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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 8 th 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 < .001), but pretreatment N2 extension (177/197) showed no impact on overall survival., Conclusions: Surgery after induction treatment for advanced T3/T4 stage including single and multiple pretreatment N2 disease resulted in 80% R0 resection rate and 7% 90-day mortality. Favorable overall survival for extended and not extended resection was demonstrated to be independent of pretreatment N status., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Identification of the prognostic factors of recurrence and survival after single pulmonary metastasectomy (PM)., Methods: Retrospective analysis of all consecutive patients who underwent PM for a single lung metastasis between 2003 and 2018., Results: A total of 162 patients with a median age of 64 years underwent single PM. Video-Assisted Thoracic Surgery (VATS) was performed in 83.9% of cases. Surgical resection was achieved by wedge in 73.5%, segmentectomy in 7.4%, lobectomy in 17.9% and pneumonectomy in 1.2% of cases. The median durations of hospital stay and of drainage were 4 days (IQR 3-7) and 1 day (IQR 1-2), respectively. During the follow-up (median 31 months; IQR 15-58), 93 patients (57.4%) presented recurrences and repeated PM could be realized in 35 patients (21.6%) achieved by VATS in 77.1%. Non-colorectal tumour (HR 1.84), age < 70 years (HR 1.77) and previous extra-thoracic metastases (HR 1.61) were identified as prognostic factors of recurrence. Overall survival at 5-year was estimated at 67%. Non-colorectal tumour (HR 2.40) and mediastinal lymph nodes involvement (HR 3.42) were significantly associated with an increased risk of death., Conclusions: Despite high recurrence rates after PM, surgical resection shows low morbidity rate and acceptable long-term survival, thus should remain the standard treatment for single pulmonary metastases., Trial Registration: The Local Ethics Committee approved the study (No. 2019-02,474) and individual consent was waived., (© 2021. The Author(s).)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

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. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2345/F1.large.jpg., (©2021 American Association for Cancer Research.)

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: Malignant pleural mesothelioma (MPM) is a deadly disease with limited treatment options. Approaches to enhance patient immunity against MPM have been tested but shown variable results. Previously, we have demonstrated interesting vascular modulating properties of low-dose photodynamic therapy (L-PDT) on MPM. Here, we hypothesized that L-PDT vascular modulation could favour immune cell extravasation in MPM and improve tumour control in combination with immune checkpoint inhibitors., Methods: First, we assessed the impact of L-PDT on vascular endothelial E-selectin expression, a key molecule for immune cell extravasation, in vitro and in a syngeneic murine model of MPM. Second, we characterized the tumour immune cell infiltrate by 15-colour flow cytometry analysis 2 and 7 days after L-PDT treatment of the murine MPM model. Third, we determined how L-PDT combined with immune checkpoint inhibitor anti-CTLA4 affected tumour growth in a murine MPM model., Results: L-PDT significantly enhanced E-selectin expression by endothelial cells in vitro and in vivo. This correlated with increased CD8+ T cells and activated antigen-presenting cells (CD11b+ dendritic cells and macrophages) infiltration in MPM. Also, compared to anti-CTLA4 that only affects tumour growth, the combination of L-PDT with anti-CTLA4 caused complete MPM regression in 37.5% of animals., Conclusions: L-PDT enhances E-selectin expression in the MPM endothelium, which favours immune infiltration of tumours. The combination of L-PDT with immune checkpoint inhibitor anti-CTLA4 allows best tumour control and regression., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Vascular-targeted low-dose photodynamic therapy (L-PDT) was shown to improve chemotherapy distribution in malignant pleural tumors such as malignant pleural mesothelioma (MPM). However, the mechanisms triggered by L-PDT on the tumor vasculature are still debated. In pericyte and endothelial cell co-cultures, we show that pericytes exhibit enhanced sensitivity towards L-PDT compared to endothelial cells, displaying actin stress fibers and cellular contraction via Rho/ROCK kinase signaling myosin light chain and focal adhesion kinase phosphorylation (MLC-P, FAK-P). We then confirm, in two separate MPM models, in mice the phosphorylation of the MLC in pericytes specifically following L-PDT. Furthermore, while L-PDT does not affect tumor vascular density or diameter, we show that it enhances tumor vascular pericyte coverage, leads to a drop in tumor interstitial fluid pressure and enhances the transport of FITC-dextran throughout tumors. In conclusion, L-PDT has the potential to stabilize the tumor vascular bed which improves vascular transport. The mechanism described in the present study may help translate and optimize this approach in patients. Lasers Surg. Med. 51:550-561, 2019. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

