High performance of F-fluorodeoxyglucose positron emission tomography and contrast-enhanced CT in a rapid outpatient diagnostic program for patients with suspected lung cancer.

BACKGROUND: The diagnostic evaluation of patients presenting with possible lung cancer is often complex and time consuming. A rapid outpatient diagnostic program (RODP) including (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contrast-enhanced computed tomography (CT) as a routine diagnostic tool may improve timeliness, however the diagnostic performance of such a combined approach of RODP remains unclear. OBJECTIVES: We evaluated timeliness of care and diagnostic performance of FDG-PET and contrast-enhanced CT (FDG-PET/CT) in an RODP for all patients referred with a chest X-ray suspicious of lung cancer. METHODS: Charts of patients referred to the 2-day RODP of our tertiary care university clinic after an abnormal chest X-ray between 1999 and 2009 were reviewed. Between 1999 and 2005 co-registered FDG-PET and CT imaging took place; from September 2005 onwards, a hybrid system was used. We analyzed timeliness of care and diagnostic performance of FDG-PET/CT to differentiate malignant from benign lesions. RESULTS: In 386 patients available for analysis, 260 were diagnosed with lung cancer and 23 had another type of malignancy; in 78 patients benign disease was confirmed, and in another 45 the diagnosis was not pathologically confirmed but a median 24.5-month follow-up confirmed a benign outcome. Sensitivity, specificity, negative and positive predictive values and accuracy of FDG-PET/CT to differentiate lung cancer from benign disease were 97.7, 60.2, 92.5, 84.0 and 85.8%, respectively. Lung cancer patients had a median referral, diagnostic and therapeutic delay of 7, 2 and 19 days, respectively. CONCLUSIONS: FDG-PET/CT in an RODP setting for suspected lung cancer has high performance in detecting cancer and facilitates timely care.

The faster the better?­A systematic review on distress in the diagnostic phase of suspected cancer, and the influence of rapid diagnostic pathways.

OBJECTIVE: To perform a systematic review of articles published in the last 25 years on prevalence and course of distress and quality of life surrounding the diagnostic process of suspected cancer, and the influence of rapid diagnostic programs. METHODS: Twenty-three articles were identified via Pubmed, PsycINFO, and reference lists of articles. Except for three randomized clinical trials and one case control study all studies were uncontrolled cohort studies. RESULTS: Most studies involved patients with suspected breast cancer and therefore had a sex selection bias. Four studies on the effect of rapid outpatient diagnostic programs were found.Studies showed very high prevalence of anxiety, decreasing in case of a benign diagnosis but increasing or sustaining in patients waiting for results or after cancer diagnosis though not significantly more in rapid programs. Quality of life was low and showed varying patterns. CONCLUSIONS: Distress in the diagnostic phase of cancer is a major problem and the rapid decrease of anxiety in patients eventually not diagnosed with cancer suggests a benefit of rapid diagnostic programs. The available evidence however is limited and shows some inconsistencies. Studies differ in subjects, objective and are limited by quality and quantity. Conflicting results prohibit a conclusion on patients ultimately diagnosed with cancer.

The role of (18)F-FDG PET in the differentiation between lung metastases and synchronous second primary lung tumours.

PURPOSE: In lung cancer patients with multiple lesions, the differentiation between metastases and second primary tumours has significant therapeutic and prognostic implications. The aim of this retrospective study was to investigate the potential of (18)F-FDG PET to discriminate metastatic disease from second primary lung tumours. METHODS: Of 1,396 patients evaluated by the thoracic oncology group between January 2004 and April 2009 at the Radboud University Nijmegen Medical Centre, patients with a synchronous second primary lung cancer were selected. Patients with metastatic disease involving the lungs served as the control group. Maximum standardized uptake values (SUVs) measured with (18)F-FDG PET were determined for two tumours in each patient. The relative difference between the SUVs of these tumours (∆SUV) was determined and compared between the second primary group and metastatic disease group. Receiver-operating characteristic (ROC) curve analysis was performed to determine the sensitivity and specificity of the ∆SUV for an optimal cut-off value. RESULTS: A total of 37 patients (21 metastatic disease, 16 second primary cancer) were included for analysis. The ∆SUV was significantly higher in patients with second primary cancer than in those with metastatic disease (58 vs 28%, respectively, p < 0.001). The area under the ROC curve was 0.81 and the odds ratio for the optimal cut-off was 18.4. CONCLUSION: SUVs from (18)F-FDG PET images can be helpful in differentiating metastatic disease from second primary tumours in patients with synchronous pulmonary lesions. Further studies are warranted to confirm the consistency of these results.

