Uric acid levels in blood are associated with clinical outcome in soft-tissue sarcoma patients.

BACKGROUND: Recent evidence indicates toward a role of uric acid (UA) as a potential antioxidant. Elevated UA levels were shown to be associated with better survival in various malignancies. The aim of the present study was to evaluate the prognostic relevance of pre-operative UA levels on cancer-specific survival (CSS) in soft-tissue sarcoma (STS) patients who underwent curative surgical resection. METHODS: Three hundred and fifty-seven patients with STS were included in the study. Pre-operative serum UA level was measured using an enzymatic colorimetric assay. The effect of UA levels on CSS was analyzed using Kaplan-Meier curves. To further evaluate the prognostic impact of UA levels, univariate and multivariate Cox proportional models were calculated. RESULTS: Among the 357 STS patients, cancer-related deaths occurred in 20 (24.7%) of 81 patients with a serum UA level <279.6 µmol/L and in 36 (13%) of 276 patients with a UA level ≥279.6 µmol/L. In univariate analysis, elevated UA levels were significantly associated with increased CSS in STS patients [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.26-0.77, p=0.004]. Furthermore, elevated UA levels remain a significant factor for better CCS in multivariate analysis (HR 0.42, 95% CI 0.23-0.75, p=0.003). CONCLUSIONS: Our study is the first one to demonstrate that higher UA levels are associated with positive clinical outcome in STS patients. UA levels are a simple and cost-effective test for the assessment of the prognosis of STS patients.

Sorafenib in advanced, heavily pretreated patients with soft tissue sarcomas.

Therapeutic options for patients with advanced pretreated soft tissue sarcomas are limited. However, in this setting, sorafenib has shown promising results. We reviewed the data of 33 patients with soft tissue sarcoma treated with sorafenib within a named patient program in Austria. Twelve physicians from eight different hospitals provided records for the analysis of data. Among the 33 patients, the predominant histological subtype of sarcoma was leiomyosarcoma (n=18, 55%). Other subtypes were represented by only one or two cases. Fifteen patients presented with metastases at the time of diagnosis. Another 17 patients developed metastases later in the course of the disease (data on one patient are missing). Most of the 33 patients had undergone resection of the primary (n=29, 88%) and half of the patients had received radiotherapy (n=17, 52%). Chemotherapy for metastatic disease had been administered to 30 patients (91%). The majority had received two or more regimens of chemotherapy (n=25, 76%) before sorafenib treatment. The use of sorafenib resulted in a median time to treatment failure of 92 days in patients with leiomyosarcoma and 45 days in patients with other histological subtypes. One-third of the patients derived benefits from treatment: four patients were documented with partial response and six with stabilized disease. In terms of treatment-related toxicity, skin problems of various degrees and gastrointestinal disturbances were frequently reported. In this retrospective analysis of heavily pretreated patients with advanced soft tissue sarcomas, sorafenib was associated with some antitumor activity and an acceptable toxicity profile.

The elevated pre-operative plasma fibrinogen level is an independent negative prognostic factor for cancer-specific, disease-free and overall survival in soft-tissue sarcoma patients.

BACKGROUND AND OBJECTIVES: Accumulating evidence indicates an important pathophysiological role of fibrinogen on tumor cell progression and metastases in different types of cancer. The aim of the present study was to evaluate the prognostic relevance of pre-operative fibrinogen levels on clinical outcome in a large cohort of STS patients. METHODS: Two hundred ninety-four consecutive STS patients were retrospectively evaluated. Cancer-specific survival (CSS), disease-free survival (DFS), and overall survival (OS) were assessed using the Kaplan-Meier curves and Cox regression models. Finally, we supplemented the well-established Kattan nomogram by the fibrinogen level and evaluated the gain of predictive accuracy of this novel nomogram by Harrell's concordance index (c-index). RESULTS: An elevated plasma fibrinogen level was significantly associated with established prognostic factors, including age, tumor grade, size, and depth (P<0.05). Furthermore, in multivariate analysis, increased fibrinogen levels were significantly associated with a poor outcome for CSS (HR=2.48; 95% CI=1.28-4.78; P=0.007), DFS (HR=2.00; 95% CI=1.11-3.60; P=0.021), and OS (HR=2.20; 95% CI=1.39-3.47; P<0.001). The estimated c-index was 0.747 using the original Kattan nomogram and 0.779 when the fibrinogen levels was added. CONCLUSION: The pre-operative plasma fibrinogen level may represent a strong and independent unfavorable prognostic factor for CSS, DFS and OS in STS patients.

