Impact of 90Y PET gradient-based tumor segmentation on voxel-level dosimetry in liver radioembolization

Abstract Background The purpose was to validate 90Y PET gradient-based tumor segmentation in phantoms and to evaluate the impact of the segmentation method on reported tumor absorbed dose (AD) and biological effective dose (BED) in 90Y microsphere radioembolization (RE) patients. A semi-automated gradient-based method was applied to phantoms and patient tumors on the 90Y PET with the initial bounding volume for gradient detection determined from a registered diagnostic CT or MR; this PET-based segmentation (PS) was compared with radiologist-defined morphologic segmentation (MS) on CT or MRI. AD and BED volume histogram metrics (D90, D70, mean) were calculated using both segmentations and concordance/correlations were investigated. Spatial concordance was assessed using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). PS was repeated to assess intra-observer variability. Results In phantoms, PS demonstrated high accuracy in lesion volumes (within 15%), AD metrics (within 11%), high spatial concordance relative to morphologic segmentation (DSC > 0.86 and MDA  0.99, MDA < 0.2 mm, AD/BED metrics within 2%). For patients (58 lesions), spatial concordance between PS and MS was degraded compared to in-phantom (average DSC = 0.54, average MDA = 4.8 mm); the average mean tumor AD was 226 ± 153 and 197 ± 138 Gy, respectively for PS and MS. For patient AD metrics, the best Pearson correlation (r) and concordance correlation coefficient (ccc) between segmentation methods was found for mean AD (r = 0.94, ccc = 0.92), but worsened as the metric approached the minimum dose (for D90, r = 0.77, ccc = 0.69); BED metrics exhibited a similar trend. Patient PS showed low intra-observer variability (average DSC = 0.81, average MDA = 2.2 mm, average AD/BED metrics within 3.0%). Conclusions 90Y PET gradient-based segmentation led to accurate/robust results in phantoms, and showed high concordance with MS for reporting mean tumor AD/BED in patients. However, tumor coverage metrics such as D90 exhibited worse concordance between segmentation methods, highlighting the need to standardize segmentation methods when reporting AD/BED metrics from post-therapy 90Y PET. Estimated differences in reported AD/BED metrics due to segmentation method will be useful for interpreting RE dosimetry results in the literature including tumor response data.https://deepblue.lib.umich.edu/bitstream/2027.42/146544/1/40658_2018_Article_230.pd

Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders

Loss of chromosome 7 (-7) or deletion of the long arm (7q-) are recurring chromosome abnormalities in myeloid leukemias. The association of - 7/7q- with myeloid leukemia suggests that these regions contain novel tumor suppressor gene(s), whose loss of function contribute to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified, one in band q22 and another in bands q32-q35. Presently there are no data available on the molecular delineation of the distal critical region. In this study we analyzed bone marrow and blood samples from 13 patients with myeloid leukemia (de novo myelodysplastic syndrome [MDS], n=3; de novo acute myeloid leukemia [AML], n=9; therapy-related (t-) AML, n=1) which, on chromosome banding analysis, exhibited deletions (n=12) or in one case a balanced translocation involving bands 7q31-qter using fluorescence in situ hybridization (FISH). As probes we used representative clones from a contig map of yeast artificial chromosome (YAC) clones that spans chromosome bands 7q31.1-qter. In the 12 cases with loss of 7q material, we identified a commonly deleted region of approximately 4 to 5 megabasepairs in size encompassing the distal part of 7q35 and the proximal part of 7q36. Furthermore, the breakpoint of the reciprocal translocation from the patient with t-AML was localized to a 1,300-kb sized YAC clone that maps to the proximal boundary of the commonly deleted region. Interestingly, in this case both homologs of chromosome 7 were affected: one was lost (-7) and the second exhibited the t(7q35). The identification and delineation of translocation and deletion breakpoints provides the first step toward the identification of the gene(s) involved in the pathogenesis of 7q35-q36 aberrations in myeloid disorders.link_to_OA_fulltex

Imaging Primary Mouse Sarcomas After Radiation Therapy Using Cathepsin-Activatable Fluorescent Imaging Agents

