Robert C. Buttery

EBUS-TBNA for the diagnosis of central parenchymal lung lesions not visible at routine bronchoscopy

BACKGROUND Obtaining a tissue diagnosis of malignancy is challenging in patients with suspected lung cancer presenting with centrally located intrapulmonary masses. OBJECTIVE (1) To evaluate the yield of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing centrally located lesions after a non-diagnostic conventional bronchoscopy. (2) To assess the impact of EBUS-TBNA on patient management for this indication. STUDY DESIGN AND PATIENTS A retrospective analysis of a series of patients with a central parenchymal lung lesion suspected to be lung cancer who had been referred to three university hospitals for EBUS-TBNA to obtain a tissue diagnosis was undertaken. If EBUS-TBNA did not result in a formal pathological diagnosis of malignancy, patients were subsequently referred for a transthoracic needle aspiration biopsy or a surgical diagnostic procedure. RESULTS Sixty patients were investigated with EBUS-TBNA. The majority (82%) had a prior (non-diagnostic) flexible bronchoscopy. EBUS-TBNA was performed in an out-patient setting in 97%. With ultrasound, the primary lung lesion was observed in all cases. EBUS-TBNA confirmed lung cancer in 46 (77%). A final reference pathology diagnosis was available in 59 (98%) cases. The sensitivity of EBUS-TBNA for diagnosing lung cancer was 82% (95% confidence intervals (CI) 69-91%) with a negative predictive value of 23% (95%CI 5-53%). Based on the EBUS-TBNA findings, transthoracic needle aspiration biopsy or a surgical diagnostic procedure was cancelled in 47% and 30% of patients, respectively. No serious procedure-related complications were reported. CONCLUSION EBUS-TBNA is a sensitive tool for the diagnosis of centrally located primary lung cancer not visible at conventional bronchoscopy. Therefore, EBUS-TBNA can impact on patient management in this setting. However, the low negative predictive value indicates that a negative EBUS-TBNA result should be confirmed by other methods. IMPLICATION EBUS-TBNA can be considered as a diagnostic test in patients with a centrally located lung lesion after a previous non-diagnostic conventional bronchoscopy.

EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international multi-centre experience

Introduction: To determine the sensitivity and accuracy of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for clarification of the nature of fluorodeoxyglucose-positron emission tomography (18FDG) positive hilar and/or mediastinal lymph nodes in patients with (suspected) lung cancer. Methods: All consecutive patients who had undergone EBUS-TBNA alone for assessment of abnormal 18FDG-uptake in hilar and/or mediastinal lymph nodes between January 2005 and August 2007 were reviewed. Results: One-hundred-nine patients underwent EBUS-TBNA of 127 positron emission tomography positive lymph nodes. Hilar (station 10 or 11) nodes (N1 or N3) were aspirated in 26 patients and mediastinal (stations 2, 4, 7) nodes (N2 or N3) in 90 patients. In 7 patients both hilar and mediastinal nodes were sampled. There were no procedure-related complications. Malignancy was detected in 77 (71%) cases. Thirty-two patients were tumor negative by EBUS-TBNA; subsequent surgical biopsy in 19 showed malignancy in 7. In four cases the false negative result was due to sampling error and in three cases due to detection error. In 13 cases surgical staging was not performed although long term follow-up in 3 showed no evidence of malignancy. The sensitivity and accuracy of EBUS-TBNA for malignancy in patients with reference pathology was 91% and 92%, respectively. The negative predictive value was 60%. If the 10 cases for which confirmatory surgical staging was not performed are assumed to be false negative results, overall sensitivity and accuracy were 82% and 84%, respectively. Conclusions: EBUS-TBNA offers an effective accurate, minimally invasive strategy for evaluating FDG avid hilar and mediastinal lymph nodes. However, negative findings should be confirmed by surgical staging.

Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum.