The ethics of space, design and color in an oncology ward.

Change affects all areas of healthcare organizations and none more so than each aspect of the oncology ward, beginning with the patient's room. It is there that the issues faced by the major players in healing environments - administrator, caregiver, family member, and, most importantly, the patient - come sharply into focus. Hospitals are building new facilities or renovating old ones in order to adapt to new environmental demands of patient care and security. Driven by ethical and professional responsibility, the oncological team headed by Professor Hellmut Samonigg of Graz Medical University Graz pursued a vision of designing a model oncology ward unique in Europe. Friedensreich Hundertwasser, the world-famous artist, was the creative force behind the design. The oncology ward became a place of healing, permeated with a colorful sense of life and harmonious holistic care. The successful outcome was confirmed by the extraordinarily positive feedback by patients, families, and healthcare staff.

Gastrointestinal stromal tumors: diagnosis, therapy and follow-up care in Austria.

Optimal treatment for patients suffering from gastrointestinal stromal tumors (GIST) is based on an interdisciplinary treatment approach. Austrian representatives of Medical and Surgical Oncology, Pathology, Radiology, Nuclear Medicine, Gastroenterology, and Laboratory Medicine issued this manuscript on a consensual base within the context of currently available and published literature. This paper contains guidelines and recommendations for diagnosis, therapy, and follow-up of GIST patients in Austria.

Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.

BACKGROUND: The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. METHODS: Patients were recruited to the trial between July 21, 1997, and November 30, 2006, at nine centres in Europe and North America. Patients with localised high-risk STS (> or = 5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00003052. FINDINGS: 341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone. All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20-67), 132 patients had local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0.58, 95% CI 0.41-0.83; p=0.003), with an absolute difference in LPFS at 2 years of 15% (95% CI 6-26; 76% EIA plus regional hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0.70 (95% CI 0.54-0.92, p=0.011) for EIA plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional hyperthermia was 28.8%, compared with 12.7% in the group who received chemotherapy alone (p=0.002). In a pre-specified per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0.66, 95% CI 0.45-0.98, p=0.038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0.005). Hyperthermia-related adverse events were pain, bolus pressure, and skin burn, which were mild to moderate in 66 (40.5%), 43 (26.4%), and 29 patients (17.8%), and severe in seven (4.3%), eight (4.9%), and one patient (0.6%), respectively. Two deaths were attributable to treatment in the combined treatment group, and one death was attributable to treatment in the EIA-alone group. INTERPRETATION: To our knowledge, this is the first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective treatment strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location. FUNDING: Deutsche Krebshilfe, Helmholtz Association (HGF), European Organisation of Research and Treatment of Cancer (EORTC), European Society for Hyperthermic Oncology (ESHO), and US National Institute of Health (NIH).

Effects of infiltrating lymphocytes and estrogen receptor on gene expression and prognosis in breast cancer.

The involvement of the immune system for the course of breast cancer, as evidenced by varying degrees of lymphocyte infiltration (LI) into the tumor is still poorly understood. The aim of this study was to evaluate the prognostic value of LI in breast cancer samples using microarray-based screening for LI-associated genes. Starting from the observation that most published ER gene signatures are heavily influenced by the LI effect, we developed and applied a novel approach to dissect molecular signatures. Further, a meta-analysis encompassing 1,044 hybridizations showed that LI alone is not sufficient to highlight breast cancer patients with different prognosis. However, for ER positive patients, high LI was associated with shorter survival times, whereas for ER negative patients, high LI is significantly associated with longer survival. Annotation of LI, in addition to ER status, is important for breast cancer patient prognosis and may have implications for the future treatment of breast cancer.

[Treatment of extensive disease]. / GIST: medikamentöse Therapie.

