Treatment with 3-aminobenzamide during ex vivo lung perfusion of damaged rat lungs reduces graft injury and dysfunction after transplantation.

Ex vivo lung perfusion (EVLP) with pharmacological reconditioning may increase donor lung utilization for transplantation (LTx). 3-Aminobenzamide (3-AB), an inhibitor of poly(ADP-ribose) polymerase (PARP), reduces ex vivo lung injury in rat lungs damaged by warm ischemia (WI). Here we determined the effects of 3-AB reconditioning on graft outcome after LTx. Three groups of donor lungs were studied: Control (Ctrl): 1 hour WI + 3 hours cold ischemia (CI) + LTx; EVLP: 1 hour WI + 3 hours EVLP + LTx; EVLP + 3-AB: 1 hour WI + 3 hours EVLP + 3-AB (1 mg. mL-1 ) + LTx. Two hours after LTx, we determined lung graft compliance, edema, histology, neutrophil counts in bronchoalveolar lavage (BAL), mRNA levels of adhesion molecules within the graft, as well as concentrations of interleukin-6 and 10 (IL-6, IL-10) in BAL and plasma. 3-AB reconditioning during EVLP improved compliance and reduced lung edema, neutrophil infiltration, and the expression of adhesion molecules within the transplanted lungs. 3-AB also attenuated the IL-6/IL-10 ratio in BAL and plasma, supporting an improved balance between pro- and anti-inflammatory mediators. Thus, 3-AB reconditioning during EVLP of rat lung grafts damaged by WI markedly reduces inflammation, edema, and physiological deterioration after LTx, supporting the use of PARP inhibitors for the rehabilitation of damaged lungs during EVLP.

Vascular-targeted low dose photodynamic therapy stabilizes tumor vessels by modulating pericyte contractility.

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.

A plea for thoracoscopic resection of solitary pulmonary nodule in cancer patients.

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 SUVmax > 2.5 on PET-CT. Upon multivariate analysis, upper lobe localization and SUVmax > 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.

Interstitial fluid pressure: A novel biomarker to monitor photo-induced drug uptake in tumor and normal tissues.

BACKGROUND: 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. MATERIAL AND METHODS: In a pleural sarcoma and adenocarcinoma rat model (n = 12/group), we applied photoinduction (0.0625 mg/kg Visudyne®, 10 J/cm2 ) followed by intravenous Lipoplatin® (5 mg/kg) administration. Tumor and normal tissue IFP were assessed before and up to 1 hour following photoinduction. Lipoplatin® uptake was determined 60 minutes following photoinduction. We then treated the pleura of tumor-free minipigs with high dose photodynamic therapy (PDT) (0.0625 mg/kg Visudyne®, 30 J/cm2 , n = 5) followed by Lipoplatin (5 mg/kg) administration. RESULTS: In rodents, photoinduction resulted in a significant decrease of IFP (P < 0.05) in both tumor types but not in the surrounding normal lung, equally exposed to light. Also, photoinduction resulted in a significant increase of Lipoplatin® uptake in both tumor types (P < 0.05) but not in normal lung. Tumor IFP variation and Lipoplatin® uptake fitted an inverted parabola. In minipigs, high dose photodynamic treatment resulted in pleural IFP increase of some animals which predicted higher Lipoplatin® uptake levels. CONCLUSION: Normal and tumor vasculatures react differently to PDT. Continuous IFP monitoring in normal and tumor tissues is a promising biomarker of vessel photoinduction. Moderate drop in tumor with no change in normal tissue IFP are predictive of specific Lipoplatin® uptake by cancer following PDT. Lasers Surg. Med. 49:773-780, 2017. © 2017 Wiley Periodicals, Inc.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.

BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

Survival and Local Recurrence After Video-Assisted Thoracoscopic Lung Metastasectomy.

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 1­120 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.

Extracorporeal support for pulmonary resection: current indications and results.

