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Significant differentially expressed Hallmarks upregulated in control versus Glut1KO TANs.

Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils.Significance:Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells.

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The success of tumor oncolytic virotherapy is limited by the poor penetration of virus in tumors. Interstitial collagen fibers and the narrow spacing between cancer cells are major barriers hindering the movement of large viral particles. To bypass the cellular barrier, we tested the hypothesis that the void space produced by cancer cell apoptosis enhances the initial spread and efficacy of oncolytic herpes simplex virus (HSV). In mice with mammary tumors, apoptosis was induced by doxycycline-regulated expression/activation of CD8/caspase-8, paclitaxel, or paclitaxel plus tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). In both collagen-poor and collagen-rich tumors, apoptosis or necrosis increased the initial intratumoral spread of HSV. Compared with the isolated pattern of HSV infection generally located in the center of control tumors, apoptosis induction and a single i.t. injection of virus produced an interconnected and diffuse pattern of infection, which extended from the tumor center to the periphery. This interconnected pattern of viral infection correlated with the formation of void spaces and channel-like structures in apoptosis-rich tumor areas. We also show that the i.t. injection of HSV after caspase-8 activation or paclitaxel-TRAIL pretreatment retards tumor growth, whereas HSV administration before tumor cell death induction did not improve therapeutic efficacy. Hence, our findings show that the induction of cancer cell death before the injection of oncolytic HSV enhances intratumoral virus delivery/penetration and antitumor efficacy. [Cancer Res 2008;68(10):3795–802]

Supplementary Figure 6 from Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors

Supplementary Figure 5 from Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors

Supplementary Figure 3 from Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors

Supplementary Figure from Lack of Telopeptides in Fibrillar Collagen I Promotes the Invasion of a Metastatic Breast Tumor Cell Line

Supplementary Movie 2 from Lack of Telopeptides in Fibrillar Collagen I Promotes the Invasion of a Metastatic Breast Tumor Cell Line

Supplementary Figure 2 from Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors

Supplementary Figure 1 from Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors

Supplementary Movie 1 from Lack of Telopeptides in Fibrillar Collagen I Promotes the Invasion of a Metastatic Breast Tumor Cell Line

Supplementary Figure Legends 1-6 from Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors

Defective fibrillar collagen polymerization in primary tumors has been correlated with increased metastasis. However, it is unclear how collagen organization influences tumor invasion. In this study, we show that collagen I polymerized without telopeptides (the flanking regions of collagen molecules) can differentially affect the three-dimensional migration of mammary carcinoma cells. MDA-MB-231 cells capable of proteolytic degradation and mesenchymal motion, invaded telopeptide-intact and telopeptide-free collagen gels to the same extent. In contrast, MDA-MB-435S cells, with typical features of amoeboid cells (poor collagenolytic activity, rounded cell morphology), were 5-fold more invasive in telopeptide-free than telopeptide-intact collagen. A fraction of the MDA-MB-435S cells that invaded telopeptide-intact or telopeptide-free collagen had a rounded morphology; however, in telopeptide-free collagen, a significant fraction of the cells switched from a rounded to elongated morphology (protrusion formation). The dynamic changes in cellular shape facilitated MDA-MB-435S locomotion through the narrow interfiber gaps, which were smaller than cell diameters. Based on the spherical morphology of MDA-MB-435S cells, we tested if the changes in cell shape and invasion were related to RhoA-ROCK activity; GTP-bound RhoA was measured in pull-down assays. RhoA activity was 1.8-fold higher for MDA-MB-435S cells seeded on telopeptide-free than telopeptide-intact collagen. Y27632 inhibition of ROCK, a Rho effector, significantly reduced the changes in cellular morphodynamics and the invasion of MDA-MB-435S cells but did not alter the invasion of MDA-MB-231 cells. Thus, the higher RhoA activity of MDA-MB-435S cells in telopeptide-free collagen enhances the changes in cellular morphodynamics associated with motility and invasion.

OBJECTIVESThe 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.METHODSMulticentre 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.RESULTSIn 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 CONCLUSIONSDespite a short follow-up, our preliminary data shows that local control is comparable for VL and VS.