Undertreatment of tracheal carcinoma: multidisciplinary audit of epidemiologic data.

National epidemiologic data were examined to determine the eligibility for curative therapy in tracheal carcinoma. An expert audit of primary tracheal carcinomas registered from 2000 to 2005 with the Netherlands Cancer Registry (NCR) included blinded patient data and radiographic review to assess diagnosis and resectability. Actual treatment was compared with the opinions of a multidisciplinary panel (Radboud panel) and a second reviewer. Of 101 NCR-registered primary tracheal carcinomas, the Radboud panel diagnosis was metastatic disease or local extension of adjacent tumors in 34. Seventeen cases were excluded for missing data. In 50 cases confirmed by panel and a second reviewer, actual treatment consisted of surgery in 12 (24%), radiotherapy in 29 (58%), endobronchial treatment in 6 (12%), and observation in 3 (6%). Both panel and second reviewer identified 16 additional surgical candidates, a total of 28 (56%) of 50. Treatment recommendations of panel and second reviewer disagreed in four cases (8%). One-third of NCR-registered primary tracheal carcinomas were misclassified nontracheal primary tumors involving the trachea. A majority of cases meeting audit criteria for diagnosis and surgical resection was treated with other modalities. Interreviewer disagreement was small. The audit of a national cancer registry suggests that incorrect diagnosis and undertreatment are common in rare airway tumors.

Chemotherapy response evaluation with 18F-FDG PET in patients with non-small cell lung cancer.

UNLABELLED: The aim of this prospective study was to evaluate the value of (18)F-FDG PET for the assessment of chemotherapy response in patients with non-small cell lung cancer. Furthermore, part of the objective of this study was to compare 2 methods to quantify changes in glucose metabolism. METHODS: In 51 patients, dynamic (18)F-FDG PET was performed before and at 5-8 wk into treatment. Simplified methods to measure glucose metabolism (standardized uptake value [SUV]) and quantitative measures (metabolic rate of glucose [MR(Glu)]), derived from Patlak analysis, were evaluated. The overall survival and progression-free survival with respect to MR(Glu) and SUV were calculated using Kaplan-Meier estimates. Fractional changes in tumor glucose use were stratified by the median value and also the predefined EORTC (European Organization for Research and Treatment of Cancer) metabolic response criteria, and criteria applying cutoff levels similar to those of RECIST (Response Evaluation Criteria in Solid Tumors) were evaluated. RESULTS: When stratifying at the median value of DeltaMR(Glu) and DeltaSUV, the difference in overall survival (P = 0.017 for DeltaMR(Glu), P = 0.018 for DeltaSUV) and progression-free survival (P = 0.002 for DeltaMR(Glu), P = 0.0009 for DeltaSUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for DeltaSUV between response categories in progression-free survival (P = 0.0003) as well as overall survival (P = 0.027). CONCLUSION: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by (18)F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of (18)F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MR(Glu)) in this patient population.

Pleiotropic Analysis of Lung Cancer and Blood Triglycerides.

Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer.

EBUS and EUS guided fine needle aspirations for molecular diagnostic analysis in lung cancer.

In daily clinical practice the diagnosis of lung cancer is often based on cytological specimens. These cytological samples are increasingly obtained by ultrasound-guided techniques with fine needle aspirations. Recent developments have shown that transesophageal ultrasound guided fine needle aspiration (EUS-FNA) and endobronchial ultrasound guided transbronchial fine needle aspiration (EBUS-TBNA) are minimally invasive diagnostic and staging procedures that have shown to be highly sensitive and accurate. Although several studies have shown that these cytological samples allow for reliable diagnosis and sub classification of non-small cell lung cancer, cytological samples for molecular analysis are not yet routinely used. In this paper we review the current literature regarding the results of molecular analysis of samples obtained by EUS-FNA and/or EBUS-TBNA, focusing on the targets for currently available treatments of non-small cell lung cancer like epidermal growth factor receptor (EGFR), Kirsten rat sarcoma oncogene (KRAS) and Echinoderm microtubule-associated protein-like 4 gene anaplastic lymphoma kinase gene translocation (EML4-ALK). We conclude that the cytological samples obtained by endosonography guided fine needle aspirations (EUS and EBUS) are highly accurate for molecular analysis. This analysis can be performed reliably in the vast majority of patients in daily practice.

