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Police have smashed a multi-million dollar match-fixing ring centred around the Victorian Premier League, with 10 people arrested.
In what may be the biggest case of match-fixing in Australian sport, the people, believed to be players and staff members from the one VPL club, were allegedly involved in an international match-fixing ring worth $2 million dollars.
According to police, the operation by the Purana Task Force and the Sporting Integrity Intelligence Unit commenced last August after Football Federation Australia (FFA) provided information to police regarding concerns surrounding unusual betting activities.
The 10 people consist of players and staff members from a single club, with the majority of the players coming from the United Kingdom and playing in Australia during the off-season.
"Further match-fixing risks are imminent in Australia, partly because of localised overseas betting on Australian sporting events due to our favourable time zone," said Victoria deputy police commissioner Graham Ashton in a media release on Sunday.
"It is vital that we continue gathering intelligence to take preventative action to make it difficult for organised crime to infiltrate our sporting codes.
"Our Sporting Integrity Intelligence Unit plays an important role in this space and will continue to conduct high level intelligence investigations across a range of serious organised and emerging crime within the sporting and racing industries.
"It's believed there has been estimated betting winnings in Australia and overseas of more than $2 million identified to date in connection with this particular operation.
"We will continue to work with the relevant sporting codes and the Australian Crime Commission to create an environment that is hostile to those seeking to engage in illegal activities involving our sporting codes."
Those arrested are expected to face match-fixing charges, which can attract a 10-year maximum penalty.
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© September 1999 by Neil Bauman, Ph.D.
Question: Are hearing aids the real answer to help me hear better?
Answer: That's a good question. Obviously, hearing aids help us hear better by making sounds louder to compensate for our diminished hearing. That is their primary purpose and they do quite a good job of it too in many cases. However, hearing aids do several other things too such as processing sounds and attempting to filter out undesirable noise. Perhaps one of the lesser-known, yet vitally important things they do is to compress sounds to fit our reduced dynamic hearing range. This means they increase the volume of soft sounds, yet at the same time, automatically limit the volume of loud sounds so they don't hurt our ears.
For example, when I listen to classical music without my hearing aids, the volume appears to vary dramatically. When only the strings are playing I often don't hear a thing. However, if I turn the volume up to hear these fainter sounds when the whole orchestra fires up that volume hurts my ears. As a result, it is very hard to enjoy such music. However, when wearing my hearing aids, they amplify the soft sounds so I can hear them and at the same time limit the loud sounds so I can bear them. The result is that I enjoy listening to music much more with my hearing aids on.
However, you must realize that as good as modern hearing aids are, you need to remember that they are still only aids to better hearing. They do not restore hearing to normal. Hearing aids are far from perfect. At best they typically only restore your hearing to the equivalent of a mild loss. Many first time hearing aid users don't like the unnatural sounds they now hear, nor do they like all the noise they now have to try to hear through. This is not so much the fault of the hearing aids as it is of our faulty ears.
You see, when we lose our hearing to some degree or other, strange things happen to our ears at the same time. One of these is that we lose our ability to filter out extraneous noise like we used to. Another is that we no longer hear as clearly as we used to. To us sounds are now "fuzzy". This means that we often cannot distinguish between two words that are similar in frequency—for example "sun" and "fun." Generally the worse our hearing loss is, the fuzzier our hearing becomes.
Therefore, we need more help than just the amplification that hearing aids give us. You must realize that hearing aids alone are not the total answer. You need to combine the help you get with hearing aids with other coping strategies. One of the most effective coping strategies is speechreading. (Lip reading was the old term.) With speechreading the words "fun" and "sun" are relatively easy to distinguish by watching the persons face. For example, I may hear the "un" sound and speechread the "s" or the "f" sound...
Click here to read more from The Center for Hearing Loss Help
Center for Hearing Loss Help
Neil Bauman, Ph.D.
