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We report the discovery and confirmation of the planetary system TOI-1288. This late G dwarf harbours two planets: TOI-1288 b and TOI-1288 c. We combine TESS space-borne and ground-based transit photometry with HARPS-N and HIRES high-precision Doppler measurements, which we use to constrain the masses of both planets in the system and the radius of planet b. TOI-1288~b has a period of $2.699835^{+0.000004}_{-0.000003}$ d, a radius of $5.24 \pm 0.09$ R$_\oplus$, and a mass of $42 \pm 3$ M$_\oplus$, making this planet a hot transiting super-Neptune situated right in the Neptunian desert. This desert refers to a paucity of Neptune-sized planets on short period orbits. Our 2.4-year-long Doppler monitoring of TOI-1288 revealed the presence of a Saturn-mass planet on a moderately eccentric orbit ($0.13^{+0.07}_{-0.09}$) with a minimum mass of $84 \pm 7$ M$_\oplus$ and a period of $443^{+11}_{-13}$ d. The 5 sectors worth of TESS data do not cover our expected mid-transit time for TOI-1288 c, and we do not detect a transit for this planet in these sectors., 16 pages, 17 figures, under review MNRAS

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.--Full list of authors: Barragan, O.; Armstrong, D. J.; Gandolfi, D.; Carleo, I; Vidotto, A. A.; D'Angelo, C. Villarreal; Oklopcic, A.; Isaacson, H.; Oddo, D.; Collins, K.; Fridlund, M.; Sousa, S. G.; Persson, C. M.; Hellier, C.; Howell, S.; Howard, A.; Redfield, S.; Eisner, N.; Georgieva, I. Y.; Dragomir, D.; Bayliss, D.; Nielsen, L. D.; Klein, B.; Aigrain, S.; Zhang, M.; Teske, J.; Twicken, J. D.; Jenkins, J.; Esposito, M.; Van Eylen, V.; Rodler, F.; Adibekyan, V; Alarcon, J.; Anderson, D. R.; Murphy, J. M. Akana; Barrado, D.; Barros, S. C. C.; Benneke, B.; Bouchy, F.; Bryant, E. M.; Butler, R. P.; Burt, J.; Cabrera, J.; Casewell, S.; Chaturvedi, P.; Cloutier, R.; Cochran, W. D.; Crane, J.; Crossfield, I; Crouzet, N.; Collins, K., I; Dai, F.; Deeg, H. J.; Deline, A.; Demangeon, O. D. S.; Dumusque, X.; Figueira, P.; Furlan, E.; Gnilka, C.; Goad, M. R.; Goffo, E.; Gutierrez-Canales, F.; Hadjigeorghiou, A.; Hartman, Z.; Hatzes, A. P.; Harris, M.; Henderson, B.; Hirano, T.; Hojjatpanah, S.; Hoyer, S.; Kabath, P.; Korth, J.; Lillo-Box, J.; Luque, R.; Marmier, M.; Mocnik, T.; Muresan, A.; Murgas, F.; Nagel, E.; Osborne, H. L. M.; Osborn, A.; Osborn, H. P.; Palle, E.; Raimbault, M.; Ricker, G. R.; Rubenzahl, R. A.; Stockdale, C.; Santos, N. C.; Scott, N.; Schwarz, R. P.; Shectman, S.; Seager, S.; Segransan, D.; Serrano, L. M.; Skarka, M.; Smith, A. M. S.; Subjak, J.; Tan, T. G.; Udry, S.; Watson, C.; Wheatley, P. J.; West, R.; Winn, J. N.; Wang, S. X.; Wolfgang, A.; Ziegler, C.; KESPRINT Team., We present the discovery and characterization of two transiting planets observed by TESS in the light curves of the young and bright (V = 9.67) star HD73583 (TOI-560). We perform an intensive spectroscopic and photometric space- and ground-based follow-up in order to confirm and characterize the system. We found that HD73583 is a young (∼500 Myr) active star with a rotational period of 12.08 ± 0.11 d, and a mass and radius of 0.73 ± 0.02 M⊙ and 0.65 ± 0.02 R⊙, respectively. HD 73583 b (Pb = 6.3980420+0.0000067−0.0000062 d) has a mass and radius of 10.2+3.4−3.1 M⊕ and 2.79 ± 0.10 R⊕, respectively, which gives a density of 2.58+0.95−0.81 gcm−3⁠. HD 73583 c (Pc = 18.87974+0.00086−0.00074 d) has a mass and radius of 9.7+1.8−1.7 M⊕ and 2.39+0.10−0.09 R⊕, respectively, which translates to a density of 3.88+0.91−0.80 gcm−3⁠. Both planets are consistent with worlds made of a solid core surrounded by a volatile envelope. Because of their youth and host star brightness, they both are excellent candidates to perform transmission spectroscopy studies. We expect ongoing atmospheric mass-loss for both planets caused by stellar irradiation. We estimate that the detection of evaporating signatures on H and He would be challenging, but doable with present and future instruments. © The Author(s) 2022. Published by Oxford University Press on behalf of Royal Astronomical Society., This work was supported by the KESPRINT collaboration, an international consortium devoted to the characterization and research of exoplanets discovered with space-based missions (http://www.kesprint.science). We thank the referee for their helpful comments and suggestions that improved the quality of this manuscript. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. This work uses observations from the LCOGT network. Part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP). MSIP is funded by NSF. This paper is in part based on data collected under the NGTS project at the ESO La Silla Paranal Observatory. The NGTS facility is operated by the consortium institutes with support from the UK Science and Technology Facilities Council (STFC) projects ST/M001962/1 and ST/S002642/1. This research has used the NASA Exoplanet Archive, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. Some of the observations in the paper used the High-Resolution Imaging instrument Zorro obtained under Gemini LLP Proposal Number: GN/S-2021A-LP-105. Zorro was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. Zorro was mounted on the Gemini North (and/or South) telescope of the international Gemini Observatory, a program of NSF’s OIR Lab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigación y Desarrollo (Chile), Ministerio de Ciencia, Tecnología e Innovación (Argentina), Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). OB, BK, and SA acknowledge that this publication is part of a project that has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 865624). DG and LMS gratefully acknowledge financial support from the Cassa di Risparmio di Torino foundation under Grant No. 2018.2323 ‘Gaseous or rocky? Unveiling the nature of small worlds’. DJA acknowledges support from the STFC via an Ernest Rutherford Fellowship (ST/R00384X/1). APH and ME acknowledges grant HA 3279/12-1 within the DFG Schwerpunkt SPP 1992, ‘Exploring the Diversity of Extrasolar Planets’. JS and PK would like to acknowledge support from MSMT grant LTT-20015. We acknowledges the support by FCT – Fundação para a Ciência e a Tecnologia through national funds and by FEDER through COMPETE2020 – Programa Operacional Competitividade e Internacionalização by these grants: UID/FIS/04434/2019; UIDB/04434/2020; UIDP/04434/2020; PTDC/FIS-AST/32113/2017 & POCI-01-0145-FEDER-032113; PTDC/FISAST /28953/2017 & POCI-01-0145-FEDER-028953. AD acknowledges the financial support of the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (project FOUR ACES; grant agreement No 724427). AD also acknowledges financial support of the the Swiss National Science Foundation (SNSF) through the National Centre for Competence in Research ‘PlanetS’. MF, IYG, JK, and CMP gratefully acknowledge the support of the Swedish National Space Agency (DNR 177/19, 174/18, 2020-00104, 65/19). FGC thanks the Mexican national council for science and technology (CONACYT, CVU-1005374). MS acknowledge financial support of the Inter-transfer grant no LTT-20015. JL-B acknowledges financial support received from ‘la Caixa’ Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 847648, with fellowship code LCF/BQ/PI20/11760023. AAV acknowledges funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 817540, ASTROFLOW). JMAM is supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1842400. JMAM acknowledges the LSSTC Data Science Fellowship Program, which is funded by LSSTC, NSF Cybertraining Grant No. 1829740, the Brinson Foundation, and the Moore Foundation; his participation in the program has benefited this work. RAR is supported by the NSF Graduate Research Fellowship, grant No. DGE 1745301. RL acknowledges financial support from the Spanish Ministerio de Ciencia e Innovación, through project PID2019-109522GB-C52, and the Centre of Excellence ‘Severo Ochoa’ award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709). PC acknowledges the generous support from Deutsche Forschungsgemeinschaft (DFG) of the grant CH 2636/1-1. SH acknowledges CNES funding through the grant 837319. VA acknowledges the support from Fundação para a Ciência e Tecnologia (FCT) through Investigador FCT contract nr. IF/00650/2015/CP1273/CT0001. ODSD is supported in the form of work contract (DL 57/2016/CP1364/CT0004) funded by national funds through Fundação para a Ciência e Tecnologia (FCT). AO is supported by an STFC studentship. XD would like to acknowledge the funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement SCORE No 851555). HJD acknowledges support from the Spanish Research Agency of the Ministry of Science and Innovation (AEI-MICINN) under the grant ‘Contribution of the IAC to the PLATO Space Mission’ with reference PID2019-107061GB-C66, DOI: 10.13039/501100011033. DD acknowledges support from the TESS Guest Investigator Program grant 80NSSC19K1727 and NASA Exoplanet Research Program grant 18-2XRP18_2-0136. AO gratefully acknowledges support from the Dutch Research Council NWO Veni grant.

