two features respectively. Both features of the STD model were identified as non-robust. MCR did not show performance significantly different from STD on the validation cohort (AUC [95%CI] = 0.72 [0.48-0.95] and 0.79 [0.63-0.95], p = 0.59). CONCLUSION: Prognostic OS CT radiomics model for NSCLC based on a heterogeneous multicentric imaging dataset with robust feature pre-selection performed equally well as a model on a standardized dataset.

Comparative immunohistochemistry of L19 and F16 in non-small cell lung cancer and mesothelioma: two human antibodies investigated in clinical trials in patients with cancer.

The antibody-mediated targeted delivery of therapeutics to tumor sites is an attractive avenue for combating cancer while sparing normal tissues. Indeed, five derivatives of the human monoclonal antibodies L19 and F16, specific to splice isoforms of fibronectin and tenascin-C, are currently being investigated in clinical trials in patients with malignancies. Until now, a comparative immunohistochemical analysis of these antibodies, which recognize components of the modified extracellular matrix, was missing. Here, we report that the majority of NSCLC and mesothelioma specimens are stained with both antibodies in the stroma, while non-tumoral lung and mesothelium samples rarely exhibit reactivity with either L19 or F16. In our analysis, the anti-tenascin F16 antibody was found to generally exhibit a stronger staining of desmoplastic stroma surrounding tumor. This superior performance was found to be particularly striking in the case of low-grade non-small cell lung cancer.

Establishing a non-intubated thoracoscopic surgery programme for bilateral uniportal sympathectomy.

AIM OF THE STUDY: Non-intubated, video-assisted thoracoscopic surgery (NiVATS) has been successfully developed in several centres worldwide. Local anaesthesia techniques and techniques to perform thoracoscopic surgery on a spontaneously breathing lung are the two key elements which must be adopted to establish a NiVATS programme. We established NiVATS by performing bilateral, uniportal sympathectomies, and compared it to classical video-assisted thoracoscopic surgery (VATS) under general anaesthesia with double-lumen intubation. METHODS: Ten consecutive bilateral VATS sympathectomies were compared with ten consecutive NiVATS procedures. Nineteen of the procedures were for palmar hyperhidrosis and one was for facial blushing. Duration of anaesthesia, surgery and hospitalisation, perioperative complications, side effects and quality of life before and after sympathectomy were analysed. RESULTS: Median age was 26.5 years (range 17–55) and mean BMI in the NiVATS group was 21.8 (range 19.1–26.3). NiVATS sympathectomies were performed as outpatient procedures significantly more often (9/10 vs 3/10, p = 0.008). Quality of life was significantly increased after sympathectomy in all patients, with no significant differences between the NiVATS and the VATS groups. There were no differences between the two groups regarding compensatory sweating (40 vs 50%, p = 0.66). The duration of anaesthesia, not including the time required for the surgery, was significantly shorter in the NiVATS group (p <0.001). The duration of surgery, from the first local anaesthesia until the last skin suture, was significantly longer in the NiVATS group (p = 0.04), but showed a constant decline during the learning curve, from 95 minutes initially to 48 minutes for the last procedure. Costs were significantly lower in the NiVATS group (p = 0.04). CONCLUSION: Thoracoscopic sympathectomy is a suitable procedure with which to establish a NiVATS programme. Patients are usually young and of healthy weight, facilitating the learning curve for the local anaesthesia techniques and the surgery. Compared to VATS, sympathectomy is more likely to be performed as an outpatient procedure and has a lower cost, while safety and efficacy are maintained.

High Levels of IL-18 and IFN-γ in Chronically Inflamed Tissue in Chronic Granulomatous Disease.

Background: Chronic granulomatous disease (CGD) is caused by a malfunctioning nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, leading to impaired bacterial and fungal killing and hyperinflammation. Objective: To characterize macrophage subsets and cytokine/chemokine signaling loops involved in CGD tissue hyperinflammation. Methods: Cytokine/chemokine production and surface marker expression were analyzed in inflamed tissue of four CGD patients and compared to cytokine/chemokine released by CGD macrophages upon priming to different macrophage subpopulations. Furthermore, the re-priming capacity of CGD pro-inflammatory M1 to M2a anti-inflammatory macrophages was evaluated. Results: In human CGD inflammatory tissue, IL-18 and IFN-γ were detected in significant quantity. Immunofluorescence analysis identified macrophages as one source of IL-18 in inflamed tissue. In vitro, CGD macrophages could be primed and re-primed into all inflammatory/anti-inflammatory macrophage subpopulations. IL-18 was also released by M1 CGD and control macrophages. Conclusion: CGD pro-inflammatory M1 macrophages remain M1 primed in vivo. As CGD M1 macrophages can be re-primed to anti-inflammatory M2a phenotype in vitro, macrophages are kept in M1 state in vivo by a persistent pro-inflammatory environment. Our results suggest a paracrine signaling loop between M1 macrophage derived IL-18 and non-macrophage derived IFN-γ maintaining macrophage pro-inflammatory activity in CGD tissue.

Acute allograft rejection and immunosuppression: influence on endogenous melatonin secretion.

Melatonin displays a dose-dependent immunoregulatory effect in vitro and in vivo. Exogenous high-dose melatonin therapy exerted an immunosuppressive effect, abrogating acute rejection (AR), significantly prolonging transplant survival. Endogenous melatonin secretion, in response to heterotopic rat cardiac allograft transplantation (Tx), was investigated during the AR response and under standardized immunosuppressive maintenance therapy with cyclosporin A (CsA) and rapamycin (RPM). Recipients of syngeneic transplants, and recipients of allogeneic grafts, either untreated or receiving immunosuppressive therapy constituted the experimental groups. Endogenous circadian melatonin levels were measured at 07:00, 19:00, and 24:00 hr, using a novel radioimmunoassay (RIA) procedure, under standardized 12-hr-light/dark-conditions (light off: 19:00 hr; light on: 07:00 hr), before and after Tx. Neither the operative trauma, nor the challenge with a perfused allograft or the AR response influenced endogenous melatonin peak secretion. Immunosuppressive therapy with CsA led to a significant increase in peak secretion, measured for days 7 (212 +/- 40.7 pg/mL; P < 0.05), 14 (255 +/- 13.9 pg/mL; P < 0.001), and 21 (219 +/- 34 pg/mL; P < 0.01) after Tx, as compared with naïve animals (155 +/- 25.8 pg/mL). In contrast, treatment with RPM significantly decreased the melatonin peak post-Tx up to day 7 (87 +/- 25.2 pg/mL; P < 0.001), compared with naïve animals (155 +/- 25.8 pg/mL). These findings imply a robust nature of the endogenous circadian melatonin secretion kinetics, even against the background of profound allogeneic stimuli. Immunosuppressive maintenance therapy with CsA and RPM modulated early melatonin secretion, indicating a specific secondary action of these drugs. Further studies are necessary to disclose the long-term effect of immunosuppressive therapy on circadian melatonin secretion in transplant recipients.