Gavin Plat

Blood inflammatory response to inhaled endotoxin in normal subjects

Previously we have reported that in asthmatics an inhalation of 20 μg lipopolysaccharide (LPS) produces a bronchial obstruction associated with an inflammatory blood response. The aim of the present study was to evaluate this response in normal subjects. Eight normal non‐atopic subjects were challenged by inhalation of a solution containing 20 μg LPS (from Escherichia coli 026:B6) a week after bronchial challenge with control solution. The lung function response was evaluated by the changes in forced expiratory volume in one second (FEV1), in specific conductance and in airway resistance while the blood inflammatory response was evaluated by serial measures of total white blood cells (WBC) and polymorphonuclear neutrophils (PMN) count, luminol enhanced‐chemiluminescence (luminol‐CL, as a marker of the PMN degree of activation), C‐reactive protein (CRP), haptoglobin, complement fraction C3, tumour necrosis factor‐α (TNF‐α) and adrenocorticotropic hormone (ACTH). No response in lung function was observed for 6 h after the LPS inhalation. The count in WBC and PMN increased 300 (P < 0.01) and 360 (P < 0.01) min after the LPS challenge associated with an increase in the level of luminol‐CL (P < 0.001). This rise in luminol‐CL level was significant at 120 min (P < 0.05) before any change in the PMN count. After 24 and 48 h the acute‐phase protein CRP raised significantly (P < 0.01), the other proteins C3 and haptoglobin being unchanged. A slight increase in ACTH was observed 240 and 360 min (P < 0.05) after the LPS challenge while the TNFα detectable level was not modified. In conclusion, in normal subjects, inhalation of a pro‐inflammatory agent is able to induce a systemic inflammatory response in the absence of any effect on lung mechanics, while in asthmatics the same bronchial challenge has been reported to induce a similar blood inflammation associated with a significant response in lung function.

Endobronchial ultrasound and positron emission tomography positive mediastinal lymph nodes

Positron emission tomography with 18F-fluoro-2-deoxy-d-glucose (FDG-PET) is more accurate than computed tomography for staging of mediastinal (hilar) lymph nodes. In the case of positive findings, tissue sampling of lymph nodes is required. The diagnostic/staging yield of transbronchial needle aspiration (TBNA) following endobronchial ultrasound (EBUS) localisation was assessed in this particular clinical setting. The number of avoided surgical procedures was evaluated. All consecutive patients referred for staging and/or diagnosis of mediastinal FDG-PET positive lesions were included. Data were prospectively collected. TBNA sampling of lymph nodes was performed after EBUS localisation. If no diagnosis was reached, further surgical sampling or adequate follow-up was performed. From January 2003 to June 2004, 33 patients were included. The average number of TBNA samples per patient was 4.2±1.5. Cytological or histological diagnoses were obtained in 27 (82%) of the patients, of which 78% were obtained after previous EBUS localisation. In 25 (76%) of the 33 patients, surgical staging procedures were suppressed. In conclusion, transbronchial needle aspiration after endobronchial ultrasound localisation should be considered as a primary method of evaluation of lymph nodes positive by positron emission tomography with 18F-fluoro-2-deoxy-d-glucose, and may replace the majority of surgical mediastinal staging/diagnostic procedures.

Techniques of endoscopic airway tumor treatment

Interventional bronchoscopy has a predominant role in the management of both early and advanced-stage airway tumors. Given the very poor prognosis of lung cancer, there is a need for new tools to improve early detection and bronchoscopic treatment of endo-bronchial precancerous lesions. In more advanced stages, interventional bronchoscopy plays an important role, as nearly a third of lung cancers lead to proximal airway obstruction. This will cause great discomfort or even life-threatening symptoms related to local extension, such as dyspnea, post-obstructive pneumonia, and hemoptysis. Surgery for very locally advanced disease is only effective for a limited number of patients and the effects of conventional antitumor therapies, like radiation therapy or chemotherapy, are inconstant and are too delayed in a palliative context. In this review, we aim to provide pulmonologists with an exhaustive technical overview of (I) the bronchoscopic management of benign endobronchial lesions; (II) the bronchoscopic management of malignant tumors, including the curative treatment of localized lesions and palliative management of malignant proximal airway stenosis; and (III) descriptions of the emerging endoscopic techniques used to treat peripheral lung tumors.