We report new photometric and spectroscopic observations of the K2-99 planetary system. Asteroseismic analysis of the short-cadence light curve from K2’s Campaign 17 allows us to refine the stellar properties. We find K2-99 to be significantly smaller than previously thought, with R⋆ = 2.55 ± 0.02 R⊙. The new light curve also contains four transits of K2-99 b, which we use to improve our knowledge of the planetary properties. We find the planet to be a non-inflated warm Jupiter, with Rb = 1.06 ± 0.01 RJup⁠. 60 new radial velocity measurements from HARPS, HARPS-N, and HIRES enable the determination of the orbital parameters of K2-99 c, which were previously poorly constrained. We find that this outer planet has a minimum mass Mcsin ic = 8.4 ± 0.2 MJup⁠, and an eccentric orbit (ec = 0.210 ± 0.009) with a period of 522.2 ± 1.4 d. Upcoming TESS observations in 2022 have a good chance of detecting the transit of this planet, if the mutual inclination between the two planetary orbits is small. © 2022 The Author(s)., This work is done under the framework of the KESPRINT collaboration (http://www.kesprint.science). KESPRINT is an international consortium devoted to the characterization and research of exoplanets discovered with space-based missions. Based on observations made with ESO Telescopes at the La Silla Observatory (Chile) under programmes 097.C-0948(A), 099.C-0491(B), 099.C-0491(A), 0100.C-0808(A), 0101.C-0829(A), 60.A-9700(G), and 1102.C-0923(A), and the TNG telescope at Roque de Los Muchachos Observatory (Spain) under programmes A33TAC_15, A34TAC_10, OPT17A_64, A35TAC_26, OPT17B_59, CAT17B_99, CAT18A_130, OPT18A_44, A37TAC_37, OPT18B_52, and A38TAC_26. This paper includes data collected by the Kepler mission. Funding for the Kepler mission is provided by the NASA Science Mission directorate. Some of the data presented in this paper were obtained from the Mikulski Archive for Space Telescopes (MAST). STScI is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS5-26555. Support for MAST for non-HST data is provided by the NASA Office of Space Science via grant NNX09AF08G and by other grants and contracts. This research has made use of the Exoplanet Follow-up Observation Program website, and the NASA Exoplanet Archive, which are operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2013-2016) under grant agreement No. 312430 (OPTICON). This research has made use of NASA’s Astrophysics Data System, the SIMBAD data base, operated at CDS, Strasbourg, France, and the Exoplanets Encyclopaedia at exoplanet.eu. We also used ASTROPY, a community-developed core PYTHON package for Astronomy (Astropy Collaboration 2013; Price-Whelan et al. 2018). This work has made use of data from the European Space Agency (ESA) mission Gaia (https://www.cosmos.esa.int/gaia), processed by the Gaia Data Processing and Analysis Consortium (DPAC, https://www.cosmos.esa.int/web/gaia/dpac/consortium). Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement. KWFL, SC, and APH were supported by Deutsche Forschungsgemeinschaft grants HA3279/12-1 and RA714/14-1 within the DFG Schwerpunkt SPP 1992, Exploring the Diversity of Extrasolar Planets. SC is also supported by Deutsche Forschungsgemeinschaft Research Unit 2440: ‘Matter Under Planetary Interior Conditions: High Pressure Planetary and Plasma Physics’. HJD acknowledges support from the Spanish Research Agency of the Ministry of Science and Innovation (AEI-MICINN) under grant PID2019-107061GB-C66, DOI: 10.13039/501100011033. JK gratefully acknowledge the support of the Swedish National Space Agency (SNSA; DNR 2020-00104). SM acknowledges support by the Spanish Ministry of Science and Innovation with the Ramon y Cajal fellowship number RYC-2015-17697 and the grant number PID2019-107187GB-I00. SNB and RAG acknowledge the support of the PLATO CNES grant. LMS and DG gratefully acknowledge financial support from the CRT foundation under Grant No. 2018.2323 ‘Gaseous or rocky? Unveiling the nature of small worlds’. We thank Erik Petigura for his contribution to the collection and analysis of the Keck/HIRES data. Finally, we thank the referee for their careful reading of the manuscript and constructive suggestions, which resulted in improvements to this paper., With funding from the Spanish government through the Severo Ochoa Centre of Excellence accreditation SEV-2017-0709.

We report on the confirmation and mass determination of a transiting planet orbiting the old and inactive G7 dwarf star HD219666 (Mstar = 0.92 +/- 0.03 MSun, Rstar = 1.03 +/- 0.03 RSun, tau_star = 10 +/- 2 Gyr). With a mass of Mb = 16.6 +/- 1.3 MEarth, a radius of Rb = 4.71 +/- 0.17 REarth, and an orbital period of P ~ 6 days, HD219666b is a new member of a rare class of exoplanets: the hot-Neptunes. The Transiting Exoplanet Survey Satellite (TESS) observed HD219666 (also known as TOI-118) in its Sector 1 and the light curve shows four transit-like events, equally spaced in time. We confirmed the planetary nature of the candidate by gathering precise radial-velocity measurements with HARPS@ESO3.6m. We used the co-added HARPS spectrum to derive the host star fundamental parameters (Teff = 5527 +/- 65 K, log g = 4.40 +/- 0.11 (cgs), [Fe/H]= 0.04 +/- 0.04 dex, log R'HK = -5.07 +/- 0.03), as well as the abundances of many volatile and refractory elements. The host star brightness (V = 9.9) makes it suitable for further characterisation by means of in-transit spectroscopy. The determination of the planet orbital obliquity, along with the atmospheric metal-to-hydrogen content and thermal structure could provide us with important clues on the formation mechanisms of this class of objects., Comment: Accepted for publication in A&A

Context. The Kepler extended mission, also known as K2, has provided the community with a wealth of planetary candidates that orbit stars typically much brighter than the targets of the original mission. These planet candidates are suitable for further spectroscopic follow-up and precise mass determinations, leading ultimately to the construction of empirical mass-radius diagrams. Particularly interesting is to constrain the properties of planets that are between Earth and Neptune in size, the most abundant type of planet orbiting Sun-like stars with periods of less than a few years. Aims. Among many other K2 candidates, we discovered a multi-planetary system around EPIC 246471491, referred to henceforth as K2-285, which contains four planets, ranging in size from twice the size of Earth to nearly the size of Neptune. We aim here at confirming their planetary nature and characterizing the properties of this system. Methods. We measure the mass of the planets of the K2-285 system by means of precise radial-velocity measurements using the CARMENES spectrograph and the HARPS-N spectrograph. Results. With our data we are able to determine the mass of the two inner planets of the system with a precision better than 15%, and place upper limits on the masses of the two outer planets. Conclusions. We find that K2-285b has a mass of M = 9.68 M and a radius of R = 2.59 R, yielding a mean density of ρ = 3.07 g cm, while K2-285c has a mass of M = 15.68 M, radius of R = 3.53 R, and a mean density of ρ = 1.95 g cm. For K2-285d (R = 2.48 R) and K2-285e (R = 1.95 R), the upper limits for the masses are 6.5 M and 10.7 M, respectively. The system is thus composed of an (almost) Neptune-twin planet (in mass and radius), two sub-Neptunes with very different densities and presumably bulk composition, and a fourth planet in the outermost orbit that resides right in the middle of the super-Earth/sub-Neptune radius gap. Future comparative planetology studies of this system would provide useful insights into planetary formation, and also a good test of atmospheric escape and evolution theories.© 2019 ESO., This work is partly financed by the Spanish MINECO through grants ESP2016-80435-C2-1-R, ESP2016-80435-C2-2-R and AYA2016-79425-C3-3-P. This work was also supported by JSPS KAKENHI Grants Numbers JP16K17660 and JP18H01265.