Extracorporeal assistances are exponentially used for patients, with acute severe but reversible heart or lung failure, to provide more prolonged support to bridge patients to heart and/or lung transplantation. However, experience of use of extracorporeal assistance for pulmonary resection is limited outside lung transplantation. Airways management with standard mechanical ventilation system may be challenging particularly in case of anatomical reasons (single lung), presence of respiratory failure (ARDS), or complex tracheo-bronchial resection and reconstruction. Based on the growing experience during lung transplantation, more and more surgeons are now using such devices to achieve good oxygenation and hemodynamic support during such challenging cases. We review the different extracorporeal device and attempt to clarify the current practice and indications of extracorporeal support during pulmonary resection.

Incidence and Risk Factors of Abdominal Complications After Lung Transplantation.

BACKGROUND: Due to the underlying diseases and the need for immunosuppression, patients after lung transplantation are particularly at risk for gastrointestinal (GI) complications that may negatively influence long-term outcome. The present study assessed the incidences and impact of GI complications after lung transplantation and aimed to identify risk factors. METHODS: Retrospective analysis of all 227 consecutively performed single- and double-lung transplantations at the University hospitals of Lausanne and Geneva was performed between January 1993 and December 2010. Logistic regressions were used to test the effect of potentially influencing variables on the binary outcomes overall, severe, and surgery-requiring complications, followed by a multiple logistic regression model. RESULTS: Final analysis included 205 patients for the purpose of the present study, and 22 patients were excluded due to re-transplantation, multiorgan transplantation, or incomplete datasets. GI complications were observed in 127 patients (62%). Gastro-esophageal reflux disease was the most commonly observed complication (22.9%), followed by inflammatory or infectious colitis (20.5%) and gastroparesis (10.7%). Major GI complications (Dindo/Clavien III-V) were observed in 83 (40.5%) patients and were fatal in 4 patients (2.0%). Multivariate analysis identified double-lung transplantation (p = 0.012) and early (1993-1998) transplantation period (p = 0.008) as independent risk factors for developing major GI complications. Forty-three (21%) patients required surgery such as colectomy, cholecystectomy, and fundoplication in 6.8, 6.3, and 3.9% of the patients, respectively. Multivariate analysis identified Charlson comorbidity index of ≥3 as an independent risk factor for developing GI complications requiring surgery (p = 0.015). CONCLUSION: GI complications after lung transplantation are common. Outcome was rather encouraging in the setting of our transplant center.

Treatment of pleural malignancies by photo-induction combined to systemic chemotherapy: Proof of concept on rodent lung tumors and feasibility study on porcine chest cavities.

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.

Fluence plays a critical role on the subsequent distribution of chemotherapy and tumor growth delay in murine mesothelioma xenografts pre-treated by photodynamic therapy.

BACKGROUND: The pre-conditioning of tumor vessels by low-dose photodynamic therapy (L-PDT) was shown to enhance the distribution of chemotherapy in different tumor types. However, how light dose affects drug distribution and tumor response is unknown. Here we determined the effect of L-PDT fluence on vascular transport in human mesothelioma xenografts. The best L-PDT conditions regarding drug transport were then combined with Lipoplatin(®) to determine tumor response. METHODS: Nude mice bearing dorsal skinfold chambers were implanted with H-Meso1 cells. Tumors were treated by Visudyne(®) -mediated photodynamic therapy with 100 mW/cm(2) fluence rate and a variable fluence (5, 10, 30, and 50 J/cm(2) ). FITC-Dextran (FITC-D) distribution was assessed in real time in tumor and normal tissues. Tumor response was then determined with best L-PDT conditions combined to Lipoplatin(®) and compared to controls in luciferase expressing H-Meso1 tumors by size and whole body bioluminescence assessment (n = 7/group). RESULTS: Tumor uptake of FITC-D following L-PDT was significantly enhanced by 10-fold in the 10 J/cm(2) but not in the 5, 30, and 50 J/cm(2) groups compared to controls. Normal surrounding tissue uptake of FITC-D following L-PDT was significantly enhanced in the 30 J/cm(2) and 50 J/cm(2) groups compared to controls. Altogether, the FITC-D tumor to normal tissue ratio was significantly higher in the 10 J/cm(2) group compared others. Tumor growth was significantly delayed in animals treated by 10 J/cm2-L-PDT combined to Lipoplatin(®) compared to controls. CONCLUSIONS: Fluence of L-PDT is critical for the optimal distribution and effect of subsequently administered chemotherapy. These findings have an importance for the clinical translation of the vascular L-PDT concept in the clinics.

Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.

BACKGROUND: Resection of lung metastases (LM) from colorectal cancer (CRC) is increasingly performed with a curative intent. It is currently not possible to identify those CRC patients who may benefit the most from this surgical strategy. The aim of this study was to perform a systematic review of risk factors for survival after lung metastasectomy for CRC. METHODS: We performed a meta-analysis of series published between 2000 and 2011, which focused on surgical management of LM from CRC and included more than 40 patients each. Pooled hazard ratios (HR) were calculated by using random effects model for parameters considered as potential prognostic factors. RESULTS: Twenty-five studies including a total of 2925 patients were considered in this analysis. Four parameters were associated with poor survival: (1) a short disease-free interval between primary tumor resection and development of LM (HR 1.59, 95 % confidence interval [CI] 1.27-1.98); (2) multiple LM (HR 2.04, 95 % CI 1.72-2.41); (3) positive hilar and/or mediastinal lymph nodes (HR 1.65, 95 % CI 1.35-2.02); and (4) elevated prethoracotomy carcinoembryonic antigen (HR 1.91, 95 % CI 1.57-2.32). By comparison, a history of resected liver metastases (HR 1.22, 95 % CI 0.91-1.64) did not achieve statistical significance. CONCLUSIONS: Clinical variables associated with prolonged survival after surgery for LM in CRC patients include prolonged disease-free interval between primary tumor and metastatic spread, normal prethoracotomy carcinoembryonic antigen, absence of thoracic node involvement, and a single pulmonary lesion.

[Management of pectus excavatum]. / Prise en charge du thorax en entonnoir.

Management of pectus excavatum Congenital chest wall deformities are considered to be anomalies in chest wall growth related to excessive or insufficient growth (aplasia or dysplasia) of the osseous or cartilaginous structures or the rib cage. These deformities are associated in 95% to overgrowth leading into depression (pectus excavatum) or protuberance of the sternum (pectus carinatum). Pectus excavatum may lead to cardiopulmonary disorder or impact on patient's self-esteem. The management of pectus excavatum has evolved this last decade with minimal invasive repair.

Objective improvement in dexterity for trainees undergoing a video-assisted thoracoscopic surgery simulation program, a prospective single center study.

Background: Video-assisted thoracoscopic surgery (VATS) is the recommended approach for the management of early-stage operable non-small cell lung carcinoma as well as for other pathologies of the thoracic cavity. Although VATS approaches have been largely adopted in Europe and North America, teaching the technique to novice thoracic surgery trainees remains challenging and non-standardized. Our objective was to assess the impact of a VATS simulation training program on the dexterity of thoracic surgery residents in a prospective single institution study. Methods: We developed a 6-month VATS simulation training program on two different dry-lab simulators (Johnson & Johnson Ethicon Stupnik® lobectomy model; CK Surgical Simulation® Crabtree perfused lobectomy model) and assessed the skills of first year thoracic surgery residents (study group, n=7) before and after this program using three standardized exercises on the Surgical Science Simball® Box (peg placement on a board, rope insertion in loops, precision circle cutting). The results were compared to those of last-year medical students who performed the same Simball® Box exercises at a 6-month interval without undergoing a training program (control group, n=5). For each participant, the travel distances of instruments, operation time and absences of periods of extreme motion were assessed for each exercise by the use of the computer-based evaluation of the Simball® Box. Results: After the 6-month VATS training program, all residents revealed a significant increase of their performance status with respect to instrument travel distances operation times and absence of periods of extreme motion in all three exercises performed. The performance of the control group was not different from the study group prior to the training program and remained unchanged 6 months later, for all exercises and parameters assessed. Conclusions: Our results suggest that the implementation of a VATS simulation training program objectively increases the dexterity of thoracic surgery residents and could be an interesting training tool for their surgical education.

