| 1. |
- Das, Anirban, et al.
(author)
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Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.
- 2024
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In: Cancer discovery. - 2159-8290. ; 14:2, s. 258-273
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Journal article (peer-reviewed)abstract
- Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
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| 2. |
- Ercan, Ayse Bahar, et al.
(author)
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Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
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In: The Lancet Oncology. - 1470-2045. ; 25:5, s. 668-682
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Journal article (peer-reviewed)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
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| 3. |
- Abdalla, H., et al.
(author)
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A very-high-energy component deep in the gamma-ray burst afterglow
- 2019
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 575:7783, s. 464-467
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Journal article (peer-reviewed)abstract
- Gamma-ray bursts (GRBs) are brief flashes of gamma-rays and are considered to be the most energetic explosive phenomena in the Universe(1). The emission from GRBs comprises a short (typically tens of seconds) and bright prompt emission, followed by a much longer afterglow phase. During the afterglow phase, the shocked outflow-produced by the interaction between the ejected matter and the circumburst medium-slows down, and a gradual decrease in brightness is observed(2). GRBs typically emit most of their energy via.-rays with energies in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with energies of tens of gigaelectronvolts have been detected by space-based instruments(3). However, the origins of such high-energy (above one gigaelectronvolt) photons and the presence of very-high-energy (more than 100 gigaelectronvolts) emission have remained elusive(4). Here we report observations of very-high-energy emission in the bright GRB 180720B deep in the GRB afterglow-ten hours after the end of the prompt emission phase, when the X-ray flux had already decayed by four orders of magnitude. Two possible explanations exist for the observed radiation: inverse Compton emission and synchrotron emission of ultrarelativistic electrons. Our observations show that the energy fluxes in the X-ray and gamma-ray range and their photon indices remain comparable to each other throughout the afterglow. This discovery places distinct constraints on the GRB environment for both emission mechanisms, with the inverse Compton explanation alleviating the particle energy requirements for the emission observed at late times. The late timing of this detection has consequences for the future observations of GRBs at the highest energies.
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| 4. |
- Abdo, A. A., et al.
(author)
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DETECTION OF GAMMA-RAY EMISSION FROM THE STARBURST GALAXIES M82 AND NGC 253 WITH THE LARGE AREA TELESCOPE ON FERMI
- 2010
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In: The Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 709:2, s. l152-L157
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Journal article (peer-reviewed)abstract
- We report the detection of high-energy gamma-ray emission from two starburst galaxies using data obtained with the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. Steady point-like emission above 200 MeV has been detected at significance levels of 6.8 sigma and 4.8 sigma, respectively, from sources positionally coincident with locations of the starburst galaxies M82 and NGC 253. The total fluxes of the sources are consistent with gamma-ray emission originating from the interaction of cosmic rays with local interstellar gas and radiation fields and constitute evidence for a link between massive star formation and gamma-ray emission in star-forming galaxies.
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| 5. |
- Abdo, A. A., et al.
(author)
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FERMI Large Area Telescope and multi-wavelength observations of the flaring activity of PKS 1510-089 between 2008 september and 2009 june
- 2010
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 721:2, s. 1425-1447
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Journal article (peer-reviewed)abstract
- We report on the multi-wavelength observations of PKS 1510-089 (a flat spectrum radio quasar (FSRQ) at z = 0.361) during its high activity period between 2008 September and 2009 June. During this 11 month period, the source was characterized by a complex variability at optical, UV, and gamma-ray bands, on timescales down to 6-12 hr. The brightest gamma-ray isotropic luminosity, recorded on 2009 March 26, was similar or equal to 2 x 1048 erg s-1. The spectrum in the Fermi Large Area Telescope energy range shows a mild curvature described well by a log-parabolic law, and can be understood as due to the Klein-Nishina effect. The. -ray flux has a complex correlation with the other wavelengths. There is no correlation at all with the X-ray band, a weak correlation with the UV, and a significant correlation with the optical flux. The. -ray flux seems to lead the optical one by about 13 days. From the UV photometry, we estimated a black hole mass of similar or equal to 5.4 x 10(8)M(circle dot) and an accretion rate of similar or equal to 0.5M(circle dot) yr(-1). Although the power in the thermal and non-thermal outputs is smaller compared to the very luminous and distant FSRQs, PKS 1510-089 exhibits a quite large Compton dominance and a prominent big blue bump (BBB) as observed in the most powerful gamma-ray quasars. The BBB was still prominent during the historical maximum optical state in 2009 May, but the optical/ UV spectral index was softer than in the quiescent state. This seems to indicate that the BBB was not completely dominated by the synchrotron emission during the highest optical state. We model the broadband spectrum assuming a leptonic scenario in which the inverse Compton emission is dominated by the scattering of soft photons produced externally to the jet. The resulting model-dependent jet energetic content is compatible with a scenario in which the jet is powered by the accretion disk, with a total efficiency within the Kerr black hole limit.
