This is the experience with the Stratos system in two surgical centres for the management of two types of rib fractures: flail chest and multiple dislocated rib fractures with significant chest wall deformity.
Antibody-drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30(+) malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies.
Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small-cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. In 2009, the International Association for the Study of Lung Cancer (IASLC) introduced a new lymph node map. Some changes in this map have an important impact on mediastinal staging. Moreover, more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of computed tomography (CT)-enlarged or positron emission tomography (PET)-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography [endobronchial ultrasonography (EBUS)/esophageal ultrasonography (EUS)] with fine-needle aspiration (FNA) is the first choice (when available), since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred to mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumours ? 3 cm located in the outer third of the lung. In central tumours or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and FNA or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumours >3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high standardized uptake value. For restaging, invasive techniques providing histological information are advisable. Both endoscopic techniques and surgical procedures are available, but their negative predictive value is lower compared with the results obtained in baseline staging. An integrated strategy using endoscopic staging techniques to prove mediastinal nodal disease and mediastinoscopy to assess nodal response after induction therapy needs further study.
In addition to direct tumor cell cytotoxicity, chemotherapy can mediate tumor reduction through immune modulation of the tumor microenvironment to promote anti-tumor immunity. Mature dendritic cells (DCs) play key roles in priming robust immune responses in tumor-bearing hosts. Here, we screened a panel of 21 anticancer agents with defined molecular targets for their ability to induce direct maturation of DCs. We identified ansamitocin P3, a microtubule-depolymerizing agent, as a potent inducer of phenotypic and functional maturation of DCs. Exposure of both murine spleen-derived and human monocyte-derived DCs to ansamitocin P3 triggered up-regulation of maturation markers and production of pro-inflammatory cytokines, resulting in an enhanced T cell stimulatory capacity. Local administration of ansamitocin P3 induced maturation of skin Langerhans cells in vivo and promoted antigen uptake and extensive homing of tumor-resident DCs to tumor-draining lymph nodes. When used as an adjuvant in a specific vaccination approach, ansamitocin P3 dramatically increased activation of antigen-specific T cells. Finally, we demonstrate that ansamitocin P3, due to its immunomodulatory properties, acts in synergy with antibody-mediated blockade of the T cell inhibitory receptors PD-1 and CTLA-4. The combination treatment was most effective and induced durable growth inhibition of established tumors. Mechanistically, we observed a reduced regulatory T cell frequency and improved T cell effector function at the tumor site. Taken together, our study unravels an immune-based anti-tumor mechanism exploited by microtubule-depolymerizing agents, including ansamitocin P3, and paves the way for future clinical trials combining this class of agents with immunotherapy.
A 85-year-old man presented to the emergency department with acute onset of right-sided chest pain after vigorous coughing. Physical examination revealed a progressive hematoma and a palpable bulge that enlarged with expiration. A CT-Scan confirmed a lateral lung herniation with a dissection of the intervertebral muscle. The Patient underwent a surgical reconstruction of the chest wall defect and an additional Mersilene Mesh repair of a consecutive diaphragmal rupture. The patient had an uneventful recovery and was discharged on postoperative day 11.
Bronchiolitis obliterans is a complication after allogeneic haematopoietic stem cell transplantation (HSCT). Management of bronchiolitis obliterans comprises intensive immunosuppression, but treatment response is poor. We investigated the effect of cyclosporine A (CsA), tacrolimus (FK506), methylprednisolone (mPRED), mycophenolate mofetil (MMF) and everolimus on the proliferation of primary lung myofibroblasts from HSCT patients with bronchiolitis obliterans syndrome (BOS). Cells were isolated from surgical lung biopsies of eight HSCT patients with BOS. Proliferation was assessed by [(3)H]-thymidine incorporation. Biopsies revealed constrictive bronchiolitis obliterans in three patients and lymphocytic bronchiolitis in five patients. CsA and FK506 significantly induced proliferation of myofibroblasts. mPRED and MMF caused a significant inhibition of proliferation, whereas everolimus had no effect. Costimulation with FK506, mPRED and MMF significantly inhibited proliferation. Serial pulmonary function tests over 12 months after lung biopsy and under triple therapy demonstrated that patients with lymphocytic bronchiolitis had a significant improvement in forced expiratory volume in 1 s (FEV1), whereas FEV1 of patients with bronchiolitis obliterans was unchanged. Our data demonstrate a pro-proliferative effect of calcineurin inhibitors on primary human lung myofibroblasts obtained from patients with BOS after HSCT. In contrast, based on the observed antiproliferative capacity of MMF in vitro, MMF-based calcineurin inhibitor-free treatment strategies should be further evaluated in patients with bronchiolitis obliterans after HSCT.