Survival after lung metastasectomy in colorectal cancer patients with previously resected liver metastases.

BACKGROUND: Resection of hepatic metastases is indicated in selected stage IV colorectal cancer (CRC) patients. A minority will eventually develop pulmonary metastases and may undergo lung surgery with curative intent. The aims of the present study were to assess clinical outcome and identify parameters predicting survival after pulmonary metastasectomy in patients who underwent prior resection of hepatic CRC metastases. METHODS: We performed a retrospective analysis of 27 consecutive patients (median age 62 years; range: 33-75 years) who underwent resection of pulmonary metastases after previous hepatic metastasectomy from CRC in two institutions from 1996 to 2009. All patients underwent complete resection (R0) for both colorectal and hepatic metastases. RESULTS: Median follow-up was 32 months (range: 3-69 months) after resection of lung metastases and 65 months (range: 19-146 months) after resection of primary CRC. Three- and 5-year overall survival rates after lung surgery were 56 and 39%, respectively, and median survival was 46 months (95% CI 35-57). Median disease-free survival after pulmonary metastasectomy was 13 months (95% CI 5-21). At the time of last follow-up, seven patients (26%) had no evidence of recurrent disease and 6 of these 7 patients presented initially with a single lung metastasis. CONCLUSIONS: Resection of lung metastases from CRC patients may result in prolonged survival, even after previous hepatic metastasectomy. Yet, prolonged disease-free survival remains the exception, and seems to occur only in patients with a single lung lesion.

Photodynamic induced uptake of liposomal doxorubicin to rat lung tumors parallels tumor vascular density.

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.

The size and sternal involvement of chest wall resections for malignant disease predict postoperative morbidity.

Background: Chest wall resections/reconstructions are a validated approach to manage tumors invading the thorax. However, how resection characteristics affect postoperative morbidity and mortality is unknown. We determined the impact of chest wall resection size and location on patient short and long-term postoperative outcomes. Methods: We reviewed all consecutive patients who underwent resections/reconstructions for chest wall tumors between 2003 and 2018. The impact of chest wall resection size and location and reconstruction on perioperative morbidity/mortality and oncological outcome were evaluated for each patient. Results: Ninety-three chest wall resections were performed in 88 patients for primary (sarcoma, breast cancer, n=66, 71%) and metastatic (n=27, 29%) chest wall tumors. The mean chest bony resection size was 107 (range, 15-375) cm2 and involved ribs only in 57% (n=53) or ribs combined to sternal/clavicular resections in 43% of patients (n=40). Chest defect reconstruction methods included muscle flaps alone (14%) prosthetic material alone (25%) or a combination of both (61%). Early systemic postoperative complications included pneumonia (n=15, 16%), atelectasis (n=6, 6%), pleural effusion (n=15, 16%) and arrhythmia (n=6, 6%). The most frequent long-term reconstructive complications included wound dehiscence (n=4), mesh infection (n=5) and seroma (n=4). Uni- and multivariable analyses indicated that chest wall resection size (>114 cm2) and location (sternum) were significantly associated with the occurrence of pneumonia and atelectasis [odds ratio (OR) =3.67, P=0.05; OR =78.92, P=0.02, respectively]. Disease-free and overall survival were 37±43 and 48±42 months for primary malignancy and of 24±33 and 48±53 months for metastatic chest wall tumors respectively with a mean follow-up of 46±44 months. Conclusions: Chest wall resections present good long-term oncological outcomes. A resection size above 114 cm2 and the involvement of the sternum are significantly associated with higher rates of postoperative pneumonia/atelectasis. This subgroup of patients should have reinforced perioperative physical therapy protocols.