Timeliness of lung cancer diagnosis and treatment in a rapid outpatient diagnostic program with combined 18FDG-PET and contrast enhanced CT scanning.

INTRODUCTION: Delays in the diagnosis of lung cancer are under debate and may affect outcome. The objectives of this study were to compare various delays in a rapid outpatient diagnostic program (RODP) for suspected lung cancer patients with those described in literature and with guideline recommendations, to investigate the effects of referral route and symptoms on delays, and to establish whether delays were related to disease stage and outcome. METHODS: A retrospective chart study was conducted of all patients with suspected lung cancer, referred to the RODP of our tertiary care university clinic between 1999 and 2009. Patient characteristics, tumor stage and different delays were analyzed. RESULTS: Medical charts of 565 patients were retrieved. 290 patients (51.3%) were diagnosed with lung cancer, 48 (8.5%) with another type of malignancy, and in 111 patients (19.6%) the radiological anomaly was diagnosed as non-malignant. In 112 (19.8%) no immediate definite diagnosis was obtained, however in 82 of these cases (73.2%) the proposed follow-up strategy confirmed a benign outcome. The median first line delay was 54 days, IQR (interquartile range) 20-104 days, median patient delay 19 days (IQR 4-52 days), median referral delay was 7 days (IQR 5-9 days), median diagnostic delay 2 days (IQR 1-19 days). In 87% a diagnosis was obtained within 3 weeks after visiting a chest physician and 52.5% started curative therapy within 2 weeks after diagnosis. Patients presenting with hemoptysis had shorter first line delays. The RODP care was generally far more timely compared to literature and published guidelines, except for both referral and palliative therapeutic delay. No specific delay was significantly related to disease stage or survival. CONCLUSIONS: An RODP results in a timely diagnosis well within guideline recommendations. Patient and first line delay account for most of total patient delay. Within the limitations of this retrospective study, we found no association with disease stage or survival.

Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: spatial distribution and prognostic value of GLUT1 and MCT4.

BACKGROUND: Hypoxia leads to changes in tumor cell metabolism such as increased glycolysis. In this study, we examined the spatial distribution of the glycolysis and hypoxia related markers glucose transporter 1 (GLUT1) and monocarboxylate transporter 4 (MCT4) expression in relation to the vasculature in stage I, II and resectable stage IIIA NSCLC. Furthermore, associations of these markers with survival were investigated. METHODS: GLUT1 and MCT4 expression were determined in 90 NSCLC fresh frozen biopsies using immunohistochemical techniques and a computerized image analysis system. Markers were analyzed for adenocarcinomas (n=41) and squamous cell carcinomas (n=34) separately. Eighty-four patients were retrospectively evaluated for relapse and survival. RESULTS: Squamous cell carcinomas demonstrated higher GLUT1 expression, relative to adenocarcinomas. Also, in squamous cell carcinomas, GLUT1 and MCT4 expression increased with increasing distance from the vasculature, whereas in adenocarcinomas upregulation of MCT4 was already found at closer distance from vessels. In adenocarcinomas, high GLUT1 expression correlated with a poor differentiation grade and positive lymph nodes at diagnosis. High GLUT1 plus high MCT4 expression was associated with a poor disease-specific survival in only adenocarcinomas (p=0.032). CONCLUSION: Analysis of GLUT1 and MCT4 expression on the histological level suggested a different metabolism for adenocarcinomas and squamous cell carcinomas. Likely, adenocarcinomas rely mainly on aerobic glycolysis for ATP production, whereas the behavior of squamous cell carcinomas is more physiologically, i.e. mitochondrial oxidation with anaerobic glycolysis under hypoxic conditions. High GLUT1 plus high MCT4 expression indicated an aggressive tumor behavior in adenocarcinomas. This subgroup of tumors may benefit from new treatment approaches, such as MCT4 inhibitors. Since this study has an exploratory character, our results warrant further investigation and need independent validation.