49 Piston Court
Stewartstown, PA 17363-8322 USA
Phone: 717-993-8555 (M-F 9:00 AM-6:00 PM EST)
"The wages of sin is death, but the gift of God is eternal life
[which also includes perfect hearing]
through Jesus Christ our Lord." (Romans 6:23)
Copyright© Center for Hearing Loss Help 2006-2010, All rights


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Sep 22, 2009
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Probabilistic models based on Bayes' rule are an increasingly popular approach to understanding human cognition. Bayesian models allow immense representational latitude and complexity. Because they use normative Bayesian mathematics to process those representations, they define optimal performance on a given task. This article focuses on key mechanisms of Bayesian information processing, and provides numerous examples illustrating Bayesian approaches to the study of human cognition. We start by providing an overview of Bayesian modeling and Bayesian networks. We then describe three types of information processing operations—inference, parameter learning, and structure learning—in both Bayesian networks and human cognition. This is followed by a discussion of the important roles of prior knowledge and of active learning. We conclude by outlining some challenges for Bayesian models of human cognition that will need to be addressed by future research. WIREs Cogn Sci 2011 2 8–21 DOI: 10.1002/wcs.80
How to cite this WIREs title:
WIREs Cogn Sci
WIREs Cogn Sci
Impact Factor: 1.869
Bayesian learning theory applied to human cognition
Published Online: May 17 2010
DOI: 10.1002/wcs.80
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Original Article
Bypass of Senescence, Immortalization, and Transformation of Human Hematopoietic Progenitor Cells
Version of Record online: 1 OCT 2005
DOI: 10.1634/stemcells.2005-0390
Copyright © 2005 AlphaMed Press
Volume 23, Issue 9, pages 1423–1433, October 2005
Additional Information
How to Cite
Akimov, S. S., Ramezani, A., Hawley, T. S. and Hawley, R. G. (2005), Bypass of Senescence, Immortalization, and Transformation of Human Hematopoietic Progenitor Cells. STEM CELLS, 23: 1423–1433. doi: 10.1634/stemcells.2005-0390
Publication History
- Issue online: 2 JAN 2009
- Version of Record online: 1 OCT 2005
- Manuscript Accepted: 1 SEP 2005
- Manuscript Received: 12 AUG 2005
- Abstract
- Article
- References
- Cited By
- Cord blood;
- Human telomerase catalytic subunit;
- Human papillomavirus E6/E7 oncogenes;
- v-H-ras;
We attempted to extend the lifespan of CD34+ stem/progenitor cells in human cord blood (CB) by transduction with lentiviral vectors carrying the human telomerase catalytic subunit (hTERT) and/or the human papillomavirus type 16 (HPV16) E6 and E7 oncogenes. We found that hTERT was incapable of prolonging the replicative capacity of CB cells maintained under serum-free conditions in the presence of stem cell factor, Flt3 ligand, thrombopoietin, and interleukin-3 beyond 4 months (n = 3). However, transduced CB cells cultured in the same cytokine cocktail constitutively expressing HPV16 E6/E7 alone (n = 2) or in concert with hTERT (n = 9) continued to proliferate, giving rise to permanent (>2 years) cell lines with a CD45+ CD34− CD133+/− CD44+ CD235a+ CD71+ CD203+ CD33+ CD13+ myeloerythroid/mast cell progenitor phenotype. Notably, CB cell cultures expressing only HPV16 E6/E7 went through a crisis period, and the resulting oligoclonal cell lines were highly aneuploid. By comparison, the CB cell lines obtained by coexpression of HPV16 E6/E7 plus hTERT exhibited near-diploid karyotypes with minimal chromosomal aberrations, concomitant with stabilization of telomere length, yet were clonally derived. The immortalized E6/E7 plus hTERT–expressing CB cells were not tumorigenic when injected intravenously or subcutaneously into sublethally irradiated immunodeficient nonobese diabetic/severe combined immunodeficient mice but could be converted to a malignant state by ectopic expression of a v-H-ras or BCR-ABL oncogene. These findings provide new insights into the mechanisms governing the senescence checkpoint of primitive human hematopoietic precursors and establish a paradigm for studies of the multistep process of human leukemogenesis.


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In addition to his role as Scott "Cyclops" Summers in "X-Men: Apocalypse," Sheridan has appeared in "The Tree of Life" and "Mud."
Zak Penn wrote the most recent draft of "Ready Player One," which is being produced by Warner Bros. and Village Roadshow Pictures.
"Ready Player One" is scheduled to hit theaters on March 30, 2018.
(via Deadline)
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Fire hits old Phitsanulok community
A massive fire broke out at an old market community in Phitsanulok's Prompiram district at 5:30 am Thursday, destroying 12 shop houses. The blaze was put out an hour later. No casualties were reported.
Police quoted a woman as saying that she heard an explosion from a foods shop before the fire spread quickly.
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- Product Information
Product DescriptionDon't worry shark lovers our Shark Tooth Bead Necklace is fake and for fun only. Wear this faux shark tooth necklace in support of our finned friends of the sea. Each set of shark beads is 18" and makes a great party favor at shark party themes and as a present for the shark fan in your life. Our shark necklaces are sure to make shark lovers happy know they are fake and in support of these fantastic fish.