Purpose: Cathepsin-activated fluorescent probes can detect tumors in mice and in canine patients. We previously showed that these probes can detect microscopic residual sarcoma in the tumor bed of mice during gross total resection. Many patients with soft tissue sarcoma (STS) and other tumors undergo radiation therapy (RT) before surgery. This study assesses the effect of RT on the ability of cathepsin-activated probes to differentiate between normal and cancerous tissue. Methods and Materials: A genetically engineered mouse model of STS was used to generate primary hind limb sarcomas that were treated with hypofractionated RT. Mice were injected intravenously with cathepsin-activated fluorescent probes, and various tissues, including the tumor, were imaged using a hand-held imaging device. Resected tumor and normal muscle samples were harvested to assess cathepsin expression by Western blot. Uptake of activated probe was analyzed by flow cytometry and confocal microscopy. Parallel in vitro studies using mouse sarcoma cells were performed. Results: RT of primary STS in mice and mouse sarcoma cell lines caused no change in probe activation or cathepsin protease expression. Increasing radiation dose resulted in an upward trend in probe activation. Flow cytometry and immunofluorescence showed that a substantial proportion of probe-labeled cells were CD11b-positive tumor-associated immune cells. Conclusions: In this primary murine model of STS, RT did not affect the ability of cathepsin-activated probes to differentiate between tumor and normal muscle. Cathepsin-activated probes labeled tumor cells and tumor-associated macrophages. Our results suggest that it would be feasible to include patients who have received preoperative RT in clinical studies evaluating cathepsin-activated imaging probes.Damon Runyon Cancer Research Foundation (Damon Runyon-Rachleff Innovation Award

The orbital period, black hole mass and distance to the X-ray transient GRS 1716-249 (=N Oph 93)

We present evidence for a 0.278(8) d (=6.7 h) orbital period in the X-ray transient GRS 1716-249 (=N Oph 93), based on a superhump modulation detected during the 1995 mini-outburst plus ellipsoidal variability in quiescence. With a quiescent magnitude of r=23.19+-0.15 N Oph 93 is too faint to warrant a full dynamical study through dedicated time-resolved spectroscopy. Instead, we apply the FWHM-K2 correlation to the disc Halpha emission line detected in Gran Telescopio Canarias spectra and obtain K2=521+-52 km/s. This leads to a mass function f(M)=4.1+-1.2 Msun, thus indicating the presence of a black hole in this historic X-ray transient. Furthermore, from the depth of the Halpha trough and the quiescent light curve we constrain the binary inclination to i=61+-15 deg, while the detection of superhumps sets an upper limit to the donor to compact star mass ratio q=M2/M1<=0.25. Our de-reddened (r-i) colour is consistent with a ~K6 main sequence star that fills its Roche lobe in a 0.278 d orbit. Using all this information we derive a compact object mass M1=6.4+3.2-2.0 Msun at 68 per cent confidence. We also constrain the distance to GRS 1716-249 to 6.9+-1.1 kpc, placing the binary ~0.8 kpc above the Galactic Plane, in support of a large natal kick.Comment: Accepted for publication in MNRAS, 12 pages, 9 figures, 2 Table

NICER observations reveal that the X-ray transient MAXI J1348-630 is a black hole X-ray binary

We studied the outburst evolution and timing properties of the recently discovered X-ray transient MAXI J1348-630 as observed with NICER. We produced the fundamental diagrams commonly used to trace the spectral evolution, and power density spectra to study the fast X-ray variability. The main outburst evolution of MAXI J1348-630 is similar to that commonly observed in black hole transients. The source evolved from the hard state (HS), through hard- and soft-intermediate states, into the soft state in the outburst rise, and back to the HS in reverse during the outburst decay. At the end of the outburst, MAXI J1348-630 underwent two reflares with peak fluxes approximately one and two orders of magnitude fainter than the main outburst, respectively. During the reflares, the source remained in the HS only, without undergoing any state transitions, which is similar to the so-called 'failed outbursts'. Different types of quasi-periodic oscillations (QPOs) are observed at different phases of the outburst. Based on our spectral-timing results, we conclude that MAXI J1348-630 is a black hole candidate

NICER observations reveal that the X-ray transient MAXI J1348-630 is a Black Hole X-ray binary