EUS-FNA for the detection of left adrenal metastasis in patients with lung cancer.

In patients with lung cancer, enlarged or (18)Fluoro-deoxyglucose positron emission tomography ((18)FDG-PET) positive left adrenal glands are suspected for distant metastases and require tissue confirmation for a definitive assessment. The aim of this study was to assess the sensitivity of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for left adrenal metastases in lung cancer patients with a suspect adrenal gland based on imaging. EUS-FNA findings of patients with (suspected) lung cancer and CT enlarged or (18)FDG-PET positive left adrenal glands were retrospectively evaluated. In the absence of metastases at EUS, clinical and radiological follow-up was obtained. In 85 patients, EUS-FNA demonstrated left adrenal metastases of lung cancer in 53 (62%), benign adrenal tissue in 25 (29%), a metastasis from colon carcinoma in 1 (1%) and a primary adrenocortical carcinoma in 1 (1%) patient. In five patients (5.9%), the aspirates contained non-representative material. EUS outcomes were false negative in two patients. Sensitivity and negative predictive value (NPV) for EUS-FNA of the left adrenal gland were at least 86% (95% CI 74-93%) and 70% (95% CI 50-85%). No complications occurred. EUS-FNA is a sensitive, safe and minimally invasive technique to provide tissue proof of left adrenal metastases in patients with (suspected) lung cancer and enlarged or (18)FDG-PET positive adrenal glands. Therefore, EUS-FNA qualifies as the staging test of choice for patients with lung cancer with suspected left adrenal metastases.

Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk.

Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 × 10(-9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 × 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.

Non-invasive mechanical ventilation for diagnostic bronchoscopy using a new face mask: an observational feasibility study.

PURPOSE: Bronchoscopy is an indispensable tool for invasive pulmonary evaluation with high diagnostic yield and low incidence of major complications. However, hypoxemia increases the risk of complications, in particular after bronchoalveolar lavage. Non-invasive positive pressure ventilation may prevent hypoxemia associated with bronchoalveolar lavage. The purpose of this study is to present a modified total face mask to aid bronchoscopy during non-invasive positive pressure ventilation. METHODS: A commercially available full face mask was modified to allow introduction of the bronchoscope without interfering with the ventilator circuit. Bronchoscopy with bronchoalveolar lavage was performed in 12 hypoxemic non-ICU patients during non-invasive positive pressure ventilation in the ICU. RESULTS: Patients had severely impaired oxygen uptake as indicated by PaO(2)/FiO(2) ratio 192 +/- 23 mmHg before bronchoscopy. Oxygenation improved after initiation of non-invasive positive pressure ventilation. In all patients the procedure could be completed without subsequent complications, although in one patient SpO(2) decreased until 86% during bronchoscopy. A microbiological diagnosis could be established in 8 of 12 patients with suspected for infection. CONCLUSIONS: Our modified face mask for non-invasive positive pressure ventilation is a valuable tool to aid diagnostic bronchoscopy in hypoxemic patients.

A brief retrospective report on the feasibility of epidermal growth factor receptor and KRAS mutation analysis in transesophageal ultrasound- and endobronchial ultrasound-guided fine needle cytological aspirates.

INTRODUCTION: Molecular testing for epidermal growth factor receptor (EGFR) and KRAS mutations is of increasing clinical importance in daily practice. In this study, we aimed to investigate the yield and applicability of molecular testing for KRAS and EGFR mutations in cytologic specimens obtained by EUS or endobronchial ultrasound (EBUS)-guided fine needle aspiration (FNA). METHODS: We selected all patients with an EUS- or EBUS-guided FNA positive for lung adenocarcinoma from the database of our tertiary care center for endosonography. Direct smears were Giemsa and Papanicolaou stained. The remaining material was processed in cell blocks. Both cell blocks and smears were considered suitable for molecular analysis when >40% of the aspirated cells were tumor cells. All eligible samples were investigated for KRAS and EGFR mutations by polymerase chain reaction followed by direct sequencing. RESULTS: Four hundred sixty-two patients underwent EUS or EBUS-FNA using 22-gauge needles. In 35 patients, FNA showed lung adenocarcinoma. In eight patients, molecular analysis could not be performed because of insufficient material after routine and immunocytochemistry (n = 3), a low percentage (<40%) of tumor cells (n = 3), or an insufficient DNA quality (n = 2). The average percentage of tumor cells was 73% ± 23%. Molecular analysis could reliably be performed in 27 patients (77%). Mutation analysis showed KRAS and EGFR mutations in tumor samples from 10 (37%) and two (7%) patients, respectively. In one patient, two EGFR mutations (p.Thr790Met and p.Leu858Arg) were detected. CONCLUSIONS: Molecular analysis for KRAS and EGFR mutations can be performed routinely in cytologic specimens from EUS- and EBUS-guided FNA.