In locally advanced inoperable patients and metastatic patients imatinib is a standard treatment. Standard dose of imatinib is 400 mg daily. Treatment should be continued indefinitely, since treatment interruption is generally followed by relatively rapid tumor progression in virtually all patients. Dose intensity should be maintained by adequate management of side effects and a correct policy of dose reductions and interruptions in the case of excessive toxicity. The standard approach in the case of tumor progression is to increase the imatinib dose to 800 mg daily with special attention to the occurrence of side effects. Patient non-compliance should be ruled out as a possible cause of tumor progression as well as drug interactions with concomitant medications. In case of progression or intolerance to imatinib standard second-line treatment is sunitinib. The drug was approved effective in terms of progression-free survival according to a 4 weeks on and 2 weeks off regimen. Preliminary data show that a continuous regimen with lower daily dose may be equally effective but possibly better tolerated. After failing on sunitinib, the patient should be considered for participation in a clinical trial of new therapeutic agents or combinations such as tyrosine-kinase inhibitors (e.g., nilotinib), sorafenib, or inhibitors of the mTOR (mammalian target of rapamycin)-pathway.

[Gastrointestinal stromal tumors: recommendations for diagnosis, treatment and aftercare in Austria]. / Klinische Empfehlungen. Gastrointestinale Stromatumore: Empfehlungen zu Diagnose, Behandlung und Nachsorge in Osterreich.

Diagnosis and treatment of gastrointestinal stromal tumors (GIST) requires an interdisciplinary treatment approach. This strategy should be reflected by the content of this article. Austrian representatives of 'GIST relevant' specialties authored this publication on a consensual base. This manuscript should be regarded as a guideline for 'GIST involved' colleagues in Austria.

Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy.

BACKGROUND: The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) bone substudy assesses zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2 years after completing adjuvant treatment with or without zoledronic acid. The aim of this substudy is to gain insight into bone health in this setting. METHODS: ABCSG-12 is a randomised, open-label, phase III, 4-arm trial comparing tamoxifen (20 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg intravenously every 6 months) for 3 years in premenopausal women with endocrine-responsive breast cancer. This prospective bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months. The primary endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months, assessed by dual-energy X-ray absorptiometry in assessable patients. Analyses were intention to treat. Statistical significance was assessed by t tests. The ABCSG-12 trial is registered on the ClinicalTrials.gov website, number NCT00295646. FINDINGS: 404 patients were prospectively included in the bone substudy and randomly assigned to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n=205). After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (-11.3%, mean difference -0.119 g/cm(2) [95% CI -0.146 to -0.091], p<0.0001) and trochanter (-7.3%, mean difference -0.053 g/cm(2) [-0.076 to -0.030], p<0.0001). In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at 36 months at the lumbar spine (-13.6%, mean difference -0.141 g/cm(2) [-0.179 to -0.102] vs -9.0%, mean difference -0.095 g/cm(2) [-0.134 to -0.057], p<0.0001 for both). 2 years after the completion of treatment (median follow-up 60 months [range 15.5-96.6]), patients not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine -6.3%, mean difference -0.067 g/cm(2) [-0.106 to -0.027], p=0.001; trochanter -4.1%, mean difference -0.03 g/cm(2) [-0.062 to 0.001], p=0.058). Patients who received zoledronic acid had stable BMD at 36 months (lumbar spine +0.4%, mean difference 0.004 g/cm(2) [-0.024 to 0.032]; trochanter +0.8%, mean difference 0.006 g/cm(2) [-0.018 to 0.028]) and increased BMD at 60 months at both sites (lumbar spine +4.0%, mean difference 0.039 g/cm(2) [0.005-0.075], p=0.02; trochanter +3.9%, mean difference 0.028 g/cm(2) [0.003-0.058], p=0.07) compared with baseline. INTERPRETATION: Goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic acid caused significant bone loss. Although there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels. Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years.

Risk stratification for venous thromboembolism in patients with testicular germ cell tumors.

BACKGROUND: Patients with testicular germ cell tumors (TGCT) have an increased risk for venous thromboembolism (VTE). We identified risk factors for VTE in this patient cohort and developed a clinical risk model. METHODS: In this retrospective cohort study at the Medical University of Graz we included 657 consecutive TGCT patients across all clinical stages. A predictive model for VTE was developed and externally validated in 349 TGCT patients treated at the University Hospital Zurich. RESULTS: Venous thromboembolic events occurred in 34 (5.2%) patients in the Graz cohort. In univariable competing risk analysis, higher clinical stage (cS) and a retroperitoneal lymphadenopathy (RPLN) were the strongest predictors of VTE (p<0.0001). As the presence of a RPLN with more than 5cm in greatest dimension without coexisting visceral metastases is classified as cS IIC, we constructed an empirical VTE risk model with the following four categories (12-month-cumulative incidence): cS IA-B 8/463 patients (1.7%), cS IS-IIB 5/86 patients (5.9%), cS IIC 3/21 patients (14.3%) and cS IIIA-C 15/70 patients (21.4%). This risk model was externally validated in the Zurich cohort (12-month-cumulative incidence): cS IA-B (0.5%), cS IS-IIB (6.0%), cS IIC (11.1%) and cS IIIA-C (19.1%). Our model had a significantly higher discriminatory performance than a previously published classifier (RPLN-VTE-risk-classifier) which is based on the size of RPLN alone (AUC-ROC: 0.75 vs. 0.63, p = 0.007). CONCLUSIONS: According to our risk stratification, TGCT patients with cS IIC and cS III disease have a very high risk of VTE and may benefit from primary thromboprophylaxis for the duration of chemotherapy.