Mesenchymal cells (fibroblasts) of the airway wall respond to cholinergic stimulation by releasing pro-inflammatory and chemotactic cytokines and may thus contribute to chronic inflammation of the lung. Here, we studied the anti-inflammatory potential of olodaterol, a long acting ?2-adrenergic receptor agonist, and tiotropium, a long-acting muscarinic receptor antagonist, and whether they interact at the level of the cyclic AMP dependent signaling pathway. Pulmonary fibroblasts of asthmatic (n = 9) and non-asthmatic (n = 8) subjects were stimulated with the muscarinic receptor agonist carbachol and interleukin-1? (IL-1 beta) in presence or absence of tiotropium or olodaterol alone, or their combination. We also measured cAMP levels and phosphorylation of the cAMP response element binding protein (CREB). As single components, carbachol, olodaterol and tiotropium did not affect IL-6 and IL-8 release. Carbachol concentration-dependently enhanced the production of IL-1?-induced IL-6 and IL-8, which was blocked by the simultaneous addition of tiotropium. The combination of olodaterol plus tiotropium further reduced IL-6 and IL-8 release. Olodaterol induced cAMP and the phosphorylation of CREB, an effect counteracted by carbachol, but rescued by tiotropium. We conclude that olodaterol plus tiotropium cooperate to decrease the inflammatory response in pulmonary fibroblasts in vitro.
Bronchiolitis obliterans (BO) is a severe complication after allogeneic hematopoietic stem cell transplantation with an unfavorable prognosis. Lung biopsy remains the gold standard for diagnosis. In this retrospective single-center study, we describe 33 patients who underwent biopsy for suspected BO. Ten patients had constrictive BO (CBO); 9 had lymphocytic bronchiolitis (LB), characterized by lymphocytic infiltration of the bronchioles. Six additional patients (4, CBO; 2, LB) had concomitant infection; 8 had other pathological diagnoses. Seven patients with CBO and 3 with LB met the National Institutes of Health consensus BO syndrome definition criteria. An additional 7 patients with histologically confirmed CBO did not meet the consensus definition, 4 of them because of concomitant airway infection. At diagnosis, there were no significant differences between the CBO and LB groups in clinical presentation; pulmonary function tests (median forced expiratory volume in one second [FEV1] at baseline, 90.4% and 99% predicted, at time of video-assisted thoracoscopic surgery, 55.1% and 60.8% for CBO and LB groups, respectively); and chest scans. Treatment was similar in both groups but outcome was different depending on histological findings. FEV1 significantly improved in LB patients compared with CBO patients. Survivals at 1 and 3 years were 77% ± 12% and 60% ± 14% for patients with CBO and 91% ± 9% for patients with LB (P = .028). Lung biopsy in patients with suspected BO enables better characterization of the pattern of BO syndrome. In contrast to CBO, LB is associated with a good long-term prognosis.
It has been substantiated that the quality of pleurodesis is reduced when non-steroidal anti-inflammatory drugs (NSAIDs) are used perioperatively. The effects of NSAID administration on the early inflammatory and fibrinolytic processes after mechanical pleurodesis were investigated in an established pig model.
Airway wall remodelling is a key pathology of asthma. It includes thickening of the airway wall, hypertrophy and hyperplasia of bronchial smooth muscle cells (BSMC), as well as an increased vascularity of the sub-epithelial cell layer. BSMC are known to be the effector cells of bronchoconstriction, but they are increasingly recognized as an important source of inflammatory mediators and angiogenic factors.
Restaging of patients with locally advanced non-small-cell lung cancer (NSCLC) is of paramount importance, since only patients with down-staging after induction therapy will benefit from surgery. In this study, we assessed the aetiology of new (18)fluoro-2-deoxy-d-glucose (FDG)-positive focal abnormalities on restaging positron emission tomography/computed tomography (PET/CT) in patients with a good response after induction chemotherapy in the primary tumour and lymph nodes.