OBJECTIVE Surgical treatment of locally advanced non-small cell lung cancer including single or multilevel N2 remains a matter of debate. Several trials demonstrate that selected patients benefit from surgery if R0 resection is achieved. We aimed to assess resectability and outcome of patients with locally advanced clinical T3/T4 (American Joint Committee on Cancer 8th edition) tumors after induction treatment followed by surgery in a pooled analysis of 3 prospective multicenter trials. METHODS A total of 197 patients with T3/T4 non-small cell lung cancer of 368 patients with stage III non-small cell lung cancer enrolled in the Swiss Group for Clinical Cancer Research 16/96, 16/00, 16/01 trials were treated with induction chemotherapy or chemoradiation therapy followed by surgery, including extended resections. Univariable and multivariable analyses were applied for analysis of outcome parameters. RESULTS Patients' median age was 60 years, and 67% were male. A total of 38 of 197 patients were not resected for technical (81%) or medical (19%) reasons. A total of 159 resections including 36 extended resections were performed with an 80% R0 and 13.2% pathological complete response rate. The 30- and 90-day mortality were 3% and 7%, respectively, without a difference for extended resections. Morbidity was 32% with the majority (70%) of minor grading complications. The 3-, 5-, and 10-year overall survivals for extended resections were 61% (95% confidence interval, 43-75), 44% (95% confidence interval, 27-59), and 29.5% (95% confidence interval, 13-48), respectively. R0 resection was associated with improved overall survival (hazard ratio, 0.41; P

OBJECTIVES Although video-assisted thoracic surgery (VATS) has shortened hospitalization duration for non-small-cell lung cancer (NSCLC) patients, the factors associated with early discharge remain unclear. This study aimed to identify patients eligible for a 72-h stay after VATS anatomical resection. METHODS Monocentric retrospective study including all consecutive patients undergoing VATS anatomical resection for NSCLC between February 2010 and December 2019. Two groups were defined according to the discharge: ‘early discharge’ (within 72 postoperative hours) and ‘routine discharge’ (at >72 postoperative hours). RESULTS A total of 660 patients with a median age of 66.5 years (interquartile range 60–73 years) (female/male: 321/339) underwent VATS anatomical pulmonary resection for NSCLC [segmentectomy in 169 (25.6%), lobectomy in 481 (72.9%), bilobectomy in 8 (1.2%) and pneumonectomy in 2 (0.3%) patients]. The cardiopulmonary and Clavien–Dindo III–IV postoperative complication rates were 32.6% and 7.7%, respectively. The median postoperative length of stay was 6 days (interquartile range 4–10 days). In total, 119 patients (18%) could be discharged within 72 h of surgery. On multivariable analysis, the factors significantly associated with an increased likelihood of early discharge were: body mass index >20 kg/m2 [odds ratio (OR) 2.37], absence of prior cardiopathy (OR 2), diffusing capacity of the lung for carbon monoxide >60% (OR 1.82), inclusion in an enhanced recovery after surgery protocol (OR 2.23), use of a single chest tube (OR 5.73) and postoperative transfer to the ward (OR 4.84). Factors significantly associated with a decreased likelihood of early discharge were: age >60 years (OR 0.53), American Society of Anaesthesiologists score >2 (OR 0.46) and use of an epidural catheter (OR 0.41). Readmission rates were not statistically different between both groups (5.9% vs 3.1%; P = 0.17). CONCLUSIONS Age, pulmonary functions and comorbidities may influence discharge after VATS anatomical resection. The early discharge does not increase readmission rates.

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options. The application of photodynamic therapy (PDT) was shown to significantly improve patient survival. Previously, we found that low dose PDT (L-PDT) enhanced the immune infiltration of MPM and increased the impact of immune checkpoint inhibitors on tumor control. However, the mechanisms behind these observations are unknown. Here, in an orthotopic murine model of MPM, we show that L-PDT upregulates tumor vascular E-Selectin expression via NF-kB. This upregulation favors enhanced leukocyte trafficking and immune mediated MPM regression. Methods: We analyzed adhesion molecules (E-Selectin, ICAM-1, VCAM-1) and canonical NF-kB activation (phosphorylated IκBα) protein levels in endothelial (ECRF-24) cells treated by L-PDT in the presence or absence of a NEMO/IKKγ siRNA in vitro. For in vivo validation, AB12-Luc MPM cells were grown in the pleural cavity of syngeneic BALB/c mice and treated with L-PDT (verteporfin 400 µg/kg, fluence 10 J/cm2, fluence rate 50 mW/cm2) alone or in presence of NF-kB or E-Selectin inhibitors (NEMO Binding Domain (NBD) peptide and E-Selectin blocking antibody respectively). For each treatment group, we determined the expression of endothelial adhesion molecules (E-Selectin, ICAM-1, VCAM-1) and the tumor immune infiltrate by immunohistochemistry and flow cytometry. In parallel, the impact of L-PDT on MPM growth and mouse survival were assessed in the presence of E-Selectin inhibition. Results: L-PDT increased the levels of endothelial adhesion molecules E-Selectin, ICAM-1 and VCAM-1 9 to 24 hours after L-PDT treatment in vitro. This was preceded by an increase of IκBα phosphorylation. In the presence of NEMO siRNAs, the expression of NEMO/IKKγ was reduced and led to E-Selectin repression. In orthotopic MPM bearing mice, the treatment of MPM by L-PDT enhanced adhesion molecules expression in tumor vasculature at 24 hours. This correlated with increased infiltration of CD4+ and CD8+ granzyme B+ T-cells and improved tumor control and mouse survival. NF-kB inhibition impaired tumor vascular adhesion molecules upregulation and the recruitment of tumor infiltrating lymphocytes in MPM. The targeted inhibition of E-Selectin abrogated the immune infiltration and tumor regression of MPM following L-PDT, which ultimately decreased animal survival in our MPM model. Conclusion: Low dose PDT relieves MPM tumor vascular anergy via NF-kB mediated adhesion molecules expression. Endothelial E-Selectin has been identified, in our MPM model, as a major determinant for L-PDT enhanced lymphocyte trafficking, tumor control and animal survival. Citation Format: Louis-Emmanuel Chriqui, Yameng Hao, Damien Marie, Michel Gonzalez, Thorsten Krueger, Etienne Meylan, Johanna Joyce, Sabrina Cavin, Jean-Yannis Perentes. Photodynamic therapy promotes immune infiltration and control of malignant pleural mesothelioma through NF-kB mediated upregulation of E-Selectin in the tumor vasculature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5152.