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| 6. |
- Abdo, A. A., et al.
(author)
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FERMI LARGE AREA TELESCOPE DETECTION OF PULSED gamma-RAYS FROM THE VELA-LIKE PULSARS PSR J1048-5832 AND PSR J2229+6114
- 2009
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 706:2, s. 1331-1340
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Journal article (peer-reviewed)abstract
- We report the detection of gamma-ray pulsations (>= 0.1GeV) from PSR J2229+ 6114 and PSR J1048-5832, the latter having been detected as a low-significance pulsar by EGRET. Data in the gamma-ray band were acquired by the Large Area Telescope (LAT) aboard the Fermi Gamma-ray Space Telescope, while the radio rotational ephemerides used to fold the gamma-ray light curves were obtained using the Green Bank Telescope, the Lovell telescope at Jodrell Bank, and the Parkes Telescope. The two young radio pulsars, located within the error circles of the previously unidentified EGRET sources 3EG J1048-5840 and 3EG J2227+6122, present spin-down characteristics similar to the Vela pulsar. PSR J1048-5832 shows two sharp peaks at phases 0.15 +/- 0.01 and 0.57 +/- 0.01 relative to the radio pulse confirming the EGRET light curve, while PSR J2229+ 6114 presents a very broad peak at phase 0.49 +/- 0.01. The gamma-ray spectra above 0.1 GeV of both pulsars are fit with power laws having exponential cutoffs near 3 GeV, leading to integral photon fluxes of (2.19 +/- 0.22 +/- 0.32) x 10(-7) cm(-2) s(-1) for PSR J1048-5832 and (3.77 +/- 0.22 +/- 0.44) x 10(-7) cm(-2) s(-1) for PSR J2229+6114. The first uncertainty is statistical and the second is systematic. PSR J1048-5832 is one of the two LAT sources whichwere entangled together as 3EG J1048-5840. These detections add to the growing number of young gamma-ray pulsars that make up the dominant population of GeV gamma-ray sources in the Galactic plane.
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| 7. |
- Abdo, A. A., et al.
(author)
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FERMI LARGE AREA TELESCOPE FIRST SOURCE CATALOG
- 2010
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In: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 188:2, s. 405-436
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Journal article (peer-reviewed)abstract
- We present a catalog of high-energy gamma-ray sources detected by the Large Area Telescope (LAT), the primary science instrument on the Fermi Gamma-ray Space Telescope (Fermi), during the first 11 months of the science phase of the mission, which began on 2008 August 4. The First Fermi-LAT catalog (1FGL) contains 1451 sources detected and characterized in the 100 MeV to 100 GeV range. Source detection was based on the average flux over the 11 month period, and the threshold likelihood Test Statistic is 25, corresponding to a significance of just over 4 sigma. The 1FGL catalog includes source location regions, defined in terms of elliptical fits to the 95% confidence regions and power-law spectral fits as well as flux measurements in five energy bands for each source. In addition, monthly light curves are provided. Using a protocol defined before launch we have tested for several populations of gamma-ray sources among the sources in the catalog. For individual LAT-detected sources we provide firm identifications or plausible associations with sources in other astronomical catalogs. Identifications are based on correlated variability with counterparts at other wavelengths, or on spin or orbital periodicity. For the catalogs and association criteria that we have selected, 630 of the sources are unassociated. Care was taken to characterize the sensitivity of the results to the model of interstellar diffuse gamma-ray emission used to model the bright foreground, with the result that 161 sources at low Galactic latitudes and toward bright local interstellar clouds are flagged as having properties that are strongly dependent on the model or as potentially being due to incorrectly modeled structure in the Galactic diffuse emission.
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| 8. |
- Abdo, A. A., et al.