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|Showing 1-20
Derbyshire v Kent, Specsavers Championship Div 2, Derby, 1st day
Madsen ton leads revival after Coles burst
May 22, 2016: Wayne Madsen and Neil Broom made it Derbyshire's day after Matt Coles had given Kent an excellent start to the Division Two match at Derby
Gloucestershire v Derbyshire, County Championship, Division Two, Bristol, 2nd day
Gloucs solid in reply to Madsen 150
Apr 18, 2016: Wayne Madsen scored his 19th first-class century for Derbyshire to put his side in a strong position against Gloucestershire on day two of the County Championship Division Two match at Bristol
Gloucestershire v Derbyshire, County Championship, Division Two, Bristol, 1st day
Hughes misses ton but Derbyshire well set
Apr 17, 2016: Chesney Hughes fell four short of a hundred as Derbyshire posted 242 for three against some accurate Gloucestershire bowling on the opening day of the Specsavers County Championship match in Bristol.
County news
Godleman appointed Derbyshire captain
Mar 24, 2016: Billy Godleman has been appointed captain of Derbyshire's County Championship side after Wayne Madsen stepped down
Derbyshire v Leicestershire, LV= Championship Div Two, Derby, 2nd day
Madsen milestone but misses ton
Sep 23, 2015: Derbyshire captain Wayne Madsen completed 8000 first-class runs but missed out on a century in his 100th Championship match on the second day of the Division Two game against Leicestershire
Surrey v Derbyshire, LV= Championship, Kia Oval, 4th day
Surrey promoted with Batty hat-trick
Sep 4, 2015: Gareth Batty took a hat-trick and 6 for 51 overall as Surrey clinched promotion from LV= County Championship Division Tw by beating Derbyshire by an innings and 98 runs at the Kia Oval
Leicestershire v Derbyshire, LV= Championship, Division Two, Grace Road, 1st day
Madsen's solo effort bolsters Derbyshire
Aug 7, 2015: Wayne Madsen has played many more fluent and attractive innings in his long and illustrious career, but the South African cannot have made a more hard-fought than that which he scored on the first day against Leicestershire
Derbyshire v Glamorgan, LV= Championship, Division Two, Queen's Park, 4th day
Rutherford resistance denies Glamorgan record
Jul 9, 2015: Hamish Rutherford's century and Wayne Madsen's unbeaten 79 denied Glamorgan a record-breaking fifth consecutive victory
Essex v Derbyshire, LV= County Championship Division Two, Chelmsford, 3rd day
Napier highlights Essex desire for momentum
Jun 16, 2015: A second Championship win for Essex, this one by an in innings, sees them get off the bottom of Division Two. Their 23 points achieved in three days work here takes them to sixth in the table, with nine left to play.
Derbyshire v Worcestershire, Derby, 4th day
Durston five as Worcestershire implode
Sep 3, 2014: Worcestershire's promotion drive ran into a road block at Derby when an inspired career-best spell of spin bowling from Wes Durston sent them crashing to a 138-run defeat.
Leicestershire v Derbyshire, Royal London Cup, Group A, Grace Road
Derbs ride on another Madsen ton
Jul 27, 2014: Derbyshire captain Wayne Madsen struck his second successive Royal London Cup century to lead the Falcons to a seven-wicket victory against Leicestershire
Derbyshire v Hampshire, Royal London Cup, Group A, Derby
Durston, Madsen tons set up crushing win
Jul 26, 2014: Derbyshire bounced back from their miserable Twenty20 campaign by thrashing Hampshire by 136 runs in the opening Group A game of the Royal London Cup
Gloucestershire v Derbyshire, Cheltenham, 2nd day
Madsen, Slater lead strong Derbyshire reply
Jul 15, 2014: Skipper Wayne Madsen led from the front as Derbyshire hit back strongly on the second day against Gloucestershire at Cheltenham
Hampshire v Derbyshire, Ageas Bowl, 1st day
Madsen made to regret toss decision
Jun 1, 2014: Hampshire openers Jimmy Adams and Will Smith took full advantage of being given first use of their own pitch as Derbyshire's miserable season continued.
