Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts.

A key unknown of the functional space in tumor immunity is whether CD4 T cells depend on intratumoral MHCII cancer antigen recognition. MHCII-expressing, antigen-presenting cancer-associated fibroblasts (apCAFs) have been found in breast and pancreatic tumors and are considered to be immunosuppressive. This analysis shows that antigen-presenting fibroblasts are frequent in human lung non-small cell carcinomas, where they seem to actively promote rather than suppress MHCII immunity. Lung apCAFs directly activated the TCRs of effector CD4 T cells and at the same time produced C1q, which acted on T cell C1qbp to rescue them from apoptosis. Fibroblast-specific MHCII or C1q deletion impaired CD4 T cell immunity and accelerated tumor growth, while inducing C1qbp in adoptively transferred CD4 T cells expanded their numbers and reduced tumors. Collectively, we have characterized in the lungs a subset of antigen-presenting fibroblasts with tumor-suppressive properties and propose that cancer immunotherapies might be strongly dependent on in situ MHCII antigen presentation.

Activin-A impedes the establishment of CD4+ T cell exhaustion and enhances anti-tumor immunity in the lung.

BACKGROUND: Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer. METHODS: To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A's function. In a translational approach, we validated activin-A's anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients. RESULTS: Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells. CONCLUSIONS: In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity.

Recent advances in sequencing technologies have allowed the in-depth molecular study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and to facilitate recurrence, metastasis, and drug resistance. In the current study, focused on early-stage operable non-small cell lung cancer, we used tumor growth in patient-derived xenograft (PDX) models in mice as a fast-forward tumor evolution process to investigate the molecular characteristics of tumor cells that grow in mice, as well as the parameters that affect the grafting efficiency. We found that squamous cell carcinomas grafted significantly more efficiently compared with adenocarcinomas. Advanced stage, patient age and primary tumor size were positively correlated with grafting. Additionally, we isolated and characterized circulating tumor cells (CTC) from patients' peripheral blood and found that the presence of CTCs expressing epithelial-to-mesenchymal (EMT) markers correlated with the grafting potential. Interestingly, exome sequencing of the PDX tumor identified genetic alterations in DNA repair and genome integrity genes that were under-represented in the human primary counterpart. In conclusion, through the generation of a PDX biobank of NSCLC, we identified the clinical and molecular properties of tumors that affected growth in mice.

Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma.

Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.

Surgical Management of Non-small Cell Lung Cancer with Solitary Hematogenous Metastases.

BACKGROUND/AIM: The treatment of patients with solitary hematogenous metastases from non-small cell lung cancer (NSCLC) remains controversial, although numerous retrospective studies have reported favorable results for patients offered combined surgical therapy. Our aim was to determine the role of surgical resection in the management of NSCLC with solitary extrapulmonary metastases and to investigate for possible prognostic factors. PATIENTS AND METHODS: Between January 2004 and December 2012, 12 patients with NSCLC, from two Institutions, underwent metastasectomy for their solitary metastatic lesion. Sites of metastases included brain (n=3), adrenal gland (n=6), thoracic wall (n=2) and diaphragm (n=1). All patients had undergone pulmonary resections for their primary NSCLC. RESULTS: Median survival for the entire cohort was 24.1 months, whereas 1- and 5-year survival rates were 73% and 39%, respectively. Patients with stage III intrathoracic disease had significantly worse survival than those with lower tumor stage. A tendency for adenocarcinomatous histology to positively affect survival was recognized, although it was proven not to be statistically significant. CONCLUSION: Despite the retrospective nature of our study and the small cohort size, it is emerging that combined surgical resection might offer patients with NSCLC with solitary hematogenous metastases a survival benefit. Limited intrathoracic disease and adenocarcinomatous histology might be associated with better outcomes.

A Novel Technique to Treat Air Leak Following Lobectomy: Intrapleural Infusion of Plasma.