Stenting of Complex Malignant Central-Airway Obstruction Guided by a Three-Dimensional Printed Model Of The Airways

Conversion of anatomic images into physical objects using three-dimensional printing (3DP) is changing the way surgeons anticipate selected technical challenges. We report herein a case of malignant central airway obstruction in the right main bronchus. Because stenting of the primary right carina is difficult, as it depends on many diameters and distance measurements, we used 3DP to plan and guide the procedure. After virtual resolution of the extrinsic compression, a three-dimensional printed model of the airways helped us choose the model and dimensions of the stent, and allowed us to modify its accuracy before insertion.

Integration of 3D printing and additive manufacturing in the interventional pulmonologist's toolbox

New 3D technologies are rapidly entering into the surgical landscape, including in interventional pulmonology. The transition of 2D restricted data into a physical model of pathological airways by three-dimensional printing (3DP) allows rapid prototyping and fabrication of complex and patient-specific shapes and can thus help the physician to plan and guide complex procedures. Furthermore, computer-assisted designed (CAD) patient-specific devices have already helped surgeons overcome several therapeutic impasses and are likely to rapidly cover a wider range of situations. We report herein with a special focus on our clinical experience: i) how additive manufacturing is progressively integrated into the management of complex central airways diseases; ii) the appealing future directions of these new technologies, including the potential of the emerging technique of bioprinting; iii) the main pitfalls that could delay its introduction into routine care.

Use of Ultrasonography for Lung Transplant Recipients on Postoperative Care: Use of Ultrasonography for Lung Transplant Recipients

The authors report their findings regarding lung ultrasound profiles in a population of transplant recipients. Twenty‐two patients were studied once each in multiple different ultrasound windows focusing on pleural, lung, and diaphragmatic signatures. All studies were performed in presumably otherwise healthy recipients at an outpatient follow‐up visit at least 3 months after transplantation. Those with recent pulmonary infections or decline in lung function were excluded from enrollment. The majority of scans revealed otherwise normal lungs with lung sliding, but there were more abnormalities than one would expect in a healthy control group.

Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non–Small-cell Lung Cancer: A Phase I Study

INTRODUCTION Because of our previous preclinical results, we conducted a phase I study associating the specific αvβ3/αvβ5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.

1208PCONTINUOUS INFUSION OF CILENGITIDE WITH RADIO-CHEMOTHERAPY IN STAGE III NSCLC: A PHASE I STUDY

ABSTRACT Aim: We have shown that avb3 integrins control radioresistance, hypoxia and angiogenesis and that co-expression of FGF-2 and avb3 integrins in the tumors of patients treated with exclusive radio-chemotherapy for stage III non-small lung carcinoma (NSCLC), was associated with a worse local control, suggesting that inhibition of avb3 integrin could induce a radiosensitization of such tumours. We designed a phase I trial associating the specific avb3/avb5 integrin inhibitor cilengitide with radio-chemotherapy in patients with stage III NSCLC. Methods: A standard 3 + 3 dose escalation design was used. Cilengitide was given in continuous infusion starting 2 weeks before and then during the whole course of the radio-chemotherapy (66 Gy combined with a Platine-Navelbine regimen), and then at a dose of 2000 mg twice a week in association with chemotherapy. Planed Cilengitide continuous infusion dose levels were 12, 18, 27 and 40 mg/h. PET-FDG and CT scan were performed before and then after the first two weeks of Cilengitide administration and then 2 months after the end of radio-chemotherapy. Patients were followed by CT scan. Toxicity for DLT was assessed during combined treatment and until 1 month after. Clinical response on CT scan and TEP was evaluated according to RECIST and PERCIST criteria. Results: Fourteen patients were included between March 2010 and July 2013. Eleven patients were evaluable for DLT. No DLT was observed at level 0, 1 and 2. One DLT, a tracheo-bronchial fistula was reported at the 40 mg/h dose. No relevant adverse event related to Cilengitide (7 grade 1 and one grade 2) was observed on the whole population. Among 11 patients evaluable for efficacy, 9 patients presented a partial response and 2 a stable disease. At 6 months after the end of radio-chemotherapy, 2 patients presented a progressive disease. At PET evaluation 2 months after radio-chemotherapy, 4 patients had a complete response and 4 patients had a partial response. Conclusions: Cilengitide given continuously with radio-chemotherapy was well tolerated and shows encouraging clinical results, suggesting that targeting avb3 integrin continuously during radio-chemotherapy in NSCLC is a promising approach to treat this disease. Disclosure: E.L. Cohen-Jonathan Moyal: E Moyal has been member of an advisory board for Merck KGaA and received a funding grant from Merck KGaA for research. All other authors have declared no conflicts of interest.