Purpose: While the overall prognosis of non-molecularly selected advanced non-small cell lung cancer (NSCLC) patients is poor, a subset of these patients has durable survival. We examined which clinical factors might be predictive for this favourable outcome.Patients and methods: Long-term NSCLC survivors (LTS, i.e. >2 years) were retrieved from all our out-and in-patient contacts in a 6 month period (March-August 2009). LTS records were compared with a group of short-term survivors (STS). Both baseline clinical factors (sex, age, smoking status, weight loss, performance status, co-morbidity, histological subtype, place and number of metastasis) and treatmentrelated features (number and type of therapeutic lines, response, duration of treatment-free interval) were compared.Results: 31 LTS were retrieved (stage IV patients with potentially radical treatment options, e.g. solitary brain or adrenal metastasis, were excluded), and compared with 34 STS. In the LTS group, median survival was 53 months, with 47% of patients alive at 5 years, in the STS patients this was 9.7 months, with 24% alive at 1-year. Baseline factors had little predictive value, but response to 1st line therapy (P=0.0001), response duration (P=0.009), and the number of systemic lines (P=0.0023) were of importance.Conclusion: These data confirm the existence of LTS in patients with advanced NSCLC. There are very little clinical factors at the time of diagnosis that help to distinguish future LTS from STS patients. Factors related to the effect of 1st line treatment are important, and further prospects of patients achieving a 2-year survival are in general quite good.(C) 2012 Elsevier Ireland Ltd. All rights reserved.

A 71-year-old man was admitted with a 2-month history of back pain, weakness, and dyspnea. Medical history reports immunoglobulin A nephropathy resulting in renal transplantation at the age of 47. He redeveloped severe chronic renal insufficiency based on allograft rejection, with a current Cockroft–Gault creatinine clearance of 24 ml/min and secondary hyperparathyroidism. Positron emission tomography–computed tomography scan shows a 25-mm tumor of the left upper lobe, malignant mediastinal lymph nodes, and extensive bone metastases (Fig. 1). Pathologic finding reports epidermal growth factor receptor wild-type nonsquamous non–small-cell lung cancer on peripheral bronchoscopic biopsy. Chronic renal impairment impedes use of chemotherapy. Denosumab 120 mg was administered subcutaneously for diffuse bone disease, along with calcium 1000 mg and vitamin D 800 I.U. per day. In the following days, several biochemical aberrations suggesting tumor lysis syndrome (TLS) were noted (Fig. 2). The patient required treatment with intravenous hydration, urine alkalization, and supplemental calcium. After a critical period, biochemical disorders resolved to baseline levels. The patient was discharged on best supportive care 2 weeks later.FIGURE 2Time course of lactate dehydrogenase (LDH), potassium, calcium, phosphorus, creatinine, and uric acid. Day 1 = administration of denosumab.View Large Image Figure ViewerDownload (PPT) TLS is a potentially fatal complication at the start of chemotherapy for bulky solid tumors.1Coiffier B Acute tumor lysis syndrome - a rare complication in the treatment of solid tumors.Onkologie. 2010; 33: 498-499Crossref PubMed Scopus (14) Google Scholar Risk factors are chronic renal impairment, high serum levels of lactate dehydrogenase or uric acid, and dehydration. The time course of the biological tests is in line with the criteria for definition of laboratory TLS in a recent review.2Howard SC Jones DP Pui CH The tumor lysis syndrome.N Engl J Med. 2011; 364: 1844-1854Crossref PubMed Scopus (540) Google Scholar Only the time course of creatinine is less typical, probably explained by nephrotoxic medication in the recent past. Consequently, we considered TLS caused by denosumab in our patient, to our knowledge, a hitherto undescribed condition. Bone-targeted therapy with the human monoclonal antibody denosumab is of proven value to reduce the risk of skeletal-related events in patients with solid tumors with bone metastases. The mode of action is inhibition of the receptor activator of nuclear factor kappa-B ligand (RANKL) responsible for formation, function, and survival of the osteoclast. Whether denosumab also has direct antitumor effects is unclear. RANKL expression has been documented in several cancer cell lines.3Dougall WC Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis.Clin Cancer Res. 2012; 18: 326-335Crossref PubMed Scopus (164) Google Scholar The role of RANKL in tumor migration and invasion in lung cancer is being examined. In mice, RANKL inhibition blocks lung cancer–induced osteolytic lesions and reduces skeletal-related events not only in RANK-expressing but also in RANK-negative lung cancers.4Miller R Jones J Tometsko M et al.RANKL inhibition blocks lung cancer-induced osteolytic lesions and reduces skeletal tumor burden in both RANK-expressing and RANK-negative lung cancers.J Bone Miner Res. 2007; 22 Suppl: 114SGoogle Scholar Exploratory data from a phase III clinical trial reported a possible delay of tumor progression and improvement of overall survival by RANKL inhibition: patients with non–small-cell lung cancer receiving denosumab had a median overall survival of 9.5 months versus 8.0 months for zoledronic acid (hazard ratio: 0.78; p = 0.0104).5Scagliotti GV Hirsh V Siena S et al.Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.J Thorac Oncol. 2012; 7: 1823-1829Crossref PubMed Scopus (246) Google Scholar Our patient had severe impairment of renal function (clearance 24 ml/min). In general, administration of denosumab does not require renal function monitoring because it does not depend on renal clearance for metabolism or excretion. Nevertheless, in all phase III studies, the use of denosumab 120 mg subcutaneously was limited to patients with a creatinine clearance of more than 30 ml/min. In a recent study, no significant difference in toxicity profile according to renal impairment and no TLS were reported.6Jamal SA Ljunggren O Stehman-Breen C et al.Effects of denosumab on fracture and bone mineral density by level of kidney function.J Bone Miner Res. 2011; 26: 1829-1835Crossref PubMed Scopus (258) Google Scholar This case report raises several unanswered questions: can denosumab act on tumor cells and cause TLS? Is this more likely in case of severe impairment of renal function? Until these questions are solved, we suggest caution using denosumab in patients with severe renal impairment and diffuse bone metastases.