BACKGROUND Persistent air leak following pulmonary lobectomy can be very difficult to treat and results in prolonged hospitalization. We aimed to evaluate the efficacy of a new method of postoperative air leak management using intrapleurally infused fresh frozen plasma via the chest tube. MATERIAL AND METHODS Between June 2008 and June 2014, we retrospectively reviewed 98 consecutive patients who underwent lobectomy for lung cancer and postoperatively developed persistent air leak treated with intrapleural instillation of fresh frozen plasma. RESULTS The study identified 89 men and 9 women, with a median age of 65.5 years (range 48-77 years), with persistent postoperative air leak. Intrapleural infusion of fresh frozen plasma was successful in stopping air leaks in 90 patients (92%) within 24 hours, and in 96 patients (98%) within 48 hours, following resumption of the procedure. In the remaining 2, air leak ceased at 14 and 19 days. CONCLUSIONS Intrapleural infusion of fresh frozen plasma is a safe, inexpensive, and remarkably effective method for treatment of persistent air leak following lobectomy for lung cancer.

Major Lung Resections Using Manual Suturing Versus Staplers During Fiscal Crisis.

AbstractObjective: During fiscal crisis there was a period of shortage of staplers in our hospital, which drove us to manual suturing of bronchi and pulmonary vessels during major lung resections. We present our experience during that period in comparison to a subsequent period when staplers became available again. METHODS: A total of 256 lobectomies and 78 pneumonectomies were performed using manual suturing (group A), between September 2009 and September 2010, and compared regarding surgical outcome to 248 lobectomies and 60 pneumonectomies using staplers (group B), between September 2011 and September 2012. RESULTS: Although we did not observe statistically significant differences but only a trend towards less operative time, for both lobectomies (p=0.21) and pneumonectomies (p=0.31), we actually noted a 41 and 47 minutes saving of operative time using staplers (group B), in comparison to manual suturing (group A). We also observed a trend towards less morbidity rates in patients of group B, who underwent lobectomy (10.48%), and pneumonectomy (20%), versus patients of group A, who underwent lobectomy (15.62%), and pneumonectomy (30.76%); we did not observe any substantial differences in the other surgical outcome variables, and in patients' demographics comorbidities, and anatomic allocation of surgical procedures performed. CONCLUSIONS: The use of staplers offers safety with secure bronchial or vascular sealing, and saving of operative time. Their unavailability at an interval during fiscal crisis although it did not affect surgical outcome, revealed their usefulness and value.

Is it safe and worthwhile to perform pulmonary resection after contralateral pneumonectomy?

A best evidence topic was written according to a structured protocol. The question addressed was whether pulmonary resection is safe and worthwhile in patients who have undergone previous pneumonectomy. A total of 141 studies were identified using the reported search, of which 8 represented the best evidence to answer the clinical question. Studies on multiple lung cancers with patients undergoing subsequent pulmonary resection after previous pneumonectomy, without outcome data specifically for this group of patients and case reports, were not included in this analysis. The authors, date, journal, country, study type, population, outcomes and key results are tabulated. All studies were retrospective. In total, 102 patients underwent pulmonary resection after contralateral pneumonectomy, of which 96 had sublobar resections and 6 had lobectomies. Postoperative complications, reported in four of the eight studies, ranged from 21 to 44% (mean from four studies 36.8%). Four of the eight studies reported no mortality after pulmonary resection following pneumonectomy, whereas the other four reported mortality rates from 6.7 to 43%. For patients undergoing sublobar resections, the postoperative mortality was 6.2% (6/96), while for those submitted to lobectomy, mortality was 33.3% (2/6). Five-year survival rates ranged from 14% for metastatic disease to 50% for metachronous lung cancer. Due to the infrequent situation of a patient being considered for a pulmonary resection after contralateral pneumonectomy, this analysis was based on a limited number of patients from eight reports. Nevertheless, analysis of the data suggests that pulmonary resection for metastatic or metachronous disease can be performed with acceptable morbidity and low mortality in appropriately selected patients who have previously undergone a pneumonectomy. Sublobar resection is the treatment of choice whenever possible, for which long-term results are rewarding especially for patients with metachronous lung cancer.