Introduction VATS pulmonary segmentectomy is increasingly proposed as a parenchyma‐sparing resection for tumors smaller than 2 cm in diameter. The aim of this study was to compare short‐term oncological results and local control in solid non‐small cell lung cancers (NSCLCs), This study analyzes the short‐term oncological results and local control of solid NSCLC smaller than 2 cm, surgically treated by intentional VATS segmentectomy or lobectomy. Despite the short follow‐up, our preliminary data shows that local control is comparable for VATS lobectomy and VATS segmentectomy for patients with NSCLC

Background This study evaluates the effect of enhanced recovery after surgery (ERAS) pathways on postoperative outcomes of non-small cell lung cancer (NSCLC) patients undergoing video-assisted thoracic surgery (VATS) lobectomy. Methods We retrospectively reviewed all consecutive patients undergoing VATS lobectomy for NSCLC between January 2014 and October 2019 and assigned them to the relevant group ("pre-ERAS" or "ERAS"). Length of stay, readmissions and complications within 30 days were compared between both groups. A propensity score-matched analysis was performed based on sex, age, type of operation, comorbidities, American Society of Anesthesiologists (ASA) score and preoperative pulmonary functions. Results A total of 307 records (164 male/143 female; 140 ERAS/167 pre-ERAS; median age: 67) were reviewed. There was no statistical difference in patient's characteristics. Overall ERAS compliance was 81%. The ERAS group presented significantly shorter length of stay (median 5 vs. 7 days; P=0.004) without significant difference in cardiopulmonary complication rate (27.1% vs. 35.9%; P=0.1). Readmission (3.6% vs. 5.4%; P=0.75) and duration of drainage (median 2 vs. 3 days; P=0.14) were similar between groups. The propensity score-matched analysis showed that the length of hospital stay was reduced by 1.4 days (P=0.034) and the postoperative cardiopulmonary complication rate by 13% (P=0.044) in the ERAS group. Conclusions Adoption of an ERAS pathway for VATS lobectomies in NSCLC patients has decreased the length of hospital stay and the cardiopulmonary complication rate without affecting the readmission rate.

Recurrence after pulmonary metastasectomy (PM) is frequent, but it is unclear to whom repeated pulmonary metastasectomy (RPM) offers highest benefits. Retrospective analysis of oncological and post-operative outcomes of consecutive patients who underwent PM from 2003 to 2018. Overall survival (OS) and disease-free interval (DFI) were calculated. Cox regression was used to identify variables influencing OS and DFI. In total, 264 patients (female/male: 114/150; median age: 62 years) underwent PM for colorectal cancer (32%), sarcoma (19%), melanoma (16%) and other primary tumors (33%). Pulmonary metastasectomy was approached by video-assisted thoracic surgery (VATS) in 73% and pulmonary resection was realized by non-anatomical resection in 76% of cases. The overall median follow-up time was 33 months (IQR 16–56 months) and overall 5-year survival rate was 62%. Local or distant recurrences were observed in 172 patients (65%) and RPM could be performed in 66 patients (25%) for a total of 116 procedures. RPM was realized by VATS in 49% and pulmonary resection by wedge in 77% of cases. In RPM patients, the 5-year survival rate after first PM was 79%. Post-operative cardio-pulmonary complication rate (13% vs. 12%; p = 0.8) and median length of stay (4 vs. 5 days; p = 0.2) were not statistically different between first PM and RPM. Colorectal cancer (HR 0.56), metachronous metastasis (HR 0.48) and RPM (HR 0.5) were associated with better survival. In conclusion, our results suggest that RPM offers favorable survival rates without increasing post-operative morbidity.