Context. The Kepler Object of Interest Network (KOINet) is a multi-site network of telescopes around the globe organised for follow-up observations of transiting planet candidate Kepler objects of interest (KOIs) with large transit timing variations (TTVs). The main goal of KOINet is the completion of their TTV curves as the Kepler telescope stopped observing the original Kepler field in 2013. Aims. We ensure a comprehensive characterisation of the investigated systems by analysing Kepler data combined with new ground-based transit data using a photodynamical model. This method is applied to the Kepler-82 system leading to its first dynamic analysis. Methods. In order to provide a coherent description of all observations simultaneously, we combine the numerical integration of the gravitational dynamics of a system over the time span of observations with a transit light curve model. To explore the model parameter space, this photodynamical model is coupled with a Markov chain Monte Carlo algorithm. Results. The Kepler-82b/c system shows sinusoidal TTVs due to their near 2:1 resonance dynamical interaction. An additional chopping effect in the TTVs of Kepler-82c hints to a further planet near the 3:2 or 3:1 resonance. We photodynamically analysed Kepler long- and short-cadence data and three new transit observations obtained by KOINet between 2014 and 2018. Our result reveals a non-transiting outer planet with a mass of $m_f=20.9\pm1.0\;M_\bigoplus$ near the 3:2 resonance to the outermost known planet, Kepler-82c. Furthermore, we determined the densities of planets b and c to the significantly more precise values $\rho_b=0.98_{-0.14}^{+0.10}\;\text{g cm}^{-3}$ and $\rho_c=0.494_{-0.077}^{+0.066}\;\text{g cm}^{-3}$., Comment: 18 pages, 9 figures. Accepted for publication in A&A

The Pretransplant Assessment of Mortality (PAM) score was developed in 2006 to predict risk of mortality after allogeneic hematopoietic cell transplantation (HCT). Transplant practices have evolved during the past decade, suggesting the need to reevaluate the performance of the PAM score. We used statistical modeling to analyze and recalibrate mortality based on overall PAM scores, its components, and conditioning regimen in a retrospective cohort of 1549 patients who had HCT from 2003 through 2009. PAM scores correlated with mortality, but the effect size was smaller in the current study than in previous studies. PAM scores also demonstrated a stronger association with mortality in patients who received myeloablative conditioning than in those who received reduced-intensity conditioning. In contrast to the original study, carbon monoxide diffusing capacity, serum alanine aminotransferase, and serum creatinine concentrations were no longer significantly associated with 2-year mortality, whereas patient and donor cytomegalovirus serology was associated with mortality in the current cohort. Based on our findings, we developed and tested a revised PAM score for clinicians to estimate survival after allogeneic HCT with myeloablative conditioning regimens for patients with hematologic malignancy. Prognostic models such as the PAM score should be updated and recalibrated periodically to accommodate changes in clinical practice.

The KESPRINT consortium identified K2-216 as a planetary candidate host star in the K2 space mission Campaign 8 field with a transiting super-Earth. The planet has recently been validated as well. Our aim was to confirm the detection and derive the main physical characteristics of K2-216b, including the mass. We performed a series of follow-up observations: high resolution imaging with the FastCam camera at the TCS, the Infrared Camera and Spectrograph at Subaru, and high resolution spectroscopy with HARPS (ESO, La Silla), HARPS-N (TNG), and FIES (NOT). The stellar spectra were analyzed with the SpecMatch-Emp and SME codes to derive the stellar fundamental properties. We analyzed the K2 light curve with the Pyaneti software. The radial-velocity measurements were modelled with both a Gaussian process (GP) regression and the floating chunk offset (FCO) technique to simultaneously model the planetary signal and correlated noise associated with stellar activity. Imaging confirms that K2-216 is a single star. Our analysis discloses that the star is a moderately active K5V star of mass 0.70+/-0.03 Msun and radius 0.72+/-0.03 Rsun. Planet b is found to have a radius of 1.75+0.17-0.10 Rearth and a 2.17-day orbit in agreement with previous results. We find consistent results for the planet mass from both models: 7.4+/-2.2 Mearth from the GP regression, and 8.0+/-1.6 Mearth from the FCO technique, which implies that this planet is a super-Earth. The planet parameters put planet b in the middle of, or just below, the gap of the radius distribution of small planets. The density is consistent with a rocky composition of primarily iron and magnesium silicate. In agreement with theoretical predictions, we find that the planet is a remnant core, stripped of its atmosphere, and is one of the largest planets found that has lost its atmosphere., Comment: 17 pages, 10 figures, accepted by Astronomy & Astrophysics 28 June 2018

The CoRoT satellite has provided high-precision photometric light curves for more than 163 000 stars and found several hundreds of transiting systems compatible with a planetary scenario. If ground-based velocimetric observations are the best way to identify the actual planets among many possible configurations of eclipsing binary systems, recent transit surveys have shown that it is not always within reach of the radial-velocity detection limits. In this paper, we present a transiting exoplanet candidate discovered by CoRoT whose nature cannot be established from ground-based observations, and where extensive analyses are used to validate the planet scenario. They are based on observing constraints from radial-velocity spectroscopy, adaptive optics imaging and the CoRoT transit shape, as well as from priors on stellar populations, planet and multiple stellar systems frequency. We use the fully Bayesian approach developed in the PASTIS (Planet Analysis and Small Transit Investigation Software) analysis software, and conclude that the planet scenario is at least 1400 times more probable than any other false-positive scenario. The primary star is a metallic solar-like dwarf, with M-s = 1.099 +/- 0.049 M-circle dot and R-s = 1.136(-0.090)(+0.038) R-circle dot. The validated planet has a radius of R-p = 4.88(-0.39)(+0.17) R-circle plus and mass less than 49 M-circle plus. Its mean density is smaller than 2.56 g cm(-3) and orbital period is 9.7566 +/- 0.0012 d. This object, called CoRoT-22 b, adds to a large number of validated Kepler planets. These planets do not have a proper measurement of the mass but allow statistical characterization of exoplanets population.

Allogeneic hematopoietic cell transplantation (HCT) is the only known cure for patients with Fanconi Anemia (FA) who develop aplasia or leukemia. However, transplant regimens typically contain high-dose alkylators, which are poorly tolerated in FA patients. Furthermore, as many patients lack human leukocyte antigen (HLA)-matched family donors, alternative donors are used, which can increase the risk of both graft rejection and graft-versus-host disease (GVHD). To improve on these three concerns, we developed a multi-institutional clinical trial using a fludarabine-based conditioning regimen with limited alkylators/low-dose radiation, HLA-haploidentical marrow, followed by reduced-dose cyclophosphamide to treat three FA patients with aplasia. All three patients engrafted with 100% donor CD3 chimerism at one month. One patient died early from disseminated toxoplasmosis infection. Of the two survivors, one had significant pre-transplant co-morbidities and inadequate immunosuppression, and developed severe acute GVHD. The other patient had only mild acute and no chronic GVHD. With a follow-up of 2 and 3 years, respectively, both patients are doing well, transfusion-independent, and maintain full donor chimerism. The patient with severe GVHD has resolving oral GVHD and good quality-of-life. We conclude that using low-intensity conditioning, HLA-haploidentical marrow, and reduced-dose cyclophosphamide for in vivo T cell depletion can correct life-threatening aplasia in FA patients.

We report on the discovery of K2-141 b (EPIC 246393474 b), an ultra-short-period super-Earth on a 6.7 h orbit transiting an active K7 V star based on data fromK2campaign 12. We confirmed the planet’s existence and measured its mass with a series of follow-up observations: seeing-limited MuSCAT imaging, NESSI high-resolution speckle observations, and FIES and HARPS high-precision radial-velocity monitoring. K2-141 b has a mass of 5.31 ± 0.46M⊕and radius of 1.54−0.09+0.10R⊕, yielding a mean density of 8.00−1.45+1.83g cm−3and suggesting a rocky-iron composition. Models indicate that iron cannot exceed ~70% of the total mass. With an orbital period of only 6.7 h, K2-141 b is the shortest-period planet known to date with a precisely determined mass.

Cytogenetics are an important prognostic factor for patients with MDS. However, existing cytogenetics grouping schemes are based on patients treated with supportive care, and may not be optimal for patients undergoing allogeneic stem cell transplantation (SCT). We previously proposed an SCT-specific cytogenetics grouping scheme for patients with MDS and AML arising from MDS, based on an analysis of patients transplanted at Dana-Farber Cancer Institute/Brigham and Women’s Hospital. Under this scheme, abnormalities of chromosome 7 and complex karyotype are considered adverse-risk, while all others are considered standard-risk. In the present retrospective study, we validated this scheme on an independent multicenter cohort of 546 patients. Adverse cytogenetics was the strongest prognostic factor for outcome in this cohort. Four-year relapse-free and overall survival were 42% and 46%, respectively, in the standard risk group, versus 21% and 23% in the adverse group (p

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces programmed cell death (apoptosis) preferentially in tumor cells. However, not all cancer cells are sensitive to TRAIL. We determined whether ligation of the retinoid receptor, RXR, would sensitize cells to TRAIL-mediated apoptosis. The leukemic cell lines KG1a (apoptosis-resistant) and ML-1 (apoptosis-sensitive) were treated with the RXR-specific retinoid bexarotene, TRAIL, or both, and apoptosis was determined. In KG1a cells, bexarotene downregulated FLIP(Long) and activated caspase-8, thereby allowing for TRAIL-triggered apoptosis. Overexpression of FLIP(Long) in ML-1 cells abrogated apoptosis. In unmodified ML-1 cells bexarotene enhanced programmed cell death via truncation of Bid and release of cytochrome C. Blockade of caspase-8 prevented enhancement in both cell lines; blockade of caspase-9 had a significant effect only in ML-1 cells. Thus, the effect of bexarotene on TRAIL-mediated programmed cell death involved proximal events of the extrinsic pathway; however, downstream signals involved the intrinsic pathway in ML-1 but not in KG1a cells. These studies add further information to the regulation of programmed cell death in leukemic cells that have to be considered when designing therapeutic strategies.