Tolerogenic signaling by pulmonary CD1c+ dendritic cells induces regulatory T cells in patients with chronic obstructive pulmonary disease by IL-27/IL-10/inducible costimulator ligand.

BACKGROUND: Increased mortality rates in patients with chronic obstructive pulmonary disease (COPD) are largely due to severe infectious exacerbations. Impaired respiratory immunity is linked to the enhanced susceptibility to infections. Dendritic cells (DCs) direct host immune responses toward immunity or tolerance. Pulmonary CD1c(+) DCs elicit robust antiviral immune responses in healthy subjects. Nevertheless, their functional specialization in patients with COPD remains unexplored. OBJECTIVE: We sought to better understand the mechanisms that suppress respiratory immunity in patients with COPD by examining the immunostimulatory and tolerogenic properties of pulmonary CD1c(+) DCs. METHODS: We analyzed the expression of costimulatory and tolerogenic molecules by pulmonary CD1c(+) DCs from patients with COPD (CD1c(+)DCCOPD) and former smokers without COPD. We isolated lung CD1c(+) DCs and determined their ability to stimulate allogeneic T-cell responses. The suppressive effects of lung CD1c(+) DCs and CD1c(+) DC-primed T cells on mixed leukocyte reactions were examined. An experimental human model of COPD exacerbation was used to investigate the levels of critical immunosuppressive molecules in vivo. RESULTS: CD1c(+) DCs from patients with COPD hinder T-cell effector functions and favor the generation of suppressive IL-10-secreting CD4(+) T cells that function through IL-10 and TGF-ß. IL-27, IL-10, and inducible T-cell costimulator ligand signaling are essential for CD1c(+)DCCOPD-mediated differentiation of IL-10-producing suppressive T cells. Exposure of lung CD1c(+) DCs from nonobstructed subjects to lungs of patients with COPD confers tolerogenic properties. IL-27 and IL-10 levels are increased in the lung microenvironment on rhinovirus-induced COPD exacerbation in vivo. CONCLUSION: We identify a novel tolerogenic circuit encompassing suppressive CD1c(+) DCs and regulatory T cells in patients with COPD that might be implicated in impaired respiratory immunity and further highlight IL-10 and IL-27 as potent therapeutic targets.

Pulmonary hypertension after pneumonectomy for lung cancer.

BACKGROUND: We aimed to consolidate our clinical observations regarding the development of pulmonary hypertension following pneumonectomy for lung cancer. METHODS: Sixty-nine of 82 initially selected patients without pulmonary or cardiac comorbidities, who underwent pneumonectomy for lung cancer between October 2009 and October 2011, accomplished our protocol. Mean patient age was 60.6 years (range 44-78 years) and 10.1% were women. RESULTS: Postoperative complications occurred in 16 (23.2%) patients. Mortality at 1, 12, and 18 months postoperatively was 4.3%, 15.9%, and 29%, respectively. One year postoperatively, 37.9% of patients developed mild to moderate pulmonary hypertension and 3.4% had severe pulmonary hypertension. The calculated mean pulmonary artery systolic pressure at 1, 6, and 12 months postoperatively was 21.9 ± 6.6, 27.3 ± 9.3, and 34.1 ± 14 mm Hg, respectively (p < 0.001). Receiver operating characteristic curve analysis showed a cutoff point at 35.5 mm Hg for late postoperative (at 12 months) pulmonary artery systolic pressure (sensitivity 80%, specificity 82%; p < 0.001) related to suboptimal clinical outcomes (decreased performance status or death), with a detected 18-fold risk for these patients (p < 0.001). CONCLUSIONS: Pulmonary hypertension may occur after pneumonectomy with its known adverse effects. Patients with late postoperative pulmonary artery systolic pressure > 35.5 mm Hg are at higher risk of a suboptimal clinical outcome.