Clinical aspects and treatment of primary tracheal malignancies.

CONCLUSIONS: Selecting patients that are candidates for surgical treatment is important in the work-up of patients with tracheal cancer. Toward this goal, centralization of care concerning tracheal tumors is advised. Centralization may increase long-term survival and decrease operative morbidity and mortality even further. OBJECTIVE: Primary tracheal tumors pose a diagnostic and therapeutic challenge for the physician when confronted with this mostly malignant tumor. Diagnosis is often delayed for months or years due to its aspecific and asthma-mimicking symptoms. Knowledge from retrospective series is limited and few clinicians have gained experience with this tumor. The available literature on the diagnosis and management of this group of tumors is reviewed to summarize the available knowledge about these uncommon tumors. New diagnostic, staging, and treatment guidelines are proposed. METHODS: PubMed was searched for English publications from 1960. The available literature was reviewed and summarized. RESULTS: Surgical resection and primary reconstruction is the best curative treatment modality available at present. In centers of experience, more than half of all patients with tracheal cancer may be candidates for surgical resection, although in population-based studies this treatment is applied in only 10-25% of patients.

Circulating DNA is a non-invasive prognostic factor for survival in non-small cell lung cancer.

INTRODUCTION: Circulating plasma DNA is present in a considerably higher concentration in lung cancer patients than in controls. Conflicting data are reported about circulating DNA as a prognostic factor. The aim of this study was to prospectively analyse the relationship of circulating plasma DNA with overall survival (OS) of previously untreated non-small cell lung cancer (NSCLC) patients. METHODS: 46 untreated NSCLC patients and 21 controls with a follow-up time of 6.5 years were analyzed. Quantification of baseline circulating plasma DNA was performed by a real-time quantitative polymerase chain reaction (qPCR) targeting the human beta-globin gene. Survival analysis was performed using the Kaplan-Meier method and compared with a Cox-regression analysis. RESULTS: The median DNA concentration of the patients who died (87%) was significantly higher compared to the patients that survived at the end of follow-up (55ng/ml versus 23ng/ml, p=0.02). In patients with higher DNA concentration overall survival was significantly worse. In this study no relation of DNA concentration with tumour characteristics, age, gender or pulmonary inflammatory conditions was found. CONCLUSION: In this study a high circulating plasma DNA concentration at time of diagnosis in NSCLC patients was a prognostic factor for poorer survival. Circulating DNA may be used as a non-invasive biomarker to refine the prognostic profile in NSCLC patients.

Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.

BACKGROUND: Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies. METHODS: Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided. RESULTS: Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer. CONCLUSIONS: In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer.

The phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (AKT) pathway is associated with all three major radiation resistance mechanisms: intrinsic radiosensitivity, tumor cell proliferation, and hypoxia. In cell signaling cascades, the PI3-K/AKT signaling pathway is a key regulator of normal and cancerous growth and cell fate decisions by processes such as proliferation, invasion, apoptosis, and induction of hypoxia-related proteins. Activation of this pathway can be the result of stimulation of receptor tyrosine kinases such as epidermal growth factor receptor or vascular endothelial growth factor receptor or from mutations or amplification of PI3-K or AKT itself which are frequently found in non-small cell lung cancer (NSCLC). Furthermore, several treatment modalities such as radiotherapy can stimulate this survival pathway. Monitoring and manipulation of this signal transduction pathway may have important implications for the management of NSCLC. Strong and independent associations were found between expression of activated AKT (pAKT) and treatment outcome in clinical trials. Direct targeting and inhibition of this pathway may increase radiosensitivity by antagonizing the radiation induced cellular defense mechanisms especially in tumors that have activated the PI3-K/AKT cascade. To successfully implement these treatments in daily practice, there is a need for molecular predictors of sensitivity to inhibitors of PI3-K/AKT activation. In conclusion, the PI3-K/AKT pathway plays a crucial role in cellular defense mechanisms. Therefore, quantification of the activation status is a potential parameter for predicting treatment outcome. More importantly, specific targeting of this pathway in combination with radiotherapy or chemotherapy may enhance tumor control in NSCLC by antagonizing cellular defense in response to treatment.