The lung is the second site of metastasis after the liver, affecting 30 to 40 % of all patients with a malignant tumor. Chemotherapy seems to be ineffective for some types of tumor. Although there are no prospective randomized studies that confirm the benefit of surgical pulmonary metastasectomy, many studies have shown the existence of a group of patients with pulmonary metastases who benefit from a complete resection for curative purposes in case of complete resection of lung metastases. Different approaches are known to achieve a complete resection with maximum lung parenchyma sparing. Minimal invasive approaches appear to offer a better quality of life and have equivalent oncologic outcomes compared to the open approach., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Solitary pulmonary nodules (SPN) are frequently detected in cancer patients. These lesions are often considered as pulmonary metastases and increasingly treated by non-surgical techniques without histological confirmation. The aim of this study is to determine the histological nature of SPN resected by thoracoscopy and to identify risk factors of malignancy., Methods: Single-institution retrospective analysis of all consecutive patients with previously known malignancies who underwent thoracoscopic resection of SPN with unknown diagnosis between 2001 and 2014., Results: One hundred and forty cancer patients underwent thoracoscopic resection of a SPN. The resected SPN was benign in 34 patients (24.3%) and malignant in 106 patients. The latter were metastasis in 70 patients (50%) and a primary lung cancer in 36 patients (25.7%). Upon univariate analysis, malignancy was significantly associated with age >60 years, disease-free interval ≥24 months, SPN size >8 mm, upper lobe localization and SUV max  > 2.5 on PET-CT. Upon multivariate analysis, upper lobe localization and SUV max  > 2.5 were associated with malignancy. Smoking was significantly associated with SPN containing primary lung cancer., Conclusion: In this series, only 50% of SPN in patients with known malignant disease were pulmonary metastases and 25% had a newly diagnosed NSCLC. Smoking was associated with primary lung cancer but no other predictor was found to allow the distinction between pulmonary metastasis and lung cancer. These results endorse the need of histological confirmation of SPN in patients with previous malignancies to avoid diagnostic uncertainty and suboptimal treatments.

Background: Pulmonary metastasectomy is increasingly performed in selected patients by video-assisted thoracic surgery (VATS) on the base of thin-slice high-resolution CT-Scan (HRCT). This study determines the overall survival and ipsilateral recurrence rate and of patients undergoing after VATS lung metastasectomy., Patients and Method: Retrospective single institution study of all patients who underwent VATS pulmonary metastasectomy on the base of HRCT with curative intent between 2005 and 2014., Results: Seventy-seven patients (41 males, 36 females) underwent VATS pulmonary metastasectomy for solitary (n = 63) or multiple (n = 14) lung metastases in the context of colorectal carcinoma (n = 26), sarcoma (n = 17), melanoma (n = 16), or other primaries (n = 18). Nine patients had bilateral lung metastases and underwent synchronous (n = 4) or sequential (n = 5) VATS resections. Preoperative CT-guided hook wire localization of the lesions was performed in 65 patients (84 %). The postoperative mortality and morbidity rates were 0 and 5.2 %, respectively. During a mean follow-up time of 24 months (range 1–120 months), tumor progression occurred in 46 patients. Twenty-three patients (30 %) had pulmonary recurrence only, of them, eight patients (10 %) in the operated lungs. Seven of eight patients with recurrence in the operated lungs underwent a second metastasectomy by VATS (n = 5) or thoracotomy (n = 2). The overall 5-year survival rate was 54 % and without difference between patients without tumor recurrence and those with pulmonary recurrence treated by re-metastasectomy., Conclusion: Ipsilateral recurrence remains low after VATS pulmonary metastasectomy guided by preoperative HRCT and can be efficiently treated by re-metastasectomy.