CXCL13 production in B cells via Toll-like receptor/lymphotoxin receptor signaling is involved in lymphoid neogenesis in chronic obstructive pulmonary disease.

RATIONALE: Little is known about what drives the appearance of lymphoid follicles (LFs), which may function as lymphoid organs in chronic obstructive pulmonary disease (COPD). In animal infection models, pulmonary LF formation requires expression of homeostatic chemokines by stromal cells and dendritic cells, partly via lymphotoxin. OBJECTIVES: To study the role of homeostatic chemokines in LF formation in COPD and to identify mechanism(s) responsible for their production. METHODS: Peripheral lung homeostatic chemokine and lymphotoxin expression were visualized by immunostainings and quantified by ELISA/quantitative reverse transcriptase-polymerase chain reaction in patients with COPD with and without LFs. Expression of lymphotoxin and homeostatic chemokine receptors was investigated by flow cytometry. Primary lung cell cultures, followed by ELISA/quantitative reverse transcriptase-polymerase chain reaction/flow cytometry, were performed to identify mechanisms of chemokine expression. Polycarbonate membrane filters were used to assess primary lung cell migration toward lung homogenates. MEASUREMENTS AND MAIN RESULTS: LFs expressed the homeostatic chemokine CXCL13. Total CXCL13 levels correlated with LF density. Lung B cells of patients with COPD were important sources of CXCL13 and lymphotoxin and also expressed their receptors. Cigarette smoke extract, H2O2, and LPS exposure up-regulated B cell-derived CXCL13. The LPS-induced increase in CXCL13 was partly mediated via lymphotoxin. Notably, CXCL13 was required for efficient lung B-cell migration toward COPD lung homogenates and induced lung B cells to up-regulate lymphotoxin, which further promoted CXCL13 production, establishing a positive feedback loop. CONCLUSIONS: LF formation in COPD may be driven by lung B cells via a CXCL13-dependent mechanism that involves toll-like receptor and lymphotoxin receptor signaling.

Sleeve lobectomy for patients with non-small-cell lung cancer: a simplified approach.

OBJECTIVE: Pulmonary parenchyma-saving procedures, indicated for central tumours, seem to have better results than pneumonectomy, an alternative procedure. The purpose of this study is to report our experience at our institution with sleeve lobectomy with regard to surgical technique and outcome. METHODS: We retrospectively reviewed the records of 45 patients who underwent sleeve lobectomy for non-small-cell lung cancer, with a curative intent, during the period of January 2004 and January 2008. Four of these patients underwent bronchovascular reconstructive procedures. A minor modification of the running suture technique used for bronchoplasties is described here. RESULTS: The study identified 40 men and five women with a median age of 64 years (range: 24-80 years). All 45 patients underwent oncological resections with negative results for malignancy bronchial resection margins. Neither bronchial nor vascular complications occurred. Complications were observed in 15% of our patients and included prolonged air leak in three, atelectasis needing daily bronchoscopy in three and respiratory failure due to pneumonia in one patient, who eventually died, accounting for a mortality rate of 2%. The follow-up period ranged from 1 to 52 months, with a median of 26 months, and it was complete for 43 (96%) of the patients. The overall 4-year survival was 57%. CONCLUSIONS: Sleeve lobectomy for lung cancer, although technically demanding, is associated with low morbidity and mortality and satisfactory immediate and long-term results. With increasing experience, more lung-sparing procedures should be performed in selected patients.

Clear-cut complete rupture of origin of right main bronchus.

Complete rupture of the main bronchus after blunt thoracic trauma is rare. Most patients with blunt traumatic injury to the trachea or bronchus die before arriving at hospital. A 26-year-old man with complete right main bronchus rupture was successfully treated by urgent surgical intervention and postoperative fiberoptic bronchoscopy for bronchial toilet.