BACKGROUNDextrathoracic malignancies metastasize to the mediastinum and/or pulmonary hilum. Mediastinoscopy and thoracoscopy are standard to obtain tissue proof of metastatic spread but are invasive. Endobronchial ultrasound with real-time-guided transbronchial fine-needle aspiration (EBUS-TBNA) is a minimally invasive alternative for surgical staging of lung cancer.METHODSwe analysed the test characteristics of EBUS-TBNA in consecutive patients with a suspicion of mediastinal or hilar metastases of various extrathoracic malignancies.RESULTSninety-two patients with concurrent (n = 33) or previously diagnosed and treated (n = 59) extrathoracic malignancies were evaluated. EBUS-TBNA detected mediastinal or hilar metastatic spread in 52 patients (57%) [metastasis of extrathoracic tumour in 40 (44%) and second malignancies (lung cancer) in 12 (13%)]. Subsequent surgical staging showed malignancy in another nine patients. With EBUS-TBNA, an alternate diagnosis was found in four. Sensitivity and negative predictive value for mediastinal or hilar metastatic spread were 85% [95% confidence interval (CI) 73-93] and 76% (95% CI 59-88). EBUS-TBNA prevented an invasive surgical procedure in 61% of the patients. One patient had a respiratory arrest during EBUS-TBNA; abortion lead to full recovery without further intervention.CONCLUSIONSEBUS-TBNA is a minimally invasive method for M staging of patients with extrathoracic malignancies to confirm mediastinal or hilar spread. EBUS-TBNA therefore may qualify as an alternative for surgical staging.

It can be postulated that patients in early stages of pulmonary emphysema have normal values of total respiratory resistance and reactance. The purpose of this study was to investigate whether pulmonary emphysema, detected functionally by a decrease of the single breath diffusing capacity (DLCO) by at least 25% of predicted, and an increase of the static lung compliance (CLst) by at least 50% of predicted, can be accompanied by normal values of respiratory resistance (Rrs) and reactance (Xrs), measured between 2 and 24 Hz by the forced oscillation technique. In a prospective study, we determined CLst in 26 patients, who had been selected on the basis of normal values of Rrs and Xrs, and a DLCO of less than 75% of predicted. In 17 of these patients, CLst was more than 150% of predicted. Since there were only minor abnormalities on routine lung function tests and chest X-ray, it is likely that these patients presented early emphysema. In the nine other patients, CLst was within normal limits: four suffered from interstitial lung disease; the remaining five were probably in a preliminary stage of early emphysema. In conclusion, early emphysema should systematically be considered as the first diagnosis in patients with normal values of Rrs and Xrs, and a decrease of DLCO. Onset of interstitial lung disease is a possible alternative.