Several lines of therapy have been established for patients with idiopathic thrombocytopenic purpura (ITP) and Evans syndrome. However, these therapies generally require prolonged administration, lead to profound immunosuppression and increased infectious risk, and are often poorly tolerated. While most patients with these disorders will respond to first-line steroid therapy, others will prove refractory or intolerant to multiple treatments. In these patients (and possibly even selected patients who are not considered refractory), autologous or allogeneic hematopoietic stem cell transplantation (HCT) may provide definitive therapy. We review the literature on the treatment of ITP and Evans syndrome with HCT and discuss its use in the management of these disorders. We also pose, for the purpose of discussion, research questions that will be important to address if HCT is to be considered a viable option for more patients with these diseases.

Recent studies in a murine model show that transferrin (Tf) interferes with Fas-mediated hepatocyte death and liver failure by decreasing pro-apoptotic and increasing anti-apoptotic signals. We show here in vitro in murine and human hepatocyte cell lines and in vivo in mice that Fas-induced apoptosis is modulated by exogenous Tf and iron. The results obtained with iron-free Tf (ApoTf), iron-saturated Tf (FeTf), and the iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) in its iron-free and iron-saturated (FeSIH) forms indicate that apoptosis-modulating effects of Tf are not mediated by iron alone. Both the Tf molecule and iron affect multiple aspects of cell death, and the route of iron delivery to the cell may be critical for the final outcome of cellular Fas signaling. Survival of hepatocytes 'stressed' by Fas signals can be manipulated by Tf and iron and may be a target for prophylactic and therapeutic interventions.

The pathophysiology of the myelodysplastic syndromes (MDS) is incompletely understood. Tumor necrosis factor (TNF)alpha levels are elevated, particularly in early-stage MDS, and apoptosis in marrow cells is upregulated. Observations in other models have shown a role for insulin-like growth factor binding protein 3 (IGFBP-3) in TNFalpha-mediated apoptosis. We observed increased levels of IGFBP-3 in the marrow plasma of patients with MDS (P = 0.005) and hypothesized that altered IGFBP-3 levels contribute to the dysregulation of hemopoiesis in MDS by affecting proliferation and apoptosis. Western analysis of marrow plasma from MDS patients revealed an increase in the ratio of intact vs fragmented IGFBP-3 in early-stage MDS (relative to controls) that decreased with MDS disease progression, suggesting increased proteolysis with more advanced disease. Thus, these results provide evidence for dysregulation of IGFBP-3 in patients with MDS. While the data are complex, they are consistent with a modulatory effect of IGFBP-3 on hemopoiesis in MDS. Conceivably, understanding these mechanisms may allow for the development of novel therapeutic strategies.

We present a study of the stellar parameters, distances and spectral energy distributions (SEDs) of HD 34282 and HD 141569, two pre-main sequence Herbig AeBe stars. Both objects have been reported to show `anomalous positions' in the HR diagram in the sense that they appear below the main sequence. A significant result of this work is that both stars are metal-deficient. The {\it Hipparcos} distance of HD 34282 is very uncertain and the current study places the star at the expected evolutionary position in the HR diagram, i.e. as a PMS star. The distance for HD 141569 found in this work matches the {\it Hipparcos} distance, and the problem of its anomalous position is solved as a result of the low metallicity of the object: using the right metallicity tracks, the star is in the PMS region. The SEDs are constructed using data covering ultraviolet to millimetre wavelengths. Physical, non-parametric models, have been applied in order to extract some properties of the disks surrounding the stars. The disk around HD 34282 is accreting actively, it is massive and presents large grains in the mid-plane and small grains in the surface. HD 141569 has a very low mass disk, which is in an intermediate stage towards a debris-type disk., 19 pages, 10 figures. Accepted by A&A

We report the spectroscopic confirmation of the Kepler object of interest KOI-183.01 (Kepler-423b), a half-Jupiter mass planet transiting an old solar-like star every 2.7 days. Our analysis is the first to combine the full Kepler photometry (quarters 1-17) with high-precision radial velocity measurements taken with the FIES spectrograph at the Nordic Optical Telescope. We simultaneously modelled the photometric and spectroscopic data-sets using Bayesian approach coupled with Markov chain Monte Carlo sampling. We found that the Kepler pre-search data conditioned (PDC) light curve of KOI-183 exhibits quarter-to-quarter systematic variations of the transit depth, with a peak-to-peak amplitude of about 4.3 % and seasonal trends reoccurring every four quarters. We attributed these systematics to an incorrect assessment of the quarterly variation of the crowding metric. The host star KOI-183 is a G4 dwarf with $M_\star=0.85\pm0.04$ M$_\rm{Sun}$, $R_\star=0.95\pm0.04$ R$_\rm{Sun}$, $T_\mathrm{eff}=5560\pm80$ K, $[M/H]=-0.10\pm0.05$ dex, and with an age of $11\pm2$ Gyr. The planet KOI-183b has a mass of $M_\mathrm{p}=0.595\pm0.081$ M$_\mathrm{Jup}$ and a radius of $R_\mathrm{p}=1.192\pm0.052$ R$_\mathrm{Jup}$, yielding a planetary bulk density of $\rho_\mathrm{p}=0.459\pm0.083$ g/cm$^{3}$. The radius of KOI-183b is consistent with both theoretical models for irradiated coreless giant planets and expectations based on empirical laws. The inclination of the stellar spin axis suggests that the system is aligned along the line of sight. We detected a tentative secondary eclipse of the planet at a 2-$\sigma$ confidence level ($\Delta F_{\mathrm{ec}}=14.2\pm6.6$ ppm) and found that the orbit might have a small non-zero eccentricity of $e=0.019^{+0.028}_{-0.014}$. With a Bond albedo of $A_\mathrm{B}=0.037\pm0.019$, KOI-183b is one of the gas-giant planets with the lowest albedo known so far., Comment: 13 pages, 13 figures, 5 tables. Accepted for publication in A&A. Planet designation changed from KOI-183b to Kepler-423b

Since its first successful application less than 15 years ago, allogeneic marrow transplantation has been used with continuously improving results for the treatment of severe aplastic anemia, leukemia and congenital immunodeficiency syndromes. With this background, a recent meeting ∗ ∗A UCN-UCLA Symposium on recent advances in bone-marrow transplantation was held in Park City, Utah, on 13–18 February 1983. provided an excellent opportunity to critically review problems and achievements of marrow transplant and non-transplant approaches to the treatment of malignant and nonmalignant lymphohemopoietic disorders.

We hypothesized that clinical risk factors could be identified within 2 weeks of onset of severe (stage 3 or 4) acute gut GVHD for identifying a patient population with a very poor outcome. Among 1462 patients who had allogeneic hematopoietic cell transplantation (HCT) between January 2000 and December 2005, 116 (7.9%) developed stage 3-4 gut GVHD. The median time for onset of stage 3-4 gut GVHD was 35 (4-135) days after allogeneic HCT. Eighty-five of the 116 patients (73%) had corticosteroid resistance before or within 2 weeks after the onset of stage 3-4 gut GVHD. Significant risk factors for mortality included corticosteroid resistance (hazards ratio (HR)=2.93; P=0.0005), age >18 years (HR=4.95; P=0.0004), increased serum bilirubin (HR 2.53; P=0.0001) and overt gastrointestinal bleeding (HR 2.88; P=0.0004). Among patients with stage 3-4 gut GVHD, the subgroup with 0, 1 or 2 risk factors had a favorable prognosis, whereas the subgroup with 3 or 4 risk factors had a dismal prognosis. This information should be considered in designing future studies of severe gut GVHD and in counseling patients about prognosis.

Background. In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT). Methods. All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m 2 ) of oral sirolimus on day 1 followed by 5 mg/m 2 /day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m 2 /day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days. Results. Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant. Conclusion. These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.

This study was undertaken to evaluate the toxicity and pharmacokinetics of a dimethyl sulphoxide (DMSO)-based intravenous formulation of busulphan in the conditioning of 45 patients undergoing allogeneic or autologous stem cell transplantation (SCT). Busulphan was given as a single daily dose. In 15 patients a single dose of intravenous busulphan, given over 3 h in 1 d, was combined with additional oral (single daily) doses. Thirty patients received all four daily doses intravenously. Busulphan plasma levels were analysed using high performance liquid chromatography. There was no major acute toxicity with daily intravenous doses of 2.8-3.1 mg/kg infused over 3 h. No veno-occlusive disease (VOD) was seen in 30 patients receiving busulphan as an intravenous formulation over 4 d. In the group of 15 patients receiving three oral doses and one intravenous single daily dose, one patient experienced mild VOD. Pharmacokinetic samples were taken over at least 2 d of treatment in 44 patients. The area under the concentration time curve (AUC) values normalized for a dose of 1 mg/kg were 7000 ng/ml x h on d 1 and 5890 ng/ml x h on d 4, thus showing a moderate decrease over time. This was accompanied by a moderate increase of the clearance from 2.6 to 3.0 ml/min/kg. Administration of busulphan as a DMSO-based intravenous formulation was well tolerated. The total dose of busulphan can be given in four (rather than the typical 16) doses. With such a regimen, the intravenous administration becomes feasible on an outpatient basis.