OBJECTIVES Patients with oligometastatic non-small-cell lung cancer (NSCLC) may benefit from therapy with curative intent. Our goal was to identify prognostic factors related to better prognosis in a multicentre analysis of patients who underwent surgery of primary tumours in combination with radical treatment of all metastatic sites. METHODS We retrospectively reviewed the records of oligometastatic patients who underwent resection of primary tumours at 4 centres (August 2001–February 2018). Oligometastasis was defined as ≤5 synchronous metastases in ≤2 organs. Radical metastatic treatment was surgery, radiotherapy or a combination. The Cox proportional hazards model was used for identification of prognostic factors on overall survival. RESULTS We treated 124 patients; 72 (58%) were men, mean age 60 ± 9.8 years, with 87 (70%) adenocarcinoma. Sixty-seven (54%) patients had positive pathologic-N stage (pN). Brain metastases were most common (n = 76; 61%) followed by adrenal (n = 13; 10%) and bone (n = 12; 10%). Systemic therapy was administered in 101 (82%) patients. Median follow-up was 60 months [95% confidence interval (CI) 41–86]. Thirty- and 90-day mortality rates were 0 and 2.4%, respectively. One-, 2-, and 5-year overall survival were 80%, 58% and 36%, respectively. Cox regression analysis showed that patients ≤60 years [hazard ratio (HR) 0.41, 95% CI 0.24, 0.69; P = 0.001] and patients with pN0 (HR 0.38, 95% CI 0.21–0.69; P = 0.002) had a significant survival benefit. The presence of bone metastases negatively affected survival (HR 2.53, 95% CI 1.05–6.09; P = 0.04). CONCLUSIONS Treatment with curative intent of selected oligometastatic NSCLC, including resection of the primary tumour, can be performed safely and with excellent 5-year survival rates, especially in younger patients with pN0 disease.

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.

We aimed to evaluate whether computed tomography (CT)-derived preoperative sarcopenia measures were associated with postoperative outcomes and survival after video-assisted thoracoscopic (VATS) anatomical pulmonary resection in patients with early-stage non-small cell lung cancer (NSCLC). We retrospectively reviewed all consecutive patients that underwent VATS anatomical pulmonary resection for NSCLC between 2012 and 2019. Skeletal muscle mass was measured at L3 vertebral level on preoperative CT or PET/CT scans to identify sarcopenic patients according to established threshold values. We compared postoperative outcomes and survival of sarcopenic vs. non-sarcopenic patients. A total of 401 patients underwent VATS anatomical pulmonary resection for NSCLC. Sarcopenia was identified in 92 patients (23%). Sarcopenic patients were predominantly males (75% vs. 25%; p < 0.001) and had a lower BMI (21.4 vs. 26.5 kg/m2; p < 0.001). The overall postoperative complication rate was significantly higher (53.2% vs. 39.2%; p = 0.017) in sarcopenic patients and the length of hospital stay was prolonged (8 vs. 6 days; p = 0.032). Two factors were associated with postoperative morbidity in multivariate analysis: BMI and American Society of Anesthesiologists score >2. Median overall survival was comparable between groups (41 vs. 46 months; p = 0.240). CT-derived sarcopenia appeared to have a small impact on early postoperative clinical outcomes, but no effect on overall survival after VATS anatomical lung resection for NSCLC.

Isolated resection of the lateral-basal segment (S9) is uncommon, and it is considered one of the most complex anatomic segmentectomies. First, the segmental arterial and venous supply is located deeply in the lung parenchyma, making the dissection difficult. Second, the cuboidal shape of the lateral basilar segment hampers the identification of the intersegmental plane. Although identifying the segmental arterial branches is easier from a fissure-based technique, the ligamentum-based approach emerges as a valid and safe alternative in cases of a fused fissure.

BACKGROUND: Video-assisted thoracic surgery (VATS) is now the preferred approach for standard anatomical pulmonary resections. This study evaluates the impact of operative time (OT) on post-operative outcomes after VATS anatomical pulmonary resection for non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed all consecutive patients undergoing VATS lobectomy or segmentectomy for NSCLC between November 2010 and December 2019. Postoperative outcomes were compared between short (2 (OR 1.87, P=0.001), FEV(1)

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.