Plasmapheresis reverses all side-effects of a cisplatin overdose--a case report and treatment recommendation.

BACKGROUND: Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. CASE PRESENTATION: We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m2 of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. CONCLUSION: To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects.

The course of serum HER-2/neu levels as an independent prognostic factor for survival in metastatic breast cancer.

The purpose of this study was to determine the impact of serum HER-2/neu level dynamics during the course of disease and treatment on the prognosis of patients with metastatic breast cancer. Two thousand and thirty-eight serum samples collected sequentially after disease relapse in 286 patients with metastatic breast cancer were measured by Bayer Immuno 1 trade mark assay retrospectively for serum HER-2/neu (cut-off level 15 ng/ml). One hundred and five patients (37%) presented with serum HER-2/neu continuously

Pre-treatment anemia is a poor prognostic factor in soft tissue sarcoma patients.

BACKGROUND: Anemia refers to low hemoglobin (Hb) levels, represents a common symptom and complication in cancer patients and was reported to negatively influence survival in patients with various malignancies. In the present study, we aimed to explore the prognostic impact of pre-operative Hb levels on clinical outcome in a large cohort of soft tissue sarcoma (STS) patients after curative surgery. METHODS: Retrospective data from 367 STS patients, which were operated between 1998 and 2013, were included in the study. Cut-off levels for anemia were defined as Hb<13 g/dl in males and Hb<12 g/dl in females according to the current WHO guidelines. The impact of pre-operative Hb levels on cancer-specific survival (CSS) and overall survival (OS) was assessed using Kaplan-Meier curves. Additionally, Hb levels were compared for the prognostic influence on CSS and OS applying univariate and multivariate Cox proportional models. RESULTS: Hb level was associated with established prognostic factors, including age, tumor grade, size and depth (p<0.05). Kaplan-Meier curves showed that low Hb levels were significantly associated with decreased CSS and OS in STS patients (p<0.001 for both endpoints, log-rank test). In multivariate analysis, we found an independent association between low Hb levels and poor CSS and OS (HR = 0.46, Cl 95% = 0.25-0.85, p = 0.012; HR = 0.34, Cl 95% = 0.23-0.51, p<0.001). CONCLUSION: The present data underline a negative prognostic impact of low pre-operative Hb levels on clinical outcome in STS patients. Thus, Hb levels may provide an additional and cost-effective tool to discriminate between STS patients that are at high risk of mortality.

[Consensus diagnosis and therapy of soft tissue sarcoma]. / Konsensus Diagnose und Therapie von Weichteilsarkomen.

Soft tissue sarcomas are heterogeneous tumours and relatively uncommon. There have been advances over the past years concerning pathology, clinical behaviour, diagnosis strategies and the treatment. To summarize these advances as well as making it public is one of the goals of the following consensus guidelines. But why do we need special guidelines for Austria? There are international guidelines published by the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN). The cause is that we need an explanation of the matrix the ESMO and the NCCN gave according to our clinical practice, the local requirements and facilities in Austria. The following recommendations were drawn up following a consensus meeting of sarcoma specialists from the three high volume centres located at the medical universities in Austria. All fields of involved physicians from diagnosis to therapy worked together to know that soft tissue sarcomas are an interdisciplinary challenge and multimodal treatment is essential. For this reason, these guidelines not only explain but also give the state of the art and clear recommendations. One of the most important guidelines is that any patient with a suspected soft tissue sarcoma should be referred to one of the three university centres and managed by a specialist sarcoma multidisciplinary team. We hope that the consensus is helpful for the clinical practice and improves the quality of care for patients with soft tissue sarcomas in Austria.