Ten patients with polycythaemia vera (PV) and nine with essential thrombocythaemia (ET) received a haemopoietic stem cell transplant (HSCT) at the Fred Hutchinson Cancer Research Center between May 1988 and March 2000. HSCT was performed because of progression to the spent phase of the disease with myelofibrosis and splenomegaly in 10 patients and evolution into a myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML) in nine patients. Patients were 18–59 years old (median 43). The interval from diagnosis to HSCT was 77–300 months (median 170). Seven patients were splenectomized before transplantation, and all but five had been treated with cytotoxic agents. Eleven patients received a transplant from a related, and eight from an unrelated, donor following conditioning with chemotherapy only or chemotherapy plus total body irradiation regimens. All evaluable patients achieved sustained engraftment. Twelve patients are surviving 5–116 months (median 41) after transplant, 10 in continued complete remission, one in haematological remission with residual marrow fibrosis and one with mixed haemopoietic chimaerism currently receiving therapy with interferon. Seven patients (six with AML/MDS and one with myelofibrosis) died of transplant-related complications. These data show that HSCT can provide curative therapy for patients with PV and ET with advanced disease.

We carried out bone marrow transplantation (BMT) in 50 patients with myelodysplastic syndrome (MDS) who were 55.3 to 66.2 years of age (median, 58.8 years). According to the criteria of the French-American-British (FAB) classification, 13 patients had refractory anemia (RA), 19 had RA with excess blasts (RAEB), 16 had RAEB in transformation or acute myelogenous leukemia (RAEB-T/AML), and 2 had chronic myelomonocytic leukemia (CMML). According to the recently established International Prognostic Scoring System (IPSS), available for 45 patients, 2 patients were considered low risk; 14, intermediate 1 risk; 19, intermediate 2 risk; and 10, high risk. Conditioning regimens were cyclophosphamide (CY) (120 mg/kg of body weight) plus 12-Gy fractionated total-body irradiation (FTBI) (n = 15), CY plus FTBI with lung and liver shielding (n = 4), busulfan (7 mg/kg) plus FTBI (n = 4), or busulfan (16 mg/kg) plus CY (n = 27). The busulfan-plus-CY group included 16 patients in whom busulfan was targeted to plasma levels of 600 to 900 ng/mL. In these 16 patients, steady-state levels of busulfan actually achieved were 714 to 961 ng/mL (mean +/- SD, 845 +/- 64 ng/mL; median, 838 ng/mL). The donors were HLA-identical siblings for 34 patients, HLA-nonidentical family members for 4, identical twins for 4, and unrelated volunteers for 6. All 46 patients surviving > 21 days had engraftment, and 22 patients (44%) are surviving 9 to 80 months after BMT. Specifically, among 13 patients with RA, 1 had relapse (cumulative incidence [CI] at 3 years, 8%) and 8 are surviving, for a Kaplan-Meier (KM) estimate of survival at 3 years of 59% (disease-free survival [DSF], 53%). Among 19 patients with RAEB, 3 had relapse (CI at 3 years, 16%), and 8 are surviving disease free (KM estimate at 3 years, 46%). Among 18 patients with RAEB-T/AML or CMML, 6 had relapse (CI at 3 years, 28%), and the KM estimate of DSF at 3 years is 33%. Relapse-free survival had an inverse correlation with cytogenetic risk classification and with the risk score according to the IPSS. Survival in all FAB categories was highest among patients enrolled in a protocol in which busulfan plasma levels were targeted to 600 to 900 ng/mL. These data indicate that BMT can be carried out successfully in patients with MDS who are older than 55 years of age. (Blood. 2000;95:1188-1194)

A CD34-negative haematopoietic progenitor cell line, D064, derived from canine bone marrow stromal cells is able to differentiate into haematopoietic progenitors under the influence of growth factor-mediated signalling. While differentiating, these cells eventually start to express MHC class II molecules (DR homologues) on their surface. The stable transfection of the fibroblast-like wild-type cells with retroviral constructs containing the cDNA for the canine MHC class II DR-genes (DRA and DRB) induces a change in morphology, accelerates cell cycle progression and leads to a loss of anchorage-dependent growth. Transfected cells show features of an immature stem cell leukaemia, such as giant cell formation. In wild-type D064 cells the accumulation of the cyclin-dependent kinase inhibitor (cdki) p27kip-1 induces differentiation, which is dependent upon signalling via the ligand for the tyrosine kinase receptor c-kit (stem cell factor). DR-transfected cells instead apparently grow independently of any growth factor-mediated signals and express high levels of the cdkis p27kip-1 and especially p21waf-1/cip-1, concurrently with accelated cell cycle progression. In contrast to the overexpression of cdkis and despite accelerated cell cycle progression, the expression of the G2/M phase transition kinase p34cdc2 is significantly reduced in DR-transfected and transformed cells as compared to the haematopoietic wild-type cell line D064. This might suggest a possible alternative cell cycle progression pathway in this experimental stem cell leukaemia by by-passing the G0/G1 phase arrest, although retinoblastoma (Rb)-phosphorylation remains unaltered. These results provide evidence that mechanisms normally controlling the cell cycle and early haematopoietic differentiation are disrupted by the constitutive transcription and expression of MHC class II genes (DR) leading to a progression and growth of this experimental stem cell leukaemia independent from cell cycle controlling regulators such as p27 and p21. © 1999 Cancer Research Campaign

ALTHOUGH MANY ASPECTS of the development of malignant tumors are still incompletely understood, conditions have been identified under which malignancies develop at a higher frequency than in the population at large.[1-3][1] These include, for example, actinic exposure of the skin and the mutagenic

The function of MHC class II (HLA-DR) Ags in hemopoiesis is not well defined. Here we investigated the effect of anti-HLA-DR mAb H81.9 on human marrow cells. mAb H81.9 inhibited colony formation from purified CD34+ marrow cells in long term culture-initiating cell assays. Inhibition was prevented, however, if c-kit ligand (stem cell factor (SCF)) was added to cultures concurrently with H81.9. DNA histograms from cultured untreated marrow mononuclear cells showed 2+/-1.2% apoptotic nuclei, whereas 14.1+/-5.4% were apoptotic after 12-h exposure to mAb H81.9. The apoptotic peak was reduced to 1.2+/-0.8% when SCF was added to cultures concurrently with mAb H81.9. The addition of Fas-Ig, a fusion protein that neutralizes Fas ligand (Fas-L), also prevented mAb H81.9-induced apoptosis. As determined by terminal deoxynucleotidyl transferase assays, agonistic anti-Fas mAb also induced apoptosis (in 13+/-4% of cells), and combined treatment with anti-Fas mAb and H81.9 was additive (27% apoptotic nuclei). The extent of apoptosis induced by anti-Fas mAb was significantly reduced by SCF. After H81.9 exposure, Fas was up-regulated on CD34+ cells, and Fas-L expression was 2.5-fold higher than in controls or CD34- cells, particularly within a small cell window with low orthogonal scatter (lymphocyte gate). These findings show that HLA-DR-mediated signals inhibit hemopoiesis in human marrow by a mechanism involving Fas/Fas-L-dependent signals that are blocked by c-kit ligand. These data suggest a possible role for MHC class II molecules in the regulation of hemopoiesis.

The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) interferes with G1/S-phase progression, and the resulting cell cycle arrest is thought to protect hematopoietic stem cells against injury by cycle-active cytotoxic agents. We investigated the radioprotective effect of AcSDKP in a canine radiation model. Dogs were given total-body irradiation (TBI) at an exposure rate of 10 cGy/min, either without further therapy (control) or with administration of AcSDKP at 0.05-500 micrograms/ kg/24 h beginning before and continuing until after completion of TBI. At 400 cGy of TBI, one of 28 control dogs and one of eight AcSDKP-treated dogs recovered hematopoiesis (p = 0.40). At 300 cGy, seven of 21 control dogs recovered hematopoiesis compared with five of five AcSDKP-treated dogs (p = 0.01). In dogs given 300 cGy and AcSDKP, the granulocyte nadirs were less profound (p = 0.04) and occurred later (p = 0.04) than among controls; platelet kinetics did not differ. These data suggest, therefore, that AcSDKP provides a radioprotective effect in dogs exposed to 300 cGy TBI. Such an effect might be beneficial in recipients of intensive radiation therapy. Conceivably, the effect on hematopoietic recovery could be amplified by growth factor administration after irradiation.