OBJECTIVES A lung retransplant has been shown to be a valid option in selected patients with chronic lung allograft dysfunction (CLAD). However, a subgroup of patients may require, in addition to invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) as a bridge to a retransplant. Overall and CLAD-free survival after ECMO-bridged retransplants are compared to first transplants with and without bridging ECMO and to retransplants without bridging ECMO. METHODS We reported a retrospective, single-institution experience based on a prospective data set of all patients undergoing lung transplants between January 2004 and December 2016 with a mean follow-up of 51 ± 41 months. RESULTS A total of 230 patients (96 men, 134 women, mean age 47.3 years) had lung transplants: 200 had first transplants without bridging ECMO; 13 had first transplants with bridging ECMO; 11 had retransplants without bridging ECMO; and 6 had retransplants with bridging ECMO. The 3- and 5-year survival rates were 81%/76%, 68%/68%, 69%/46% and 50%/25%, respectively. There was no significant difference in overall survival between those who had first transplants with and without bridging ECMO or retransplants without bridging ECMO. In contrast, patients undergoing ECMO-bridged retransplants had a significantly lower overall survival rate than those with a first transplant without bridging ECMO (P = 0.007). In addition, the post-transplant CLAD-free survival curves varied significantly among the 4 treatment groups (P = 0.041), paralleling overall survival. CONCLUSIONS Patients requiring ECMO as a bridge to a retransplant had lower overall and CLAD-free survival rates compared to those who had a first transplant with and without bridging ECMO and a retransplant without bridging ECMO.

Background Sleeve lobectomy (SL) is a lung-sparing procedure, which is accepted as a valid operation for centrally-located advanced tumors. These tumors often require induction treatment by chemotherapy and/or radiotherapy to downstage the disease and thus facilitate subsequent surgery. However, induction therapy may potentially increase the risk of bronchial anastomotic complications and related morbidity. This meta-analysis aims to determine the impact of induction therapy on the outcomes of pulmonary SL. Methods We compared studies of patients undergoing SL or bilobectomy for non-small cell lung cancer (NSCLC) with and without induction therapy. Outcomes of interest were in-hospital mortality, morbidity, anastomosis complication and 5-year survival. Odds ratio (OR) were computed following the Mantel-Haenszel method. Results Ten studies were included for a total of 1,204 patients. There was no statistical difference for between patients who underwent induction therapy followed by surgery and patients who underwent surgery alone in term of post-operative mortality (OR: 1.80, 95% confidence interval (CI): 0.76-4.25, P value =0.19) and morbidity (OR: 1.17, 95% CI: 0.90-1.52, P value =0.237). Anastomosis related complications rate were 5.2% and appears increased after induction therapy with a statistical difference close to the significance (OR: 1.65, 95% CI: 0.97-2.83, P value =0.06). Patients undergoing surgery alone showed better survival at 5 years (OR: 1.52, 95% CI: 1.15-2.00, P value =0.003). Conclusions SL following induction therapy can be safely performed with no increase of mortality and morbidity. However, the need for induction therapy before surgery is associated with increased anastomotic complications and poorer survival prognosis at 5 years.

Objective A prospective single center study to assess the objective impact on motion performance of a VATS simulation program on thoracic surgery trainees. Methods We developed a 6-month VATS simulation training program including exercises of progressive complexity on 3 different black box simulators: a 2D and 3D lobectomy model (Stupnik®) and a 3D perfused lobectomy model (Crabtree®). Between November 2019 and 2020, all consecutive thoracic surgery residents (study group) were prospectively enrolled in this weekly training program that was supervised by a board certified thoracic surgeon. We compared an objective performance evaluation of the study group before and after the training program by assessing movement parameters (distance in cm, time in sec) and absence of shock/extreme motion (%) on 3 simple standardized thoracoscopic exercises (peg placement on a board, rope insertion in loops and precision circle cutting) using the Simball®. Also, we determined the objective performance 6 months apart of 5 final year medical students (unexperienced controls) that were not trained. Results There were 7 residents (2 female and 5 male, median age: 29 [range: 26-34] years) who completed the 6-month VATS simulation training program. Five residents were in their first year while two had >3 year experience. The study group's objective performance improved significantly for all three movement parameters in all standardized exercises (Figure 1) after the training program. The objective performance of the unexperienced control group was comparable to the study group before training, but it remained unchanged at 6 months (p > 0.05). When comparing unexperienced and advanced residents, we observed that the training program had more impact on improving the performance for unexperienced residents (p Conclusion This study suggests that the implementation of a VATS simulation training program improves the objective performance of trainees compared to controls. Such programs could be interesting adjuncts for residents.

