Multimodality approach to mediastinal staging in non-small cell lung cancer. Faults and benefits of PET-CT: a randomised trial.

BACKGROUND: Correct mediastinal staging is a cornerstone in the treatment of patients with non-small cell lung cancer. A large range of methods is available for this purpose, making the process of adequate staging complex. The objective of this study was to describe faults and benefits of positron emission tomography (PET)-CT in multimodality mediastinal staging. METHODS: A randomised clinical trial was conducted including patients with a verified diagnosis of non-small cell lung cancer, who were considered operable. Patients were assigned to staging with PET-CT (PET-CT group) followed by invasive staging (mediastinoscopy and/or endoscopic ultrasound with fine needle aspiration (EUS-FNA)) or invasive staging without prior PET-CT (conventional work up (CWU) group). Mediastinal involvement (dichotomising N stage into N0-1 versus N2-3) was described according to CT, PET-CT, mediastinoscopy, EUS-FNA and consensus (based on all available information), and compared with the final N stage as verified by thoracotomy or a conclusive invasive diagnostic procedure. RESULTS: A total of 189 patients were recruited, 98 in the PET-CT group and 91 in the CWU group. In an intention-to-treat analysis the overall accuracy of the consensus N stage was not significantly higher in the PET-CT group than in the CWU group (90% (95% confidence interval 82% to 95%) vs 85% (95% CI 77% to 91%)). Excluding the patients in whom PET-CT was not performed (n=14) the difference was significant (95% (95% CI 88% to 98%) vs 85% (95% CI 77% to 91%), p=0.034). This was mainly based on a higher sensitivity of the staging approach including PET-CT. CONCLUSION: An approach to lung cancer staging with PET-CT improves discrimination between N0-1 and N2-3. In those without enlarged lymph nodes and a PET-negative mediastinum the patient may proceed directly to surgery. However, enlarged lymph nodes on CT needs confirmation independent of PET findings and a positive finding on PET-CT needs confirmation before a decision on surgery is made. CLINICAL TRIAL NUMBER: NCT00867412.

An extremely metal-deficient globular cluster in the Andromeda Galaxy.

Globular clusters (GCs) are dense, gravitationally bound systems of thousands to millions of stars. They are preferentially associated with the oldest components of galaxies, so measurements of their composition can constrain the build-up of chemical elements in galaxies during the early Universe. We report a massive GC in the Andromeda Galaxy (M31), RBC EXT8, that is extremely depleted in heavy elements. Its iron abundance is about 1/800 that of the Sun and about one-third that of the most iron-poor GCs previously known. It is also strongly depleted in magnesium. These measurements challenge the notion of a metallicity floor for GCs and theoretical expectations that massive GCs could not have formed at such low metallicities.

Globular cluster formation and evolution in the context of cosmological galaxy assembly: open questions.

We discuss some of the key open questions regarding the formation and evolution of globular clusters (GCs) during galaxy formation and assembly within a cosmological framework. The current state of the art for both observations and simulations is described, and we briefly mention directions for future research. The oldest GCs have ages greater than or equal to 12.5 Gyr and formed around the time of reionization. Resolved colour-magnitude diagrams of Milky Way GCs and direct imaging of lensed proto-GCs at z∼6 with the James Webb Space Telescope (JWST) promise further insight. GCs are known to host multiple populations of stars with variations in their chemical abundances. Recently, such multiple populations have been detected in ∼2 Gyr old compact, massive star clusters. This suggests a common, single pathway for the formation of GCs at high and low redshift. The shape of the initial mass function for GCs remains unknown; however, for massive galaxies a power-law mass function is favoured. Significant progress has been made recently modelling GC formation in the context of galaxy formation, with success in reproducing many of the observed GC-galaxy scaling relations.

Fluorescence versus X-ray cholangiography during laparoscopic cholecystectomy: protocol for a randomised trial.

INTRODUCTION: Intraoperative fluorescent cholangiography is a novel non-invasive imaging technique to visualise the extrahepatic biliary tract during laparoscopic cholecystectomy. It has been proven feasible, fast and cost effective. Never-theless, there is only sparse data on the capacity of fluorescent cholangiography to visualise the biliary anatomy. METHODS: Based on a non-inferiority design, patients with complicated gallstone disease are randomised to either -intraoperative conventional X-ray cholangiography (reference group, n = 60) or intraoperative fluorescent cholangiography (n = 60). The primary outcome is visualisation of the junction between the cystic duct, the common hepatic duct and the common bile duct. CONCLUSION: The present study may show that fluorescent cholangiography is as valid for visualisation of important structures of the extrahepatic biliary tract as conventional X-ray cholangiography. This may lead to the introduction of online imaging of the extrahepatic tract during dissection of the gallbladder during cholecystectomy. FUNDING: none. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov (No. NCT02344654), with the National Committee on Health Research Ethics (Reg. no. H-15000817) and with the Danish Data Protection Agency (Reg no. AHH- 2015-005).