Hypertrophic osteoarthrpathy (HO) is a rare paraneoplasic syndrome associated with non-small cell lung cancer (NSCLC). The pathophysiology of HO is unknown but was recently related to enhanced levels of urine prostaglandin E2 (PGE2). Here, we report the case of a patient that presented HO in association with a resectable left upper lobe NSCLC. Following surgery and adjuvant chemotherapy, HO resolved and did not recur with development of a brain metastasis 1 year later. Interestingly, tumor cyclooxygenase-2, an enzyme responsible the synthesis of PGE2, was expressed in the primary tumor but not in the resected metastasis., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Video-assisted thoracic surgery (VATS) is currently performed to diagnose and treat solitary pulmonary nodules (SPN). However, the intra-operative identification of deep nodules can be challenging with VATS as the lung is difficult to palpate. The aim of the study was to report the utility and the results of pre-operative computed tomography (CT)-guided hook wire localization of SPN., Methods: All records of the patients undergoing CT-guided hook wire localization prior to VATS resection for SPN between 2002 and 2013 were reviewed. The efficacy in localizing the nodule, hook wire complications, necessity to convert VATS to thoracotomy and the histology of SPN are reported., Results: One hundred eighty-one patients (90 females, mean age 63 y, range 28-82 y) underwent 187 pulmonary resections after CT-guided hook wire localization. The mean SPN diameter was 10.3 mm (range: 4-29 mm). The mean distance of the lesion from the pleural surface was 11.6 mm (range: 0-45 mm). The mean time interval from hook wire insertion to VATS resection was 224 min (range 54-622 min). Hook wire complications included pneumothorax requiring chest tube drainage in 4 patients (2.1%) and mild parenchymal haemorrhage in 11 (5.9%) patients. Migration of the hook wire occurred in 7 patients (3.7%) although it did not affect the success of VATS resection (nodule location guided by the lung puncture site). Three patients underwent additional wedge resection by VATS during the same procedure because no lesion was identified in the surgical specimen. Conversion thoracotomy was required in 13 patients (7 %) for centrally localized lesions (6 patients) and pleural adhesions (7 patients). The mean operative time was 60 min (range 18-135 min). Pathological examination revealed a malignant lesion in 107 patients (59 %). The diagnostic yield was 98.3 %., Conclusion: VATS resection for SPN after CT-guided hook wire localization for SPN is safe and allows for proper diagnosis with a low thoracotomy conversion rate.

Background: Low-dose, Visudyne®-mediated photodynamic therapy (photo-induction) was shown to selectively enhance tumor vessel transport causing increased uptake of systemically administered chemotherapy in various tumor types grown on rodent lungs. The present experiments explore the efficacy of photo-induced vessel modulation combined to intravenous (IV) liposomal cisplatin (Lipoplatin®) on rodent lung tumors and the feasibility/toxicity of this approach in porcine chest cavities., Material and Methods: Three groups of Fischer rats underwent orthotopic sarcoma (n = 14), mesothelioma (n = 14), or adenocarcinoma (n = 12) implantation on the left lung. Half of the animals of each group had photo-induction (0.0625 mg/kg Visudyne®, 10 J/cm(2) ) followed by IV administration of Lipoplatin® (5 mg/kg) and the other half received Lipoplatin® without photo-induction. Then, two groups of minipigs underwent intrapleural thoracoscopic (VATS) photo-induction (0.0625 mg/kg Visudyne®; 30 J/cm(2) hilum; 10 J/cm(2) apex/diaphragm) with in situ light dosimetry in combination with IV Lipoplatin® administration (5 mg/kg). Protocol I (n = 6) received Lipoplatin® immediately after light delivery and Protocol II (n = 9) 90 minutes before light delivery. Three additional animals received Lipoplatin® and VATS pleural biopsies but no photo-induction (controls). Lipoplatin® concentrations were analyzed in blood and tissues before and at regular intervals after photo-induction using inductively coupled plasma mass spectrometry., Results: Photo-induction selectively increased Lipoplatin® uptake in all orthotopic tumors. It significantly increased the ratio of tumor to lung Lipoplatin® concentration in sarcoma (P = 0.0008) and adenocarcinoma (P = 0.01) but not in mesothelioma, compared to IV drug application alone. In minipigs, intrapleural photo-induction combined to systemic Lipoplatin® was well tolerated with no toxicity at 7 days for both treatment protocols. The pleural Lipoplatin® concentrations were not significantly different at 10 and 30 J/cm(2) locations but they were significantly higher in protocol I compared to II (2.37 ± 0.7 vs. 1.37 ± 0.7 ng/mg, P  < 0.001)., Conclusion: Visudyne®-mediated photo-induction selectively enhances the uptake of IV administered Lipoplatin® in rodent lung tumors. Intrapleural VATS photo-induction with identical treatment conditions combined to IV Lipoplatin chemotherapy is feasible and well tolerated in a porcine model. Lasers Surg. Med. 47:807-816, 2015. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Video-assisted thoracoscopic surgery (VATS) is currently a routinely performed procedure for the management of early non small cell lung cancer. The oncological results of VATS in terms of local recurrence and overall survival are equivalent or superior to those of conventional thoracotomy with lower morbidity and hospital stay. In the field of pulmonary metastasectomy, current guidelines support a thoracotomy approach in order to properly palpate the lung and detect nodules too small to be identified on standard radiological examinations (typically less than 5mm in diameter). However, the oncological and clinical significance of these millimetric nodules is not known. This has led some thoracic surgeons to rethink the approach of solitary pulmonary metastasectomy: because of improvements in thin slice helical CT-scans, some support a VATS approach for solitary pulmonary nodules without formal bimanual palpation and suggest this allows equivalent oncological results and decreased surgical morbidity., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Induction radiochemotherapy, followed by resection, for T4 non-small cell lung cancer, has shown promising long-term survival but may be associated with increased postoperative morbidity and death, depending on patient selection. Here, we determined the effect of induction radiochemotherapy on pulmonary function and whether postinduction pulmonary function changes predict hospital morbidity and death and long-term survival., Methods: A consecutive prospective cohort of 72 patients with T4 N0-2 M0 non-small cell lung cancer managed by radiochemotherapy, followed by resection, is reported. All patients underwent thoracoabdominal computed tomography or fusion positron emission tomography-computed tomography, brain imaging, mediastinoscopy, echocardiography, ventilation-perfusion scintigraphy, and pulmonary function testing before and after induction therapy. Resection was performed if the postoperative forced expiratory volume in 1 second and diffusion capacity of the lung for carbon monoxide exceeded 30% predicted and if the postoperative maximum oxygen consumption exceeded 10 mL/kg/min., Results: The postoperative 90-day mortality rate was 8% (lobectomy, 2%; pneumonectomy, 21%; p=0.01). All deaths after pneumonectomy occurred after right-sided procedures. The 3-year and 5-year survival was 50% (95% confidence interval, 36% to 62%) and 45% (95% confidence interval, 31% to 57%) and was significantly associated with completeness of resection (p=0.004) and resection type (pneumonectomy vs lobectomy, p=0.01). There was no correlation between postinduction pulmonary function changes and postoperative morbidity or death or long-term survival in patients managed by lobectomy or pneumonectomy., Conclusions: In properly selected patients with T4 N0-2 M0 non-small cell lung cancer, resection after induction radiochemotherapy can be performed with a reasonable postoperative mortality rate and long-term survival, provided the resection is complete and a right-sided pneumonectomy is avoided. Postinduction pulmonary function changes did not correlate with postoperative morbidity or death or with long-term outcome., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Visudyne®-mediated photodynamic therapy (PDT) at low drug/light conditions has shown to selectively enhance the uptake of liposomal doxorubicin in subpleural localized sarcoma tumors grown on rodent lungs without causing morphological alterations of the lung. The present experiments explore the impact of low-dose PDT on liposomal doxorubicin (Liporubicin™) uptake to different tumor types grown on rodent lungs., Material and Methods: Three groups of Fischer rats underwent subpleural generation of sarcoma, mesothelioma, or adenocarcinoma tumors on the left lung. At least five animals of each