Objective The ventilation-to-carbon dioxide output (VE/VCO2) slope could predict morbidity and mortality after lung resection. The aim of the study was to identify whether VE/VCO2 slope obtained from cardiopulmonary exercise test (CPET) was an independent predictor of cardiopulmonary complications after anatomical pulmonary resection by video-assisted thoracic surgery (VATS). Methods We reviewed the files of all consecutive patients that underwent pulmonary anatomical resections by VATS between January 2010 and October 2020. The data were extracted from the registry of the Centre for Thoracic Surgery of Western Switzerland. Pneumonectomies were excluded from the study. We used a multivariable Cox regression to investigate the risk of cardiopulmonary complications associated with the VE/VCO2 slope and other possible confounders, including the Charlson Comorbidity Index (CCI), the CPET data and pulmonary functions. Results In total, 1392 patients (mean age: 66±11 years; ratio female: 47%) underwent anatomical resection by VATS. CPET was performed in 204 patients (15%). However, the VE/VCO2 slope data were available in 145 patients, which were included for the analysis. Patients underwent segmentectomies (N = 42) and lobectomies (N = 101) mainly for lung cancer (96%). The average percentage of the predicted VO2max was of 70±17%. Maximal effort during the CPET (respiratory coefficient ratio >1.1) was not reached in 30% of patients, without impact on the VE/VCO2 slope (39±6 vs 37±7, P = 0.21). Cardiopulmonary complications appeared in 32% of patients with no mortality at 90 days. In the multivariate analysis, VE/VCO2 slope >35 was correlated with cardiopulmonary complications (OR 3.5, 95% CI [1.3-9.3], P = 0.012). CCI, pulmonary functions, peak VO2 and the extension of the anatomical resection was not associated with cardiopulmonary complications. Conclusion VE/VCO2 slope above 35 predicts postoperative cardiopulmonary complications in anatomical resections by VATS. The VE/VCO2 slope is independent of the intensity of effort during the CPET. The impact of prehabilitation on the slope should be determined.

Objective Video-Assisted Thoracic Surgery (VATS) is now the preferred approach for standard anatomical pulmonary resections. However, operative time (OT) for this technique is correlated to many aspects, such as the surgical complexity or the surgeon’s experience and skills. The aim of this study was to identify the factors associated with prolonged OTs and to assess the impact of OT on the development of post-operative complications after VATS anatomical pulmonary resections. Methods Retrospective monocentric study including all consecutive patients undergoing a VATS anatomical pulmonary resection for benign or malignant lesions between January 2010 and December 2019. Postoperative outcomes were compared between short ( Results A total of 836 patients underwent a VATS anatomical pulmonary resection for malignant (n = 767, 91.7%) or benign (n = 69, 8.3%) lesions. Lobectomies were performed in 555 (66.4%), segmentectomies in 250 (29.9%), sleeve lobectomies in 16 (1.9%), bilobectomies in 11 (1.3%) and pneumonectomy in 4 (0.5%) patients. The conversion rate to thoracotomy was 7.7%. Of those 836 patients, 495 (59.2%) were operated within 150 minutes. During the 30-postoperative day period, the overall morbidity was significantly lower in the short OT group (29.1% vs. 40.5%; p = 0.001). Both the duration of drainage (3 vs. 4 days; p Conclusion A prolonged OT is an individual risk factor for postoperative complications in patients undergoing VATS anatomical pulmonary resection.

Invasive mold infections (IMIs) are difficult to diagnose. This analysis of histopathologically proven IMIs at our institution (2010–2019) showed that 11/41 (27%) of them were not suspected at the time of biopsy/autopsy (9/17, 53% among autopsies). The rate of missed diagnosis was particularly high (8/16, 50%) among nonhematologic cancer patients.

Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils., Significance: Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells.

Background Lung transplantation (LTx) is associated with sterile inflammation, possibly related to the release of damage associated molecular patterns (DAMPs) by injured allograft cells. We have measured cellular damage and the release of DAMPs and cytokines in an experimental model of LTx after cold or warm ischemia and examined the effect of pretreatment with ex-vivo lung perfusion (EVLP). Methods Rat lungs were exposed to cold ischemia alone (CI group) or with 3h EVLP (CI-E group), warm ischemia alone (WI group) or with 3 hour EVLP (WI-E group), followed by LTx (2 hour). Bronchoalveolar lavage (BAL) was performed before (right lung) or after (left lung) LTx to measure LDH (marker of cellular injury), the DAMPs HMGB1, IL-33, HSP-70 and S100A8, and the cytokines IL-1β, IL-6, TNFα, and CXCL-1. Graft oxygenation capacity and static compliance after LTx were also determined. Results Compared to CI, WI displayed cellular damage and inflammation without any increase of DAMPs after ischemia alone, but with a significant increase of HMGB1 and functional impairment after LTx. EVLP promoted significant inflammation in both cold (CI-E) and warm (WI-E) groups, which was not associated with cell death or DAMP release at the end of EVLP, but with the release of S100A8 after LTx. EVLP reduced graft damage and dysfunction in warm ischemic, but not cold ischemic, lungs. Conclusions The pathomechanisms of sterile lung inflammation during LTx are significantly dependent on the conditions. The release of HMGB1 (in the absence of EVLP) and S100A8 (following EVLP) may be important factors in the pathogenesis of LTx.