The integrin family of heterodimeric cell-surface receptors are fundamental in cell-cell and cell-matrix adhesion. Changes to either integrin-ligand affinity or integrin gene expression are central to a variety of disease processes, including inflammation, cardiovascular disease and cancer. In screening for novel activators of integrin-ligand affinity we identified the previously uncharacterised multi-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER). siRNA knockdown of Fam38A in epithelial cells inactivates endogenous β1 integrin, reducing cell adhesion. Fam38A mediates integrin activation by recruiting the small GTPase R-Ras to the ER, which activates the calcium-activated protease calpain by increasing Ca2+ release from cytoplasmic stores. Fam38A-induced integrin activation is blocked by inhibition of either R-Ras or calpain activity, or by siRNA knockdown of talin, a well-described calpain substrate. This highlights a novel mechanism for integrin activation by Fam38A, utilising calpain and R-Ras signalling from the ER. These data represent the first description of a novel spatial regulator of R-Ras, of an alternative integrin activation-suppression pathway based on direct relocalisation of R-Ras to the ER, and of a mechanism linking R-Ras and calpain signalling from the ER with modulation of integrin-ligand affinity.

Small cell lung cancer: the importance of the extracellular matrix.

Lung cancer is the leading cause of cancer deaths in the UK and the small cell lung cancer (SCLC) phenotype is the most aggressive form of this disease, with a high metastatic potential and the development of resistance to chemotherapy. Evidence now suggests that these features may be due to important links between the cancer cells and proteins in their local extracellular matrix (ECM). This article reviews the evidence for a chemoprotective effect of extracellular matrix in small cell lung cancer and discusses the importance of integrin-mediated signalling pathways in this setting.

Serum from patients with fulminant hepatic failure causes hepatocyte detachment and apoptosis by a β1-integrin pathway

Hepatocyte transplantation is restricted by the impaired ability of hepatocytes to engraft and survive in the damaged liver. Understanding the mechanisms that control this process will permit the development of strategies to improve engraftment. We studied changes in liver matrix during acute injury and delineated the mechanisms that perturb the successful adhesion and engraftment of hepatocytes. Collagen IV expression was increased in sinusoidal endothelium and portal tracts of fulminant hepatic failure explants, whereas there were minimal changes in the expression of fibronectin, tenascin, and laminin. Using an in vitro model of cellular adhesion, hepatocytes were cultured on collagen‐coated plates and exposed to serum from patients with liver injury to ascertain their subsequent adhesion and survival. There was a rapid, temporally progressive decrease in the adhesive properties of hepatocytes exposed to such serum that occurred within 4 hours of exposure. Loss of activity of the β1‐integrin receptor, which controls adhesion to collagen, was seen to precede this loss of adhesive ability. Addition of the β1‐integrin activating antibody (TS2/16) to cells cultured with liver injury serum significantly increased their adhesion to collagen, and prevented significant apoptosis. In conclusion, we have identified an important mechanism that underpins the failure of infused hepatocytes to engraft and survive in liver injury. Pretreating cells with an activating antibody can improve their engraftment and survival, indicating that serum from patients with liver injury exerts a defined nontoxic biological effect. This finding has important implications in the future of cellular transplantation for liver and other organ diseases. (HEPATOLOGY 2004;40:636–645.)

Galectin‐3: differential expression between small‐cell and non‐small‐cell lung cancer

Aims:  To compare the histological expression of galectin‐3 in different lung cancers, including small‐cell lung cancer (SCLC) and non‐small‐cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer deaths in the UK. Galectin‐3 is a β‐galactoside binding protein with a controversial role in malignant transformation. SCLC metastasizes early and is initially chemosensitive; NSCLC metastasizes later, offering the chance of surgical cure, but is much less chemosensitive. Mixed tumours present a diagnostic and therapeutic problem, with a poorer response to therapy. Insight into the cellular mechanisms that govern metastasis and chemoresistance will profoundly influence the future management of this disease.