(author)
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Fermi large area telescope observations of the crab pulsar and nebula
- 2010
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 708:2, s. 1254-1267
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Journal article (peer-reviewed)abstract
- We report on gamma-ray observations of the Crab Pulsar and Nebula using 8 months of survey data with the Fermi Large Area Telescope (LAT). The high quality light curve obtained using the ephemeris provided by the Nancay and Jodrell Bank radio telescopes shows two main peaks stable in phase with energy. The first gamma-ray peak leads the radio main pulse by (281 +/- 12 +/- 21) mu s, giving new constraints on the production site of non-thermal emission in pulsar magnetospheres. The first uncertainty is due to gamma-ray statistics, and the second arises from the rotation parameters. The improved sensitivity and the unprecedented statistics afforded by the LAT enable precise measurement of the Crab Pulsar spectral parameters: cut-off energy at E-c = (5.8 +/- 0.5 +/- 1.2) GeV, spectral index of Gamma = (1.97 +/- 0.02 +/- 0.06) and integral photon flux above 100 MeV of (2.09 +/- 0.03 +/- 0.18) x 10(-6) cm(-2) s(-1). The first errors represent the statistical error on the fit parameters, while the second ones are the systematic uncertainties. Pulsed gamma-ray photons are observed up to similar to 20 GeV which precludes emission near the stellar surface, below altitudes of around 4-5 stellar radii in phase intervals encompassing the two main peaks. A detailed phase-resolved spectral analysis is also performed: the hardest emission from the Crab Pulsar comes from the bridge region between the two gamma-ray peaks while the softest comes from the falling edge of the second peak. The spectrum of the nebula in the energy range 100 MeV-300 GeV is well described by the sum of two power laws of indices Gamma(sync) = (3.99 +/- 0.12 +/- 0.08) and Gamma(IC) = (1.64 +/- 0.05 +/- 0.07), corresponding to the falling edge of the synchrotron and the rising edge of the inverse Compton (IC) components, respectively. This latter, which links up naturally with the spectral data points of Cherenkov experiments, is well reproduced via IC scattering from standard magnetohydrodynamic nebula models, and does not require any additional radiation mechanism.
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| 9. |
- Abdo, A. A., et al.
(author)
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FERMI OBSERVATIONS OF THE VERY HARD GAMMA-RAY BLAZAR PG 1553+113
- 2010
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 708:2, s. 1310-1320
-
Journal article (peer-reviewed)abstract
- We report the observations of PG 1553+113 during the first similar to 200 days of Fermi Gamma-ray Space Telescope science operations, from 2008 August 4 to 2009 February 22 (MJD 54682.7-54884.2). This is the first detailed study of PG 1553+113 in the GeV gamma-ray regime and it allows us to fill a gap of three decades in energy in its spectral energy distribution (SED). We find PG 1553+113 to be a steady source with a hard spectrum that is best fit by a simple power law in the Fermi energy band. We combine the Fermi data with archival radio, optical, X-ray, and very high energy (VHE) gamma-ray data to model its broadband SED and find that a simple, one-zone synchrotron self-Compton model provides a reasonable fit. PG 1553+113 has the softest VHE spectrum of all sources detected in that regime and, out of those with significant detections across the Fermi energy bandpass so far, the hardest spectrum in that energy regime. Thus, it has the largest spectral break of any gamma-ray source studied to date, which could be due to the absorption of the intrinsic gamma-ray spectrum by the extragalactic background light (EBL). Assuming this to be the case, we selected a model with a low level of EBL and used it to absorb the power-law spectrum from PG 1553+113 measured with Fermi (200 MeV-157 GeV) to find the redshift, which gave the best fit to the measured VHE data (90 GeV-1.1 TeV) for this parameterization of the EBL. We show that this redshift can be considered an upper limit on the distance to PG 1553+113.
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| 10. |
- Abdo, A. A., et al.
(author)
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FERMI OBSERVATIONS OF THE VERY HARD GAMMA-RAY BLAZAR PG 1553+113
- 2010
-
In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 708:2, s. 1310-1320
-
Journal article (peer-reviewed)abstract
- We report the observations of PG 1553+113 during the first similar to 200 days of Fermi Gamma-ray Space Telescope science operations, from 2008 August 4 to 2009 February 22 (MJD 54682.7-54884.2). This is the first detailed study of PG 1553+113 in the GeV gamma-ray regime and it allows us to fill a gap of three decades in energy in its spectral energy distribution (SED). We find PG 1553+113 to be a steady source with a hard spectrum that is best fit by a simple power law in the Fermi energy band. We combine the Fermi data with archival radio, optical, X-ray, and very high energy (VHE) gamma-ray data to model its broadband SED and find that a simple, one-zone synchrotron self-Compton model provides a reasonable fit. PG 1553+113 has the softest VHE spectrum of all sources detected in that regime and, out of those with significant detections across the Fermi energy bandpass so far, the hardest spectrum in that energy regime. Thus, it has the largest spectral break of any gamma-ray source studied to date, which could be due to the absorption of the intrinsic gamma-ray spectrum by the extragalactic background light (EBL). Assuming this to be the case, we selected a model with a low level of EBL and used it to absorb the power-law spectrum from PG 1553+113 measured with Fermi (200 MeV-157 GeV) to find the redshift, which gave the best fit to the measured VHE data (90 GeV-1.1 TeV) for this parameterization of the EBL. We show that this redshift can be considered an upper limit on the distance to PG 1553+113.
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