Engraftment of clonal hematopoietic precursor cells from patients with myelodysplastic syndrome (MDS) in immunodeficient mice has been difficult to achieve by intravenous (i.v.) injection. We used i.v. coadministration of the human marrow stroma cell line HS27a with CD34+ MDS cells in Nod.cg-Prkdc(scid) Il2rg(tm1wjll) (NSG) mice to provide signals that would facilitate engraftment. Hematopoietic cells from 24 MDS patients were transplanted. Cells from all patients were engrafted, and engraftment was documented in 44 of 46 evaluable mice (95%). Immunohistochemistry revealed human HS27a stroma colocalizing with human hematopoietic cells in mouse spleens. Human CD34+ precursors harvested from marrow and spleen of primary murine recipients, when combined with HS27a cells, were also engrafted successfully in secondary NSG recipients, showing persistence of the original clonal characteristics. This observation supports the concept that clonal markers were present in long-term repopulating cells. We suggest that HS27a stroma cells 'traveled' in direct contact with hematopoietic precursors and enabled their propagation. An essential signal for engraftment appears to be CD146, which is prominently expressed on HS27a cells. This xenotransplantation model will allow to further dissect signals that control engraftment of MDS cells and should be amenable to in vivo treatment studies.

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus-host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno-occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan-Meier estimates of disease-free survival at 2 years for good-risk, poor-risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.

Acute graft-versus-host disease (GVHD) is most often treated with high dose glucocorticoids, but less than half of patients have durable overall improvement. Previous phase I and phase II studies suggested that treatment with a CD5-specific immunotoxin (XomaZyme-CD5 Plus) could ameliorate symptoms of GVHD. In a randomized, double-blind trial, we compared XomaZyme-CD5 Plus and glucocorticoids versus placebo and glucocorticoids as initial therapy for 243 patients who developed acute GVHD after allogeneic marrow transplantation. The study drug (XomaZyme. CD5-Plus or an identical appearing placebo) was administered at a dose of 0.1 mg/kg body weight on each of 14 consecutive days. All patients were treated concomitantly with a standard regimen of methylprednisolone. At the time of entry on study, 94% of patients had a rash, 56% had hyperbilirubinemia, 61% had diarrhea, and 84% had nausea and vomiting. At 3, 4, and 5 weeks after starting treatment, symptom severity was less in the CD5 group than in the placebo group. At 4 weeks, 40% of patients assigned to the CD5 group had complete response compared with 25% of those assigned to the control group (P = .019). At 6 weeks, 44% of patients assigned to the CD5 group had complete response as compared with 38% in the placebo group (P = .36). Clinical extensive chronic GVHD developed in 65% of patients in the CD5 group compared with 72% in the control group (P = .35). Survival at 1 year after treatment was 49% in the CD5 group and 45% in the control group (P = .68). Side effects required close monitoring and appropriate adjustment of treatment. The combined administration of a CD5-specific immunotoxin and glucocorticoids controls GVHD manifestations more effectively than treatment with glucocorticoids alone during the first 5 weeks after starting treatment. Use of this immunotoxin does not result in any long-term clinical benefit for patients with acute GVHD.

We have studied graft-versus-host disease (GVHD) after transplantation of allogeneic peripheral blood stem cells (PBSC) mobilized by either recombinant canine granulocyte colony-stimulating factor (rcG-CSF) alone or combined with stem cell factor (rcSCF). These studies were prompted by the observation of extremely rapid and sustained engraftment of growth factor-mobilized PBSC in the autologous setting using genetically marked cells and changes in function of T lymphocytes from donors that had undergone mobilization. Specifically, lymphocytes from growth factor-treated donors were hyporesponsive in mixed leukocyte culture and in response to Con A, raising hopes that GVHD in dogs given growth factor mobilized allogenic PBSC might be altered in a beneficial way. Eighteen dogs were given a median of 17.1 x 10(8) PBSC/kg from littermate donors after 920 cGy of total body irradiation without postgrafting immunosuppression. Donors were either genotypically DLA-identical (n = 9) or DLA-haploidentical (n = 9). The median number of colony-forming unit-granulocyte macrophage (CFU-GM) infused was 27 x 10(4)/kg, and the number of CD34+ cells in the transplant was on the order of 4.6 x 10(6)/kg. The dogs received a median of 52.8 x 10(7) CD4 cells/kg and 13.7 X 10(7) CD8 cells/kg. All 18 dogs had prompt hematopoietic engraftment of donor cells as assessed by chimerism studies using variable number tandem repeat, as well as cytogenetic markers. Three of the nine dogs given grafts from DLA- identical littermates had fatal GVHD, five had transient GVHD, and one had no GVHD. All nine DLA-haploidentical recipients of PBSC developed fatal hyperacute GVHD. In conclusion, the expectation about rapid engraftment was fulfilled. However, incidence and severity of acute GVHD after transplantation of mobilized PBSC were not different than previously reported for nonmobilized PBSC or marrow. This model will allow for further studies, including T-cell depletion to minimize GVHD without increasing graft rejection.

Risk factors for the development of a new (secondary) malignancy after marrow transplantation are still incompletely defined. In the present study, we analyzed results in 700 patients with severe aplastic anemia treated with allogeneic marrow transplantation at the Fred Hutchinson Cancer Research Center in Seattle, WA, or at the Hopital St Louis in Paris, France. Twenty-three patients developed a malignancy 1.4 to 221 months (median, 91 months) after transplantation for a Kaplan-Meier estimate of 14% (95% confidence interval, 4% to 24%) at 20 years. Five cases were lymphoid malignancies (two acute lymphoblastic leukemias and three lymphoproliferative disorders) occurring 1.4 to 14.6 months (median, 3 months) posttransplant, and 18 were solid tumors (17 squamous cell and one mucoepidermoid carcinoma) presenting 30 to 221 months (median, 99 months) posttransplant. Thus, the hazard for lymphoid malignancies declined rapidly posttransplant, while the hazard for solid tumors increased progressively with time posttransplant. Risk factors for solid tumors identified in univariable analysis included the underlying diagnosis of Fanconi anemia (P = .0002), azathioprine therapy for chronic graft-versus-host disease (GVHD) (P < .0001), irradiation (total body or thoracoabdominal) as part of the conditioning regimen (P = .0002), chronic GVHD (P = .0099), acute GVHD (P = .0135), and male sex (P = .0499). In multivariable, stepwise proportional hazards models, azathioprine therapy (P < .0001) and the diagnosis of Fanconi anemia (P < .0001) were significant factors for all patients. Irradiation was a significant factor (P = .004) only if the time-dependent variable azathioprine was not included in the analysis. If only non-Fanconi patients were considered, azathioprine (P = .0043), age (P = .025), and irradiation (P = .042) were significant factors. Results in patients with Fanconi anemia and malignancies other than solid tumors were not subjected to an analysis because of the small number of events. It is of note, however, that no case of myeloproliferative disorder was observed. In summary, the highest risk of developing a solid tumor was associated with the diagnosis of Fanconi anemia. Better prevention of GVHD or omission of azathioprine as GVHD therapy (or both) may reduce the risk of late tumor development. Similarly, nonirradiation conditioning regimens may reduce the tumor risk, at least in patients without Fanconi anemia. Interactions between potential risk factors are complex, and further observation and additional analyses will be of interest.

Previous studies found that marrow allografts from DLA-identical littermates resulted in survival of 60% of recipient dogs after an otherwise lethal dose of 450 cGy of total body irradiation (TBI), either because of successful allografts or autologous recovery after rejection of the allografts. Forty percent of dogs died with marrow aplasia after allograft rejection. The current study asked whether allogeneic engraftment could be enhanced and survival improved by treating allograft recipients with high doses of corticosteroids or with cyclosporine (CSP), administered either before or after transplantation. Five dogs in group 1 received corticosteroids beginning on day -5 and ending on day 32 after transplant. The starting dose was 12.5 mg of prednisone per kilogram orally twice daily. All five dogs rejected their allografts; three died early with marrow aplasia and two showed endogenous marrow recovery. Nine dogs received CSP from day -6 to day -1 before transplantation at a dose of 20 mg/kg/d intravenously administered in divided doses. All nine dogs rejected the marrow allograft; six died with marrow aplasia and three survived with endogenous marrow recovery. Seven dogs received CSP after transplantation at a dose of 30 mg/kg/d orally from day -1 to day 35. All seven had sustained allografts (two mixed chimeras and five complete donor-type chimeras) and became healthy long-term survivors without graft-versus-host disease. These results extend previous observations and confirm that grafts of marrow from DLA-identical littermates improved survival of dogs exposed to low but otherwise lethal doses of TBI. Additional therapy with high-dose corticosteroids administered peritransplantation and posttransplantation or CSP administered before transplantation neither enhanced the rate of allogeneic engraftment nor improved survival; however, CSP administered after transplantation resulted in successful allografts and event-free survival in all cases.