The thymus selects T cells, thus ensuring T cell tolerance. Thymoma can be associated with immune dysregulation manifesting as autoimmunity and/or immunodeficiency. Immune dysregulation in thymoma patients has only been described in case reports and small case series. The current study was a retrospective single-center study, covering the period 1/2000 to 12/2010. Clinical data were collected by chart review. We identified 29 patients with thymoma. The median age at diagnosis was 60 years (range: 23-87). Median follow-up time was 1,326 days (range: 15-3,710), and 20 patients (69%) were alive at last follow-up. Overall, in 13 of 29 patients (45%) autoimmunity and infection were observed in 7 of 29 (24%) and 3 of 29 patients (10%) infection and autoimmunity only was observed, respectively. Both opportunistic and nonopportunistic infections were recorded. Myasthenia gravis (10 of 29 patients) was the most frequent autoimmune disease. Additional entities included pemphigus, pure red cell aplasia, lichen planus, Sjögrens syndrome, systemic lupus erythematosus (n = 2 each), and cutaneous lupus erythematosus, sarcoidosis, vitiligo, polymyositis, and chronic inflammatory demyelinating polyradiculoneuropathy (n = 1 each). Six of 29 patients (21%) had more than 1 autoimmune disorder. In thymoma patients, infection, autoimmunity, and in particular a combination of both pose a challenge to treating physicians. Prospective multicenter studies are required to more precisely define the thymoma-associated immune dysregulation syndrome.
Thoracic surgery mandates usually a one-lung ventilation (OLV) strategy with the collapse of the operated lung and ventilation of the non-operated lung. These procedures trigger a substantial inflammatory response. The aim of this study was to analyze the cytokine and chemokine reaction in both lungs, pleural space and blood in patients undergoing lung resection with OLV with special interest in the chemokine growth-regulated peptide alpha (GRO?) which is the human equivalent to the rat cytokine-induced neutrophil chemoattractant-1 (CINC-1).
Primary mediastinal lymph node staging is important to select properly patients who can benefit from an induction treatment. The accuracy of CT scan in the evaluation of mediastinal lymph nodes is low. Further staging can be omitted in patients with negative mediastinal PET in most of the cases. PET positive findings should always be histologically or cytologically confirmed. Endoscopic techniques are accurate minimally invasive techniques mostly used to confirm a PET-positive finding but not for complete mediastinal staging. Mediastinoscopy is an invasive technique which provides a complete statging of the upper mediastinum. At least one ipsilateral, one contralateral and the subcarinal nodes should be routinely biopsied. Restaging of the mediastinum after induction treatment is necessary to select the patients who can benefit from surgery. There are no imaging techniques which can accurately determine the biological response of the tumour to the induction treatment. Neither CT, PET or PET-CT seem good enough to make further therapeutic decisions, based on their results. The accuracy of PET in mediastinal restaging is not optimal, mainly due to its low sensitivity. Fusion images with PET-CT seem to improve the results with a very favourable sensitivity, specificity and accuracy. An invasive technique providing cytohistological information is necessary. For restaging techniques, endoscopic techniques or surgical invasive techniques can be used. If they yield a positive result, definitive nonsurgical treatment seems to be indicated in most patients. Remediastinoscopy has proven to be feasible but due to adhesions and fibrosis, the intervention is technically challenging. The technique of lymph-node assessment during surgery for non-small-cell lung cancer (NSCLC) is not standardised to date. Accurate intra-operative staging is necessary to compare the results from different institutions and to conduct multi-institutional trials. Systematic mediastinal lymph-node dissection is recommended in all cases for complete resection of NSCLC and improves pathologic staging and the prospect for adjuvant therapy. The role of mediastinal lymphadenectomy regarding overall survival and local control remains controversial but systematic lymph-node dissection might be associated with a better outcome in stage I NSCLC. Lobe-specific systematic nodal dissection is acceptable for peripheral squamous T1 tumours, if hilar and interlobar nodes are negative on frozen section studies.