The effect of the new SERM arzoxifene on growth and gene expression in MCF-7 breast cancer cells.

The benzothiophene arzoxifene is a new 3rd generation selective estrogen receptor (ER) modulator (SERM). We have investigated the effect of arzoxifene on growth and gene expression in the estrogen receptor alpha (ERalpha) positive human breast cancer cell line MCF-7. Arzoxifene inhibits cell growth as effectively as the antiestrogen tamoxifen. Northern analysis revealed that arzoxifene exerts a statistically significant inhibition of pS2 and progesterone receptor B mRNA expression. Significant agonistic effect was observed on the antitrypsin mRNA expression. In contrast to estradiol and tamoxifen, arzoxifene does not upregulate cathepsin D mRNA and protein expression. The metabolite of arzoxifene (ARZm) is a more potent growth inhibitor of MCF-7 cells than arzoxifene. A tamoxifen resistant MCF-7 subline displayed a significant dose-dependent growth inhibition to ARZm, whereas an ICI 182,780 resistant cell line only responded to high concentration. Our results indicate that arzoxifene and especially ARZm are efficient growth inhibitors of ER positive human breast cancer cells, including tamoxifen resistant cells. Moreover, arzoxifene displays less estrogen agonistic effects in MCF-7 cells than tamoxifen.

Non-radiographic intraoperative fluorescent cholangiography is feasible.

INTRODUCTION: Intraoperative fluorescent cholangiography (IFC) with concomitant fluorescent angiography was recently developed for non-invasive identification of the anatomy during laparoscopic cholecystectomy. The objective of this study was to assess the time required for routine-use of IFC and to evaluate the success rate of the procedures. MATERIAL AND METHODS: A total of 35 patients scheduled for laparoscopic cholecystectomy and operated by the same surgeon were consecutively enrolled. A standardised protocol with IFC including angiography was performed during laparoscopic cholecystectomy. Intraoperative time and exposure of predefined anatomical structures were recorded. RESULTS: The median time used for IFC was 2.6 minutes (range: 1.5-11.4 minutes) corresponding to a median of 6.2% (range: 3.0-15.2%) of the operation time. The junction between the cystic duct, the common bile duct and the common hepatic duct was identified by IFC in all patients. In 29 of the 35 patients (83%; 95% confidence interval: 71-96%), the cystic artery was visualised by fluorescent angiography. No adverse effects or complications were recorded. CONCLUSION: Routine-use of IFC with fluorescent angiography during laparoscopic cholecystectomy is feasible and associated with an acceptable time expenditure and a satisfactory success-rate. FUNDING: Not relevant. TRIAL REGISTRATION: The Regional Ethics Committee approved the study (J. No. H-3-2013-FSP45). The study is registered with clinicaltrials.gov (ID: NCT02136095).

Young and intermediate-age massive star clusters.

An overview of our current understanding of the formation and evolution of star clusters is given, with the main emphasis on high-mass clusters. Clusters form deeply embedded within dense clouds of molecular gas. Left-over gas is cleared within a few million years and, depending on the efficiency of star formation, the clusters may disperse almost immediately or remain gravitationally bound. Current evidence suggests that a small percentage of star formation occurs in clusters that remain bound, although it is not yet clear whether this fraction is truly universal. Internal two-body relaxation and external shocks will lead to further, gradual dissolution on time scales of up to a few hundred million years for low-mass open clusters in the Milky Way, while the most massive clusters (>10(5) M(o)) have lifetimes comparable to or exceeding the age of the Universe. The low-mass end of the initial cluster mass function is well approximated by a power-law distribution, dN/dM proportional to M(-2), but there is mounting evidence that quiescent spiral discs form relatively few clusters with masses M > 2 x 10(5) M(o). In starburst galaxies and old globular cluster systems, this limit appears to be higher, at least several x10(6) M(o). The difference is likely related to the higher gas densities and pressures in starburst galaxies, which allow denser, more massive giant molecular clouds to form. Low-mass clusters may thus trace star formation quite universally, while the more long-lived, massive clusters appear to form preferentially in the context of violent star formation.