Pulmonary infection by Mycoplasma hominis (M hominis) in lung transplant (LTx) recipients is an uncommon yet potentially severe complication. Bronchial dehiscence in the context of M hominis infection has not been previously reported. In this report, we discuss a case of donor-derived M hominis infection in a LTx recipient with bilateral bronchial anastomoses dehiscence and stenosis. The infection was managed using a multidisciplinary approach: repeat surgical revision of the necrotic anastomosis; targeted antibiotic therapy with the combination of oral and inhaled fluoroquinolones, and oral doxycycline and continuous ventilatory support. Response to therapy was monitored through repeat bronchoscopy and serial quantitative PCR assays for M hominis in bronchoalveolar lavage and aspiration. The rare nature of M hominis infection after LTx, its difficult detection in conventional cultures and innate resistance to beta-lactams make diagnosis and timely treatment of this organism challenging. We recommend that transplant centers have a low threshold for screening for Mycoplasma infection, particularly in patients with unsatisfactory postoperative course and little response to broad-spectrum antimicrobial and antifungal coverage. Monitoring with PCR may help to adapt the duration of antibiotic therapy.

Mediastinal infections are divided into four categories according to their etiology: post-sternotomy mediastinitis, descending necrotizing mediastinitis, post esophageal perforation mediastinitis and chronic mediastinitis. Acute mediastinal infections are life-threatening conditions that should be promptly recognized and managed. A delay in the establishment of the diagnosis of mediastinitis will impact morbidity and mortality of patients. Adequate antibiotic treatment, resuscitative measures and surgical management are generally necessary to treat mediastinitis. The exact surgical approach depends on the type of mediastinitis, the clinical features of the patient, the hemodynamic stability and the surgical expertise.

The “superior vena cava (SVC) syndrome” results from an obstruction of the blood flow in the SVC due either to an external compression by a (tumoral) mass located in the mediastinum or to an intra-vascular thrombosis. Two types of SVC syndromes exist: the acute and the chronic forms. These conditions differ by the symptoms that they cause, which are related to alternate drainage pathways that may or may not have the time to develop. From a pathophysiological point of view, the SVC syndrome results in increased venous pressure in the upper part of the body, which causes facial, conjunctival swelling and head cyanosis, especially when patients lay down. In cases of acute SVC syndrome, venous return from the upper part of the body is compromised and swelling of the head is very important. Hemodynamic instability is frequent, mostly due to the absence of collateral drainage. In situations of chronic SVC obstruction, symptoms of swelling are less common and hemodynamic instability is rare, even in presence of hypotension, because the venous return to the heart is possible through collateral drainage. Therefore, with these differences in mind, the strategy for SVC obstruction management will be different. Causes of SVC obstruction are generally linked to SCLC, NSCLC, lymphoma and mediastinal diseases. Their management is decided in a multidisciplinary fashion and include a combination of systemic therapy, radiation therapy, endovascular stenting when indicated and/or surgical resection and reconstruction. Total SVC clamping to perform the surgical intervention should be limited in time to avoid cerebral edema, decreased venous return and patient hemodynamic instability. Various methods to avoid the physiopathological effects of SVC clamping have been described including jugulo-femoral bypasses, intra-field bypasses and catecholamine administration. These methods allow safe and efficient shunting during the period of SVC replacement. Most complications observed following SVC surgery are respiratory or thrombotic events. Thus, cases requiring SVC resection should be discussed to ensure that the risk sustained for venous replacement will be balanced by a real oncological benefit.

Surgical resection of lung cancer is the mainstay in patients with a curative intent. In centrally located lung cancers, pneumonectomy is indicated in case of clear involvement of different lobes or central broncho-vascular structures. However, a parenchyma-sparing surgical option including sleeve resection of the bronchus, the pulmonary artery or both was proven to be valid in centrally-located non-small cell lung cancer (NSCLC) (1).