Expression of major histocompatibility complex (MHC) class II molecules is developmentally regulated and lineage dependent. Their role in hematopoiesis is not well defined. Previous studies in a canine model showed that dogs given 920 cGy of total body irradiation, transplanted with autologous marrow, and treated with anti-MHC class II monoclonal antibody (MoAb) immediately posttransplant experienced only a transient granulocyte recovery that was followed by graft failure. In the present study, the effect of anti-MHC class II MoAbs on canine in vitro hematopoiesis was investigated. Anti-MHC class II MoAb H81.9 or B1F6 (both recognizing nonpolymorphic determinants) had no inhibitory effect when added directly to colony-forming unit-granulocyte-macrophage (CFU- GM) grown in agar. However, the addition of intact MoAb or as F(ab')2 fragments to long-term marrow cultures (LTMCs) resulted in a dose- dependent inhibition of the generation of CFU-GM among nonadherent cells. Inhibition was most profound with MoAb added at the time of initiation of culture. However, even if MoAb was added 3 weeks after recharging LTMCs, CFU-GM generation rapidly decreased. In addition, the number of adherent cells in LTMCs decreased; predominantly fibroblast- like cells with prominent cytoplasmic vesiculation remained. Acridine orange/ethidium bromide staining and TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) tests showed an increase in the proportion of apoptotic cells in both the nonadherent and adherent compartments. Binding of anti-MHC class II MoAb to unfractionated marrow cells resulted in an increase in free (Ca2+)i; no changes in tyrosine phosphorylation pattern were observed. The addition of stem cell factor (SCF), but not granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, to LTMCs prevented apoptosis, and the generation of CFU-GM was indistinguishable from controls. Similarly, a supportive adherent layer was maintained. Thus, anti-MHC class II MoAbs interfere with hematopoiesis both in vitro and in vivo. The mechanism involves programmed cell death in subpopulations of adherent and nonadherent cells. Inhibition of hematopoiesis is abrogated by exogenous SCF.

Administration of recombinant canine granulocyte-macrophage colony- stimulating factor (rcGM-CSF) to normal dogs in previous studies induced an increase in peripheral blood neutrophils and a dose- dependent decrease in platelet counts. In six dogs that received the highest tested dose of rcGM-CSF (50 micrograms/kg/d) for a minimum of 12 days, the mean nadir of the platelet count was 46,000/microL (range, 4,000 to 91,000/microL) on day 9 +/- 1.1 after starting therapy, compared with a mean baseline platelet count of 398,000/microL (range, 240,000 to 555,000/microL). In three dogs, survival of autologous 111In- labeled platelets was reduced from a mean of 4.9 days to 1.3 days during the administration of rcGM-CSF. Biodistribution studies with gamma camera imaging indicated that there was an increase in mean hepatic uptake during the administration of rcGM-CSF, from 15% to 44% of the total injected 111In-labeled platelets at 2 hours, whereas splenic uptake was not significantly changed. In contrast, in two evaluable dogs who were recipients of 111In-labeled platelets from matched allogeneic donors receiving rcGM-CSF, platelet survival was not reduced and no increased hepatic uptake was noted. A third dog became alloimmunized to the matched donor platelets and was not evaluable. Immunohistologic studies of liver and spleen were performed with monoclonal antibodies specific for canine gpIIb/IIIa and P-selectin in dogs treated with rcGM-CSF and compared with untreated controls. On treatment, a marked reduction of platelets in the red pulp of the spleen was evident, and in general, the presence of platelet antigen in the liver was unchanged. Therefore, platelets were not being sequestered, but destroyed in the liver and spleen. The platelet antigens, P-selectin and gpIIb/IIIa, were identified in association with Kupffer cells in the liver, but no difference in the number of distribution of these Kupffer cells was found between controls and rcGM- CSF-treated dogs. In the spleen during rcGM-CSF treatment, most platelet antigens were associated with large mononuclear cells in the marginal zone. During administration of rcGM-CSF, CD1c and CD11c expression was increased on Kupffer cells. Platelet P-selectin expression and binding of leukocytes to circulating platelets were unchanged from baseline studies with rcGM-CSF treatment. In conclusion, during the administration of rcGM-CSF to dogs, a local process in the liver and spleen is induced resulting in thrombocytopenia.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell-cell interactions and the presence of growth factors such as stem cell factor (SCF; or c-kit ligand) or interleukin-6 (IL-6) are involved in the proliferation and differentiation of the canine marrow-derived stromal cell line DO64. In the presence of SCF, stromal cells are induced to differentiate, but not to proliferate. In contrast, in the presence of IL-6, stromal cells are induced to proliferate rather than to differentiate in culture. Both SCF and IL-6 are produced by the stromal cells themselves and, thus, act as autocrine factors. In addition, DO64 cells also interact physically with each other in culture when grown under optimal culture conditions (70% to 90% cell confluence and in the presence of serum), thereby supporting proliferation and maintaining viability. Under conditions of lower cell density or low serum or growth factor concentrations in culture, DO64 cells tend to aggregate and form clusters. This increase in local cell concentration is associated with preservation of viability, presumably because of the accumulation of autocrine factors. If no signal, neither intercellular nor soluble, is provided, and DO64 cells are not able to reach a critical cell density or to produce sufficient factors in an autocrine fashion, the cells cease to proliferate and eventually die.

We report the discovery by the CoRoT space mission of a new giant planet, CoRoT-20b. The planet has a mass of 4.24 +/- 0.23 MJ and a radius of 0.84 +/- 0.04 RJ. With a mean density of 8.87 +/- 1.10 g/cm^3, it is among the most compact planets known so far. Evolution models for the planet suggest a mass of heavy elements of the order of 800 ME if embedded in a central core, requiring a revision either of the planet formation models or of planet evolution and structure models. We note however that smaller amounts of heavy elements are expected from more realistic models in which they are mixed throughout the envelope. The planet orbits a G-type star with an orbital period of 9.24 days and an eccentricity of 0.56. The star's projected rotational velocity is vsini = 4.5 +/- 1.0 km/s, corresponding to a spin period of 11.5 +/- 3.1 days if its axis of rotation is perpendicular to the orbital plane. In the framework of Darwinian theories and neglecting stellar magnetic breaking, we calculate the tidal evolution of the system and show that CoRoT-20b is presently one of the very few Darwin-stable planets that is evolving towards a triple synchronous state with equality of the orbital, planetary and stellar spin periods.

Context. CoRoT is a pioneering space mission whose primary goals are stellar seismology and extrasolar planets search. Its surveys of large stellar fields generate numerous planetary candidates whose lightcurves have transit-like features. An extensive analytical and observational follow-up effort is undertaken to classify these candidates.Aims. We present the list of planetary transit candidates from the CoRoT LRa01 star field in the Monoceros constellation toward the Galactic anti-center direction. The CoRoT observations of LRa01 lasted from 24 October 2007 to 3 March 2008.Methods. We acquired and analyzed 7470 chromatic and 3938 monochromatic lightcurves. Instrumental noise and stellar variability were treated with several filtering tools by different teams from the CoRoT community. Different transit search algorithms were applied to the lightcurves.Results. Fifty-one stars were classified as planetary transit candidates in LRa01. Thirty-seven (i.e., 73% of all candidates) are “good” planetary candidates based on photometric analysis only. Thirty-two (i.e., 87% of the “good” candidates) have been followed-up. At the time of writing twenty-two cases were solved and five planets were discovered: three transiting hot-Jupiters (CoRoT-5b, CoRoT-12b, and CoRoT-21b), the first terrestrial transiting planet (CoRoT-7b), and another planet in the same system (CoRoT-7c, detected by radial velocity survey only). Evidence of another non-transiting planet in the CoRoT-7 system, namely CoRoT-7d, was recently found as well. Context. The space mission CoRoT is devoted to the analysis of stellar variability and the photometric detection of extrasolar planets. Aims: We present the list of planetary transit candidates detected in the first short run observed by CoRoT that targeted SRc01, towards the Galactic center in the direction of Aquila, which lasted from April to May 2007. Methods: Among the acquired data, we analyzed those for 1269 sources in the chromatic bands and 5705 in the monochromatic band. Instrumental noise and the stellar variability were treated with several detrending tools, to which several transit-search algorithms were subsequently applied. Results: Fifty-one sources were classified as planetary transit candidates and 26 were followed up with ground-based observations. Until now, no planet has been detected in the CoRoT data from the SRc01 field. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with contributions from Austria, Belgium, Brazil, ESA, Germany, and Spain. The CoRoT data are available to the community from the CoRoT archive: http://idoc-corot.ias.u-psud.frBased in part on observations made with the 1.93-m telescope at Observatoire de Haute Provence (CNRS), France (SOPHIE Program 08A.PNP.MOUT).Based in part on observations made with the ESO-3.60-m telescope at La Silla Observatory (ESO), Chile (HARPS Program ESO - 081.C-0388) and with the ESO-VLT telescope at Paranal Observatory (ESO), Chile (FLAMES Program ESO - 081.C-0413).