[Histology-based algorithm in the molecular diagnosis of mutations of the Epidernal Growth Factor Receptor (EGFR) in non-small cell lung cancer]. / Histologie-basierter Algorithmus der molekularen Diagnostik des epidermalen Wachstumsfaktor-Rezeptorgens (Epidermal Growth Factor Receptor, EGFR) beim nicht-kleinzelligen Lungenkarzinom (non-small cell lung cancer, NSCLC).

Patients with stage IIIB and IV non-small cell lung carcinoma (NSCLC) harboring an activating mutation of the Epidermal Growth Factor Receptor (EGFR) Gene should be treated first-line with Gefitinib, an EGFR tyrosine kinase inhibitor (TKI). EGF receptor mutations are most common in adenocarcinomas, especially non-mucinous type, rare in squamous cell carcinomas and sarcomatoid carcinomas, and do not occur in neuroendocrine carcinomas. Therefore, the Pulmonary Pathology Working Group of the Austrian Society of Pathology, after intense discussions and in consensus with Oncologists and Pulmonologists, recommends a priori EGFR mutation analysis for all cases of adenocarcinoma, and for all other NSCLC upon clinical request. This will markedly reduce waiting time for those patients, which most likely will have the greatest benefit from EGFR TKI therapy.

Rationale of a relaunch of gefitinib in Caucasian non-small cell lung cancer patients.

In 2002 results of two-phase II studies with the new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib showed not only promising efficacy in second and third line non-small cell lung cancer (NSCLC) therapies but also an excellent tolerability. Since then, thousands of patients have been treated in one of the largest expanded access programs ever performed and the successful application in daily routine led to a preliminary approval of the drug by the U.S. Food and Drug Administration in 2003. In the light of the negative results of a subsequent phase III trial comparing gefitinib with best supportive care, the approval was withdrawn. In 2009 gefitinib was relaunched for Caucasian patients in the US and Europe based on new data and on the re-interpretation of previous studies. The approval is now recommended exclusively for patients with an activating EGFR mutation. For the first time in lung cancer, molecular work-up is of clinical relevance and will change the diagnostic and therapeutic algorithms. The present review summarizes these data, presents the rationale for this development and proposes a diagnostic work-up.

Gastrointestinal stromal tumors: Recommendations on diagnosis, therapy and follow-up care in Austria.

Adequate treatment of gastrointestinal stromal tumors (GISTs) is linked to an interdisciplinary treatment approach. Austrian representatives of medical oncology, surgery, pathology, radiology and gastroenterology have issued this consensus manuscript within the context of currently available and published literature. The paper contains guidelines and recommendations for diagnosis, therapy and follow-up of GIST patients in Austria.

Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy.

BACKGROUND: Death receptor 4 (DR4) and death receptor 5 (DR5) are tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) receptors that activate apoptosis via the extrinsic apoptosis pathway. DcR1 and DcR2 are decoy receptors for TRAIL that act antagonistically. Intracellular trafficking of TRAIL receptors has been described, but the role of the subcellular localization of TRAIL receptors in non-small cell lung cancer (NSCLC) progression is unclear. METHODS: Expression and intracellular localization of pro-apoptotic and decoy TRAIL receptors were analyzed by immunohistochemistry in 50 samples of advanced or recurrent NSCLC. Using confocal microscopy, localization of TRAIL receptors was studied in NSCLC cell lines. RESULTS: Cytoplasmic staining for all four TRAIL receptors was observed in the majority of samples. Nuclear staining was infrequent in the case of DR4 (12%) and DcR2 (8%), while DR5 and DcR1 were localized in the nucleus in 27% and 60% of samples. When overall survival was analyzed, cytoplasmic staining for DR5 in tumor cells (P=0.025) and nuclear staining for DR5 in tumor cells (P=0.007) were significant prognostic factors in univariate, as well as in multivariate analysis including clinicopathologic factors (P=0.026 and 0.021, respectively). In A549, NCI-H358, and A427 NSCLC cells all four TRAIL receptors were found to be mainly located perinuclearly, but also in the nucleus. CONCLUSION: The study for the first time shows that TRAIL receptors are found in different intracellular compartments including the nucleus in NSCLC cells and that both nuclear and cytoplasmic DR5 might predict improved survival in patients with advanced NSCLC.