Background: Enhanced recovery after surgery (ERAS) programs have been reported to decrease complications and shorten hospital stays after lung resections, but their implementation requires time and financial investment with dedicated staff. The aim of this study was to evaluate the clinical and economic outcomes of video-assisted thoracoscopic surgery (VATS) anatomical pulmonary resections before and after implementation of an ERAS program. Methods: The first 50 consecutive patients undergoing VATS lobectomy or segmentectomy for malignancy after implementation of an ERAS program were compared with 50 consecutive patients treated before its introduction. The ERAS protocol included preoperative counseling, reduced preoperative fasting with concomitant carbohydrate loading, avoidance of premedication, standardized surgery, anesthesia and postoperative analgesia, early removal of chest tube, nutrition and mobilization. Length of stay, readmissions and cardio-pulmonary complications within 30 days were compared. Total costs were collected for each patient and a cost-minimization analysis integrating ERAS-specific costs was performed. Results: Both groups were similar in terms of demographics and surgical characteristics. The ERAS group had significantly shorter postoperative length of stay (median: 4 vs . 7 days, P vs . 38%; P=0.01) and decreased overall post-operative complications (24% vs . 48%, P=0.03). One patient in each group was readmitted and there was no 30-day mortality. ERAS-specific costs were calculated at €729 per patient including the clinical nurse and database costs. Average total hospitalization costs were significantly lower in ERAS group (€15,945 vs . €20,360, P vs . €11,454, P vs . €8,906, P=0.303). Cost-minimization analysis showed a mean saving in the ERAS group of €3,686 per patient. Conclusions: An ERAS program for VATS anatomical lung resection is cost-effective and is associated with a lower complication rate and a shorter postoperative hospitalization.

Colorectal cancer (CRC) is a frequently occurring disease, yet diagnosed at a local stage in only 40% of cases. Lung metastases (LM) appear in 5–15% of patients and, left untreated, carry a very poor prognosis. Some CRC patients may benefit from a potentially curative LM resection, but success and benefit are difficult to predict. We discuss prognostic factors of survival after lung metastasectomy in CRC patients under several scenarios (with/ without prior liver metastases; repetitive pulmonary resections). We reviewed all studies (2005–2015) about pulmonary metastases surgical management with curative intent in CRC patients, with a minimum threshold on the number of patients reported (without prior liver metastases: n ≥ 100; with prior resection of liver metastases: n ≥ 50; repetitive thoracic surgery: n ≥ 30). The picture of the prognostic factors of survival is nuanced: surgical management demonstrates clear successes and steady progress, yet there is no single success criterion; stratification of patients and selection bias impact the conclusions. Surgical management of liver and lung metastases may prolong life or cure CRC patients, provided the lesions are fully resected and patients carefully selected. Repeat lung metastasectomy is a safe approach to treat patients in selected cases. In conclusion, there is no standard for surgical management in CRC patients with pulmonary metastases. Patients with isolated unilateral lung metastasis with normal CEA level and no lymph node involvement benefit the most from surgery. Most series report good results in highly selected patients, but instances of long-term disease-free survival remain exceptional.

Background Extrathoracic muscle flaps can be used as airway substitutes for the closure of complex bronchopleural or tracheoesophageal fistulas or in the context of tracheocarinal reconstructions after resection for centrally localized tumors in order to alleviate excess anastomotic tension. Methods Evaluation of all patients undergoing tracheocarinal reconstructions with extrathoracic muscle flap patches as airway substitutes in our institution from 1996 to 2016. Results A total of 73 patients underwent tracheocarinal reconstructions using extrathoracic muscle flap patches as airway substitutes for the closure of bronchopleural fistulas (n = 17) and complex tracheoesophageal fistulas (n = 7), or in the context of airway reconstructions after carinal resections in combination with pneumonectomy/sleeve lobectomy for centrally localized lung tumors (n = 36) and noncircumferential tracheal resections for tracheal disease processes (n = 14). The size of airway defects replaced by muscle patches ranged from 2 × 2 to 8 × 4 cm and was at most 40% of the airway circumference. The postoperative 90-day mortality was 8.2% and was only observed after right-sided pneumonectomy. Complications at the airway reconstruction site occurred in 8 patients (10%): 4 airway dehiscence (5%) with uneventful healing after reoperation (n = 2) or temporary stenting (n = 2) and 4 airway stenosis (5%) that required repeated bronchoscopy and stenting. Overall, 63 of 67 surviving patients (94%) revealed intact airways without further bronchoscopic interventions or tracheal appliance during follow-up. Conclusions Extrathoracic muscle flaps used as airway substitutes are an interesting and sometimes life-saving option to close difficult tracheocarinal airway defects or to reduce anastomotic tension in the context of complex tracheocarinal surgeries.

Low-dose photodynamic therapy PDT (photoinduction) can modulate tumor vessels and enhance the uptake of liposomal cisplatin (Lipoplatin®) in pleural malignancies. However, the photo-induction conditions must be tightly controlled as overtreatment shuts down tumor vessels and enhances normal tissue drug uptake.