Previous studies found that bone marrow (BM) allografts from DLA- identical littermates resulted in survival of two thirds of recipient dogs after otherwise lethal doses of 450 to 600 cGy of total body irradiation (TBI) because of successful allografts or autologous recovery after rejection of the allografts. The current study asked whether survival could be further improved by treating allograft recipients with recombinant canine granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), or G-CSF/SCF. Of 21 dogs, 14 (67%) receiving allografts but no growth factors survived, 10 with successful allografts (including 5 mixed chimeras) and 4 with autologous recovery; whereas 7 animals died, 5 from infections during BM aplasia and 2 from acute graft-versus-host disease. By comparison, 30 of 34 dogs (88%) receiving hematopoietic growth factors in addition to the BM graft survived, 17 with successful allografts (including 10 mixed chimeras) and 13 with autologous recovery; whereas 4 died, all with infection related to BM aplasia after rejection of the allograft. Survival was similar for recipients of G-CSF, SCF, or the combination of G-CSF and SCF. Logistic regression analyses, which accounted for possible effects of TBI dose, showed a trend for improved survival in dogs receiving growth factors (P = .09), no change in allogeneic engraftment (P = .74), and a slight increase in autologous recovery (P = .22). In agreement with previous data, we found that grafts of BM from DLA-identical littermates improved survival of recipient dogs exposed to low but otherwise lethal doses of TBI. A further improvement in survival could be achieved by additional treatment with G-CSF, SCF, or G-CSF/SCF. Results suggest that treatment by hematopoietic growth factors along with BM grafts should be considered for victims of radiation accidents.

A prospective randomized study was conducted comparing two conditioning regimens for the treatment of patients with chronic myeloid leukemia in chronic phase by marrow transplantation from HLA identical siblings. Sixty-nine patients received 60 mg/kg of cyclophosphamide on each of 2 successive days followed by 6 fractions of total body irradiation each of 2.0 Gy (CY-TBI), and 73 patients received 16 mg/kg of busulfan delivered over 4 days followed by 60 mg/kg CY on each of 2 successive days (BU-CY). There was no significant difference between the CY-TBI and the BU-CY groups in the 3-year probabilities of survival (0.80 for both), relapse (0.13 for both), or event-free survival (CY-TBI, 0.68; BU-CY, 0.71) or in speed of engraftment or incidence of venocclusive disease of the liver. The 4-year probabilities of survival and event- free survival for patients transplanted within 1 year of diagnosis were 0.86 and 0.72, respectively, for each group. Significantly more patients in the CY-TBI group experienced major creatinine elevations. There was significantly more acute graft-versus-host disease in the CY- TBI group. Fever days, positive blood cultures, hospitalizations, and inpatient hospital days were significantly more common in the CY-TBI group than in the BU-CY group. In conclusion, the BU-CY regimen was better tolerated than, and associated with survival and relapse probabilities that compare favorably with, the CY-TBI regimen.

Humanized anti-Tac is a genetically engineered human IgG1 monoclonal antibody specific for Tac, the alpha subunit of the interleukin-2 (IL- 2) receptor, and blocks IL-2-dependent activation of human T lymphocytes. The safety, pharmacokinetics, and immunosuppressive activity of humanized anti-Tac were evaluated in 20 patients who developed acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. Patients had developed acute GVHD at 5 to 26 (median, 14) days after transplantation and had failed to respond to primary therapy with glucocorticoids. Sequential groups of 4 patients each received a single 1-hour infusion of antibody in escalating doses of 0.5, 1.0, or 1.5 mg/kg; 8 additional patients were then treated with 1.5 mg/kg. A second infusion of antibody was administered after 11 to 48 (median, 16) days in 8 patients who had transient improvement of GVHD after the first infusion. Acute side effects, limited to chills in 1 patient and diaphoresis in another, were observed during or shortly after the antibody infusion. Overall improvement of acute GVHD occurred in 8 patients, 6 of whom were treated with a single antibody infusion and 2 with two infusions. Four responses were complete and 4 were partial. Three additional patients had improvement in one organ but progression in another. Responses occurred in 9 of 16 cases with skin disease, 3 of 15 with liver disease, and 6 of 12 with gastrointestinal disease. Two patients survive at 529 and 645 days after antibody treatment. Two patients died after relapse of leukemia. Sixteen patients died of infection or organ failure between 5 and 211 (median, 55) days. The terminal elimination half-life of the antibody was 44 to 363 hours, with a harmonic mean of 79, 88, and 94 hours, respectively, for the three doses studied. Absolute peripheral blood T-lymphocyte counts remained unchanged during the 56 days after infusion of the antibody. A fraction of circulating T cells expressed the alpha chain of the IL-2 receptor that, in some patients, was bound by antibody in vivo up to 28 days after treatment. No patient developed a measurable antibody response to humanized anti-Tac. Humanized anti-Tac has a long half-life after intravenous injection in humans, superior to any rodent monoclonal antibody specific for human T cells, and does not appear to induce antibody formation in recipients of marrow transplants. Improvement of steroid-refractory GVHD in 40% of patients after only one or two antibody infusions indicates that humanized anti-Tac is immunosuppressive.

Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor“s peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival.

We explored in dogs the immunosuppressive properties of 450 cGy total body irradiation (TBI) delivered from two opposing 60Co sources, as assessed by the criterion of successful engraftment of allogeneic genotypically DLA-identical littermate marrow. Two questions were asked in this study. Firstly, does dose rate affect the immunosuppressive effect of TBI when administered in a single dose? Secondly, does fractionation alter the immunosuppression of TBI when delivered at a very fast dose rate? Dose rates studied included 7 and 70 cGy/min, and fractionation involved four fractions of 112.5 cGy each, with 6-hour minimum interfraction intervals. Six of 7 dogs receiving 450 cGy single- dose TBI at 70 cGy/min showed sustained engraftment of the allogeneic marrow, compared with 1 of 7 dogs receiving single-dose TBI at 7 cGy/min (P = .01). Fractionated TBI at 70 cGy/min resulted in sustained allogeneic engraftment in 3 of 10 dogs, a result that was statistically significantly worse than that with single-dose TBI at 70 cGy/min (P = .03) and not statistically different (P = .24) from that with fractionated TBI delivered at 7 cGy/min (0 of 5 dogs engrafted). A single dose of 450 cGy of TBI delivered at a rate of 70 cGy/min is significantly more immunosuppressive than the same total dose delivered at 7 cGy/min. Fractionated TBI at 70 cGy/min is significantly less immunosuppressive than single-dose TBI at 70 cGy/min and not significantly different from fractionated TBI administered at 7 cGy/min. Results are consistent with the notion that significant DNA repair in lymphoid cells is possible during interfraction intervals at the relatively high dose rate of 70 cGy/min.

We conclude that the most common secondary cancers which develop after marrow transplantation are lympho-proliferative disorders and solid tumors. The consequences of the secondary malignancies are serious, with more than 90% of the patients with non-Hodgkin lymphomas associated with EBV infection and more than 75% of the patients with solid tumors dying despite treatment. Secondary leukemia developing in donor T-s is rare, but was fatal in all cases. EBV infection plays a major role in leading to the non-Hodgkin lymphomas in a setting of immune dysregulation from ATG or anti-T-cell monoclonal antibody treatment of acute GVHD. Other factors are also important for development of non-Hodgkin lymphoma and include T-cell depletion of donor marrow and HLA-mismatching between donor and recipient, known to lead to dysregulation of T-lymphocyte function. These factors set up an environment of proliferative stimuli which cannot be controlled by the recovering immune system, setting the stage for a secondary cancer. The role of irradiation is becoming more prominent in association with solid tumors, particularly in aplastic anemia patients conditioned with irradiation. The final event of tumor expression is most likely the result of a cascade of events, perhaps initiated with the conditioning regimen or with stimuli to proliferation, which, after later signals, leads to malignant transformation. For lymphoproliferative disorders, the time of latency is shorter than for solid tumors, suggesting a different molecular mechanism. The incidence of oncogene expression or mutation in tumor suppressor genes in these solid tumor patients has not been investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) was studied in normal dogs and in dogs receiving otherwise lethal total body irradiation (TBI) without marrow transplant. Five normal dogs receiving 25 micrograms/kg of rcGM-CSF by subcutaneous (SC) injection twice daily (BID) for 14 days showed increases in peripheral blood neutrophil counts of three to five times the baseline. Platelet counts decreased during administration of rcGM-CSF to a mean nadir of 52,800. Ten dogs received 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow graft. Within 2 hours of TBI, rcGM-CSF was begun at a dose of 50 micrograms/kg SC BID for 5 doses and then continued at 25 micrograms/kg SC BID for 21 days. Only 1 of the 10 dogs receiving rcGM-CSF survived with complete and sustained recovery of hematopoiesis. One of 13 historical control dogs survived after 400 cGy with no hematopoietic growth factor or marrow infusion. Results with rcGM-CSF were compared with previous and concurrent data with G-CSF studied in the same model. Of 10 dogs receiving G-CSF, 8 survived with complete and sustained hematopoietic recovery, a significantly better survival than that seen with rcGM-CSF (P = .006). Neutrophil counts were sustained at higher levels after TBI for the first 18 days in the G-CSF group (P < .016) and the neutrophil nadirs were higher. No differences in neutrophil nadirs were noted between the rcGM-CSF and control groups. Dogs treated with rcGM-CSF experienced a more rapid decline of platelet counts than G-CSF-treated or control dogs over the first 18 days (P < .001). The nadir of the platelet count was higher in the control group than in either the G-CSF or rcGM-CSF group and no significant difference was observed between the G-CSF and rcGM-CSF groups. After otherwise lethal TBI (400 cGy) in dogs, rcGM-CSF was not effective in promoting hematopoietic recovery or improving survival.