group (sarcoma, n = 5; mesothelioma, n = 7; adenocarcinoma, n = 5) underwent intraoperative low-dose (10 J/cm(2) at 35 mW/cm(2) ) PDT with 0.0625 mg/kg Visudyne® of the tumor and the lower lobe. This was followed by intravenous (IV) administration of 400 µg Liporubicin™. After a circulation time of 60 min, the tumor-bearing lung was processed for HPLC analyses. At least five animals per group underwent the same procedure but without PDT (sarcoma, n = 5; mesothelioma, n = 5; adenocarcinoma, n = 6). Five untreated animals per group underwent CD31 immunostaining of their tumors with histomorphometrical assessment of the tumor vascularization., Results: Low-dose PDT significantly enhanced Liporubicin™ uptake to all tumor types (sarcoma, P = 0.0007; mesothelioma, P = 0.001; adenocarcinoma, P = 0.02) but not to normal lung tissue compared to IV drug administration alone. PDT led to a significantly increased ratio of tumor to lung tissue drug uptake for all three tumor types (P < 0.05). However, the tumor drug uptake varied between tumor types and paralleled tumor vascular density. The vascular density was significantly higher in sarcoma than in adenocarcinoma (P < 0.001) and mesothelioma (P < 0.001), whereas there was no significant difference between adenocarcinoma and mesothelioma., Conclusion: Low-dose Visudyne®-mediated PDT selectively enhances the uptake of systemically administered liposomal doxorubicin in tumors without affecting the drug uptake to normal lung. However, drug uptake varied significantly between tumor types and paralleled tumor vascular density., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: In specific conditions, photodynamic therapy (PDT) can enhance the distribution of macromolecules across the endothelial barrier in solid tumors. It was recently postulated that tumor neovessels were more responsive to PDT than the normal vasculature. We hypothesized that Visudyne(R)-mediated PDT could selectively increase liposomal doxorubicin (Liporubicin) uptake in sarcoma tumors to rodent lungs while sparing the normal surrounding tissue., Materials and Methods: Sarcoma tumors were generated subpleurally in the left lower lung lobe of 66 Fischer rats. Ten days following sarcoma implantation, tumors underwent different pre-treatment schemes: no PDT (controls), low-dose PDT (0.0625 mg/kg Visudyne(R), 10 J/cm(2) and 35 mW/cm(2)) and high-dose PDT (0.125 mg/kg Visudyne(R), 10 J/cm(2) and 35 mW/cm(2)). Liporubicin was then administered and allowed to circulate for 1, 3, or 6 hours. At the end of each treatment scheme, we assessed the uptake of Liporubicin in tumor and lung tissues by high-performance liquid chromatography and fluorescence microscopy., Results: In all PDT-treated groups, there was a significant enhancement of Liporubicin uptake in tumors compared to controls after 3 and 6 hours of drug circulation. In addition, Liporubicin distribution within the normal lung tissue was not affected by PDT. Thus, PDT pre-treatment significantly enhanced the ratio of tumor-to-lung drug uptake compared to controls. Finally, fluorescence microscopy revealed a well-detectable Liporubicin signaling throughout PDT-treated tumors but not in controls., Conclusions: PDT is a tumor-specific enhancer of Liporubicin distribution in sarcoma lung tumors which may find a translation in clinics.

The distribution of free and liposomal doxorubicin (Liporubicin) administered by intravenous injection (IV) or isolated lung perfusion (ILP) was compared in normal and tumor tissues of sarcoma bearing rodent lungs. A single sarcomatous tumor was generated in the left lung of 35 Fischer rats, followed 10 days later by left-sided ILP (n=20) or IV drug administration (n=12), using 100 microg and 400 microg free or liposomal doxorubicin, respectively. The tumor and lung tissue drug concentration was measured by HPLC. Free doxorubicin administered by ILP resulted in a three-fold (100 microg) and 10-fold (400 microg) increase of the drug concentration in the tumor and normal lung tissue compared to IV administration. In contrast, ILP with Liporubicin resulted in a similar drug uptake in the tumor and lung tissue compared to IV injection. For both drug formulations and dosages, ILP resulted in a higher tumor to lung tissue drug ratio but also in a higher spatial heterogeneity of drug distribution within the lung compared to IV administration. ILP resulted in a higher tumor to lung tissue drug ratio and in a more heterogeneous drug distribution within the lung compared to IV drug administration.