Pleural malignant mesothelioma is a rare but deadly tumour mainly induced by asbestos inhalation. Despite the ban of asbestos in 1990 in 52 countries, mesothelioma cases still increase worldwide. In pleural mesothelioma, p38 mitogen activated protein kinases (MAPK) have been suggested to play a major role in carcinogenesis and aggressiveness of tumours. The aim of this study was to determine the role of the different four p38 MAPK isoforms and their effect on proliferation together with the underlying signalling pathways in a rat pleural mesothelioma cell line. Rat pleural mesothelioma cells were stimulated with platelet-derived growth factor (PDGF)-BB and/or transforming growth factor beta (TGF)-?. MAPK and transcription factor expression and activation was monitored in the cytosol and nucleus by immuno-blotting. Proliferation was determined by manual cell count and siRNAs were used to control MAPK and transcription factor expression and action. Only PDGF-BB, but not TGF-?1 induced proliferation via activated Erk1/2 and p38 MAPK. The p38? and ? isoforms were expressed in the cytosol, and upon activation p38? translocated into the nucleus, while p38? remained in the cytosol. No other p38 isoform was expressed by rat mesothelioma cells. C/EBP-? was found in both the cytosol and the nucleus, while C/EBP-? was not expressed at all. PDGF-BB induced proliferation was suppressed by down-regulation of either Erk1/2, or p38? MAPK, or C/EBP-?. Furthermore, TGF-? inhibited PDGF-BB induced proliferation by interruption of p38 MAPK signalling. From this rat model, we conclude that in pleural mesothelioma, p38? in C/EBP-? mediate proliferation and thus may represent new targets in mesothelioma therapy.
We present an unusual case of a contralateral recurrence of malignant solitary fibrous tumor of the pleura (SFTP) nine years after a complete resection. Recurrence of malignant SFTP has already been described, but is usually localized. In our case the patient underwent surgical resection for a malignant SFTP of the left upper lobe in 2000. Nine years later computed tomography (CT)-scans showed lesions that were suspicious of tumor recurrence in the right lung. Thoracoscopy, wedge-resections and pathological findings revealed four nodules of a malignant SFTP of the right middle and lower lobe, histopathologically identical to the tumor, which had been resected nine years ago. A coincidental mucinous bronchioloalveolar carcinoma of the left lower lobe was resected by thoracotomy. To our knowledge this is the first report of contralateral recurrence of a malignant SFTP years after complete resection in the literature. The possibility of a new primary tumor on the right with local metastasis could not be excluded in the clinical and histopathological examinations. Therefore, contralateral recurrence of malignant SFTP should be considered in the postoperative follow-up even years after complete resection.
Anastomotic complications following lung transplantation (LuTx) have been described in up to 15% of patients. Challenging to treat, they are associated with high morbidity and a mortality rate of 2-5%. The aim of this study was to analyze the incidence of complications in a consecutive series of bronchial anastomosis after LuTx at our center and to delineate the potential risk factors.
The purpose of this study was to evaluate whether favorable short-term results achieved by lung volume reduction surgery in selected patients with homogeneous emphysema would persist for longer periods. Their symptoms, lung function, and survival for several years were analyzed in comparison to patients with heterogeneous emphysema.
To investigate the diagnostic value of whole-body magnetic resonance imaging (MRI) including diffusion-weighted imaging with background signal suppression (DWIBS) for preoperative assessment of non-small-cell lung cancer (NSCLC) in comparison to (18)F-fluorodeoxyglucose (18)FDG) positron emission tomography/computed tomography (PET/CT).
Background. Calreticulin controls the C/EBP?p42/p30 at the translational level trough a cis-regulatory CNG rich loop in the CEBPA mRNA. We determined the effects of steroids and long-acting beta-agonists on the p42/p30 ratio and on calreticulin expression in primary human bronchial smooth muscle (BSM) cells. Methods. The effects of budesonide (10(-8)?M) and formoterol (10(-8)?M) were studied in BSM cells pre-treated with siRNA targeting calreticulin. The expression of C/EBP? and calreticulin was determined by immuno-blotting. Automated cell counts were performed to measure proliferation. Results. All tested BSM cell lines (n = 5) expressed C/EBP? and calreticulin. In the presence of 5% FBS, the p42/p30 ratio significantly decreased (n = 3, P < 0.05) and coincided with BSM cell proliferation. High levels of calreticulin were associated with a decreased p42/p30 isoform ratio. FBS induced the expression of calreticulin (n = 3, P < 0.05), which was further increased by formoterol. siRNA targeting calreticulin increased the p42/p30 ratio in non-stimulated BSM cells and significantly inhibited the proliferation of PDGF-BB-stimulated BSM cells (n = 5, P < 0.05). Neither budesonide nor formoterol restored the p42 isoform expression. Conclusions. Our data show calreticulin is a negative regulator of C/EBP? protein expression in BSM cells. Modulation of calreticulin levels may provide a novel target to reduce BSM remodeling.
Pulmonary invasive fungal disease is a frequent complication in patients with hematologic malignancies. Surgical resection in addition to antifungal therapy is an option for selected cases but often feared because of immunosuppression.
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