An unusual case of a swallowed thermometer perforated in the mediastinum.

A 39-year-old woman, who was addicted to drugs, was admitted because of referred chest pain and dysphagia after deliberate ingestion of a thermometer in a suicide attempt 6 hours earlier. Rigid esophagoscopy was unrevealing. On awakening, the patient confessed that the thermometer had been swallowed more than a month be operated on and get narcotic pain medications. Her history disclosed multiple admissions and laparotomies after suicide attempts with swallowed thermometers in the last 3 years.

Video-thoracoscopic and open surgical management of thoracic empyema.

PURPOSE: To evaluate the outcomes of video-thoracoscopic and open surgical management of patients with thoracic empyema. METHODS: We studied 122 patients retrospectively who underwent surgery for thoracic empyema in our hospital between January, 1999 and January, 2005. Patients' medical records, surgical procedures, and outcomes were reviewed. The study identified 97 affected men and 25 affected women with a mean age of 54 years (range 16-78 years). The empyema was parapneumonic in 95 patients (78%). RESULTS: Forty-four patients who had stage II empyema underwent video-assisted thoracic surgery (VATS). The procedure was converted to thoracotomy in 13 patients (29.5%); the morbidity and mortality rates of VATS were 13% and 0, respectively. Seventy-eight patients had stage III empyema and, along with those 13 who were converted, underwent thoracotomy for decortication. The associated morbidity rate was 12%, and the mortality rate was 6.6%. Thoracotomy was considered successful in 90 of 91 patients (99%); one patient needed a reoperative thoracotomy for an organ space/surgical site infection with pus in the pleural cavity. CONCLUSIONS: Many treatment modalities are available for thoracic empyema, depending on the results of appropriate clinical and laboratory investigations. In fibrinopurulent empyema, VATS debridement is safe and effective, with minimal morbidity and no deaths. Lung decortication via thoracotomy is the only option for organized empyema and is associated with a substantial mortality rate.

Huge Extrapleural Hematoma After a Blunt Chest Trauma: An Unusual Presentation.

Massive extrapleural hematoma secondary to blunt chest trauma is exceedingly rare especially in nonanticoagulated patients. Significant amounts of blood can be sequestered between parietal pleura and the endothoracic facia leading to ventillatory and circulatory disturbances and even death. We report a case of a huge extrapleural hematoma in a non-anticoagulated 70-year-old patient secondary to blunt chest trauma. Etiology, surgical and treatment implications of this injury are briefly discussed.

Lung cancer after heart transplantation: a 17-year experience.

BACKGROUND: The effects of heart transplantation on lung cancer incidence in heart transplant recipients are unclear. METHODS: In an observational study, we retrospectively reviewed the charts of all patients undergoing heart transplantation at our institution from July 1982 to July 1999. Data on lung cancer incidence, risk factors, treatment, and outcome were collected. RESULTS: Five hundred seventy-two patients (mean age, 50 +/- 11 years; range, 18 to 73) were considered at risk for lung cancer. Of these, 324 (57%) had a more than 20 pack-year history of smoking before transplantation. Lung cancer developed in 2 patients 1 year or less after transplantation and in 8 patients more than 1 year after transplantation (incidence, 2.2 per 1,000 patients per year of follow-up). Non-small cell lung cancer was diagnosed in all cases. Median survival was 10.8 months (range, 2 to 37.5). Routine annual chest radiographs after transplantation enabled early diagnosis in 5 cases (stages Ia and IIa), which correlated with better mean survival (28.1 months [range, 19 to 37.5] versus 5.1 months [range, 2 to 10.8]; p = 0.0002). CONCLUSIONS: The incidence of lung cancer in our population of heart transplant recipients appears to be no higher than in nontransplant populations with similar risk factors (ie, smoking and age). Routine radiographic imaging of transplant recipients may allow earlier detection of lung cancer and thus offer a survival benefit.