We studied the outburst evolution and timing properties of the recently discovered X-ray transient MAXI J1348-630 as observed with NICER. We produced the fundamental diagrams commonly used to trace the spectral evolution, and power density spectra to study the fast X-ray variability. The main outburst evolution of MAXI J1348-630 is similar to that commonly observed in black hole transients. The source evolved from the hard state, through hard- and soft-intermediate states, into the soft state in the outburst rise, and back to the hard state in reverse during the outburst decay. At the end of the outburst, MAXI J1348-630 underwent two reflares with peak fluxes ~1 and ~2 orders of magnitude fainter than the main outburst, respectively. During the reflares, the source remained in the hard state only, without undergoing any state transitions, which is similar to the so-called "failed outbursts". Different types of quasi-periodic oscillations (QPOs) are observed at different phases of the outburst. Based on our spectral-timing results, we conclude that MAXI J1348-630 is a black hole candidate.Comment: 12 pages, 8 figures, 1 table, accepted for publication in MNRA

A NICER look at the state transitions of the black hole candidate MAXI J1535−571 during its reflares

The black hole candidate and X-ray binary MAXI J1535−571 was discovered in 2017 September. During the decay of its discovery outburst, and before returning to quiescence, the source underwent at least four reflaring events, with peak luminosities of ∼1035?36 erg s−1 (d/4.1 kpc)2. To investigate the nature of these flares, we analysed a sample of NICER (Neutron star Interior Composition Explorer) observations taken with almost daily cadence. In this work, we present the detailed spectral and timing analysis of the evolution of the four reflares. The higher sensitivity of NICER at lower energies, in comparison with other X-ray detectors, allowed us to constrain the disc component of the spectrum at ∼0.5 keV. We found that during each reflare the source appears to trace out a q-shaped track in the hardness?intensity diagram similar to those observed in black hole binaries during full outbursts. MAXI J1535−571 transits between the hard state (valleys) and softer states (peaks) during these flares. Moreover, the Comptonized component is undetected at the peak of the first reflare, while the disc component is undetected during the valleys. Assuming the most likely distance of 4.1 kpc, we find that the hard-to-soft transitions take place at the lowest luminosities ever observed in a black hole transient, while the soft-to-hard transitions occur at some of the lowest luminosities ever reported for such systems.Fil: Cuneo, Virginia. Universidad de La Laguna; España. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Alabarta, K.. University of Southampton; Reino UnidoFil: Zhang, L.. University of Southampton; Reino UnidoFil: Altamirano, D.. University of Southampton; Reino UnidoFil: Méndez, M.. University Of Groningen; Países BajosFil: Armas Padilla, M.. Universidad de La Laguna; EspañaFil: Remillard, R.. MIT Kavli Institute For Astrophysics And Space Research; Estados UnidosFil: Homan, J.. Sron Netherlands Institute For Space Research; Países BajosFil: Steiner, J. F.. Harvard University; Estados UnidosFil: Combi, Jorge Ariel. Universidad Nacional de La Plata; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Muñoz- Darias, T.. Universidad de La Laguna; España. Instituto Astrofisico de Canarias; EspañaFil: Gendreau, K. C.. Nasa Goddard Space Flight Center; Estados UnidosFil: Arzoumanian, Z.. Nasa Goddard Space Flight Center; Estados UnidosFil: Stevens, A. L.. Michigan State University; Estados UnidosFil: Loewenstein, M.. University of Maryland; Estados UnidosFil: Tombesi, F.. Universita Tor Vergata; Italia. University of Maryland; Estados UnidosFil: Bult, P.. University of Maryland; Estados UnidosFil: Fabian, A. C.. Institute of Astronomy; Reino UnidoFil: Buisson, D.J.K.. University of Southampton; Reino UnidoFil: Neilsen, J.. Villanova University; Estados UnidosFil: Basak, A.. University of Amsterdam; Países Bajo

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes

NEMO: A Project for a km3^3 Underwater Detector for Astrophysical Neutrinos in the Mediterranean Sea

The status of the project is described: the activity on long term characterization of water optical and oceanographic parameters at the Capo Passero site candidate for the Mediterranean km$^3$ neutrino telescope; the feasibility study; the physics performances and underwater technology for the km$^3$; the activity on NEMO Phase 1, a technological demonstrator that has been deployed at 2000 m depth 25 km offshore Catania; the realization of an underwater infrastructure at 3500 m depth at the candidate site (NEMO Phase 2).Comment: Proceeding of ISCRA 2006, Erice 20-27 June 200