Leukocyte-endothelial cell interaction is necessary for photodynamic therapy induced vascular permeabilization.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) affects vascular barrier function and thus increases vessel permeability. This phenomenon may be exploited to facilitate targeted drug delivery and may lead to a new clinical application of photodynamic therapy. Here, we investigate the role of leukocyte recruitment for PDT-induced vascular permeabilization. STUDY DESIGN/MATERIAL AND METHODS: Fluorescein isothiocyanate dextran (FITC-D, 2,000 kDa) was injected intravenously 120 minutes after focal PDT on striated muscle in nude mice bearing dorsal skinfold chambers (Visudyne® 800 µg/kg, fluence rate 300 mW/cm2 , light dose of 200 J/cm2). Leukocyte interaction with endothelial cells was inhibited by antibodies functionally blocking adhesion molecules ("MABS-PDT" group, n = 5); control animals had PDT but no antibody injection (group "PDT", n = 7). By intravital microscopy, we monitored leukocyte rolling and sticking in real-time before, 90 and 180 minutes after PDT. The extravasation of FITC-D from striated muscle vessels into the interstitial space was determined in vivo during 45 minutes to assess treatment-induced alterations of vascular permeability. RESULTS: PDT significantly increased the recruitment of leukocytes and enhanced the leakage of FITC-D. Neutralization of adhesion molecules before PDT suppressed the rolling of leukocytes along the venular endothelium and significantly reduced the extravasation of FITC-D as compared to control animals (156 ± 27 vs. 11 ± 2 (mean ± SEM, number of WBC/30 seconds mm vessel circumference; P < 0.05) at 90 minutes after PDT and 194 ± 21 vs. 14 ± 4 at 180 minutes after PDT). In contrast, leukocyte sticking was not downregulated by the antibody treatment. CONCLUSION: Leukocyte recruitment plays an essential role in the permeability-enhancing effect of PDT.

Photodynamic therapy selectively enhances liposomal doxorubicin uptake in sarcoma tumors to rodent lungs.

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.

Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.

BACKGROUND: Stage IIIB non-small-cell lung cancer (NSCLC) is usually thought to be unresectable, and is managed with chemotherapy with or without radiotherapy. However, selected patients might benefit from surgical resection after neoadjuvant chemotherapy and radiotherapy. The aim of this multicentre, phase II trial was to assess the efficacy and toxicity of a neoadjuvant chemotherapy and radiotherapy followed by surgery in patients with technically operable stage IIIB NSCLC. METHODS: Between September, 2001, and May, 2006, patients with pathologically proven and technically resectable stage IIIB NSCLC were sequentially treated with three cycles of neoadjuvant chemotherapy (cisplatin with docetaxel), immediately followed by accelerated concomitant boost radiotherapy (44 Gy in 22 fractions) and definitive surgery. The primary endpoint was event-free survival at 12 months. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030810. FINDINGS: 46 patients were enrolled, with a median age of 60 years (range 28-70). 13 (28%) patients had N3 disease, 36 (78%) had T4 disease. All patients received chemotherapy; 35 (76%) patients received radiotherapy. The main toxicities during chemotherapy were neutropenia (25 patients [54%] at grade 3 or 4) and febrile neutropenia (nine [20%]); the main toxicity after radiotherapy was oesophagitis (ten patients [29%]; nine grade 2, one grade 3). 35 patients (76%) underwent surgery, with pneumonectomy in 17 patients. A complete (R0) resection was achieved in 27 patients. Peri-operative complications occurred in 14 patients, including two deaths (30-day mortality 5.7%). Seven patients required a second surgical intervention. Pathological mediastinal downstaging was seen in 11 of the 28 patients who had lymph-node involvement at enrolment, a complete pathological response was seen in six patients. Event-free survival at 12 months was 54% (95% CI 39-67). After a median follow-up of 58 months, the median overall survival was 29 months (95% CI 16.1-NA), with survival at 1, 3, and 5 years of 67% (95% CI 52-79), 47% (32-61), and 40% (24-55). INTERPRETATION: A treatment strategy of neoadjuvant chemotherapy and radiotherapy followed by surgery is feasible in selected patients. Toxicity is considerable, but manageable. Survival compares favourably with historical results of combined treatment for less advanced stage IIIA disease. FUNDING: Swiss Group for Clinical Cancer Research (SAKK) and an unrestricted educational grant by Sanofi-Aventis (Switzerland).

Outcome after extracorporeal membrane oxygenation-bridged lung retransplants: a single-centre experience.

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.