Impaired isotonic contractility and structural abnormalities in the diaphragm of congestive heart failure rats.

BACKGROUND: Metabolic alterations and decreased isometric force generation have been demonstrated in different animal models for congestive heart failure (CHF). However, as few morphological examinations have been performed on the CHF diaphragm, it is unknown if structural abnormalities comprise a substrate for diaphragm dysfunction in CHF. Therefore, we investigated CHF diaphragm isometric and isotonic contractility together with the presence of structural abnormalities. METHODS: Isometric twitch (P(t)) and maximal (P(o)) force, shortening velocity and power generation were determined in diaphragm bundles from rats with CHF, induced by myocardial infarction, and sham-operated rats. Immunofluorescence staining of myosin and sarcolemmal components fibronectin, laminin and dystrophin was performed on diaphragm cryosections. Electron microscopy was used to study the ultrastructure of diaphragm fibres. RESULTS: P(t) and P(o) were respectively approximately 30% and approximately 20% lower in CHF diaphragm bundles than sham. Maximal shortening velocity was reduced by approximately 20% and maximal power generation by approximately 35%. Structural abnormalities were frequently observed in CHF diaphragm fibres and were mainly marked by focal degradation of sarcomeric constituents and expansion of intermyofibrillar spaces with swollen and degenerated mitochondria. Immunofluorescence microscopy showed reduced staining intensities of myosin in CHF diaphragm fibres compared to sham. No differences were found regarding the distribution of fibronectin, laminin and dystrophin, indicating an intact sarcolemma in both groups. CONCLUSION: This study demonstrates impaired isometric and isotonic contractility together with structural abnormalities in the CHF diaphragm. The sarcolemma of CHF diaphragm fibres appeared to be intact, excluding a role for sarcolemmal injuries in the development of CHF diaphragm dysfunction.

Prognostic value of different metabolic measurements with fluorine-18 fluorodeoxyglucose positron emission tomography in resectable non-small cell lung cancer: a two-center study.

INTRODUCTION: Standard uptake value (SUV) is a quantitative measure for the preferential uptake of a radiopharmaceutical in a tumor compared with the homogeneous distribution in the body. SUV can be based on the maximal value of one pixel (SUVmax) or on the mean value in a region outlined by isodensity contours. The prognostic value of different SUVs in non-small cell lung cancer (NSCLC) is not established. We evaluated this value for SUVmax, SUV70%, and SUV50% among patients with resectable NSCLC. METHODS: All consecutive patients with resectable NSCLC who underwent an attenuation-corrected whole-body fluorine-18 fluorodeoxyglucose positron emission tomography scan from two university hospitals were selected. By adjusting the isocontour in the region of interest on the scan, SUVmax, SUV70%, and SUV50% of the primary tumor were calculated. RESULTS: Sixty-six patients (50 male, median age 63 years) were included. Of the tumors, 16 were pathological stage IA, 23 were IB, 4 were IIA, 14 were IIB, and 9 were IIIA. Median (range) values for SUVmax, SUV70%, and SUV50% were 6.4 (1.6-19.1), 5.1 (1.0-15.7), and 4.0 (0.9-13.4), respectively. SUVs were associated with survival. Analysis of residuals of SUVmax as a continuous variable in a Cox's proportional hazard model for survival suggested no cutoff point and no indication of time-dependency. Patients with a SUV higher than the median value had a worse survival than patients with a SUV lower than median (hazard ratios for SUVmax, SUV70%, and SUV50% all were 2.9; p = 0.02). CONCLUSIONS: SUVmax, SUV70%, and SUV50% measured with fluorine-18 fluorodeoxyglucose positron emission tomography have a similar prognostic value, and no "natural" cutoff point for SUVmax in resectable NSCLC was identified.