Worcestershire v Derbyshire, New Road, 4th day
Apr 30, 2014: Saeed Ajmal led the charge as Worcestershire ripped through Derbyshire to secure their second LV=County Championship victory of the season at New Road
Worcestershire v Derbyshire, New Road, 2nd day
Madsen counters Ajmal's threat
Apr 28, 2014: Derbyshire captain Wayne Madsen led the recovery as the visitors shrugged off their Sunday nightmare on the second day against Worcestershire at New Road
County news
Madsen extends Derbyshire contract
Nov 8, 2013: Derbyshire's captain and leading batsman Wayne Madsen has signed a contract extension that will keep him at the club for another three years
Not walking when you nick it? That's cheating
Oct 3, 2013: You have no choice but to walk when you're caught at cover. It ought to be the same if you feather it to slip
England news
Stokes wins Cricket Writers' award
Sep 30, 2013: Ben Stokes, the Durham and England allrounder, has capped an impressive season by winning the Cricket Writers' Club Young Cricketer of the Year award
County cricket
Madsen wins first CMJ award for walking
Sep 22, 2013: Wayne Madsen, the Derbyshire captain, has been awarded the inaugural Christopher Martin-Jenkins Spirit of Cricket Elite Award
|Showing 1-20
England's mastery of swinging conditions cannot mask progress (63)
Sri Lanka are not the first touring team to struggle in typical English conditions, but that fact does not detract from James Anderson's magnificence
IPL scenarios: Mumbai Indians need home teams to lose big (48)
A win for Kolkata Knight Riders will mean they finish in the top four, leaving the final league match to decide the fourth team in the playoffs
Malinga-less Mumbai patchy despite strong line-up (24)
Despite having most bases covered and unearthing an exciting young talent, defending champions Mumbai Indians endured a frustrating, stop-start season
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Kolkata Knight Riders opener Robin Uthappa is aiming for a maiden T20 hundred and an international comeback
The return of the outswing (19)
James Anderson has fantastic variation to his bowling, but the value of the stock ball should never be underestimated


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Sony Cyber-shot DSC-T90 digital camera
Solid feel build, small form factor, large-ish LCD, HD movies
Video isn't full HD, no HDMI out, screen can get confusingly packed out with info at times
Sony's latest snapshot, the DSC-T90, takes up the gauntlet thrown down by its predecessors and delivers beauty and simplicity married to almost anorexic proportions. No wonder it's referred to as a "fashion" model, here boasting a maximum width of a mere 15.1mm, weighing just 151g with battery inserted, and operated by basically sliding open its faceplate and pointing the lens in the right direction.
Brushing aside for the moment the observation that the T90 doesn't offer a great deal more than its T77 and T500 predecessors - except (granted) a resolution hike to 12 megapixels - what we do get is an internally stacked 4x optical zoom with a 35-140mm 35mm equivalent range plus renowned Carl Zeiss optics, High Definition 1280 x 720 video clips, and 3-inch widescreen-format touchscreen LCD with 230k dot resolution. Even so, the £289 asking price marks this out as a premium model rather than a value added one.
Though less of a big deal these days thanks to the ubiquitous iPhone, the Sony's touchscreen takes a little getting used to. A plastic stylus that attaches to the wrist strap is provided as a means of tapping and selecting cartoon-ish on-screen icons, which in turn provide access to fold-out or drop-down toolbars, the latter cropping the screen if shooting regular 4:3 ratio snaps rather than 16:9. If that proves too fiddly then a fingertip works just as well, albeit leaving smears on the glass.
With the T90 feeling lightweight yet solid when held in the palm thanks to a mainly metal construction, the screen itself is pleasantly responsive to every prod and effects an action with impressive speed.
At times however the options presented can get a little busy for its LCD size - particularly if shooting in the more extensive program mode. There is however a pared down easy mode, plus an "auto everything" intelligent auto (iA) mode that automatically analyses the scene or subject and adjusts settings accordingly. So, point the camera at something close and it will select macro mode, affording focus down to 8cm from the lens, with 10 other possible options for it to choose from.
If wanting to concentrate on your composition rather than what the camera is doing, then this is the mode to choose. That said, at times our review sample was a little lethargic in distinguishing one scene and setting from the next. More positively, we were up and shooting fairly quickly, a wait of around 2 seconds and a musical "sting" as the camera powers up from cold.
With the only physical controls being a shutter release button, on/off button, tiny rocker switch for the zoom and a playback button at the back, what the T90 misses is an HDMI port for connecting it directly to an HD TV set. Regular AV out and USB 2.0 connections are present and correct, accessed with the aid of a multi-purpose cable included in the box.
Given the fact that this pocket camera puts as much emphasis on style as substance we were pleased to find that light sensitivity of up to ISO 3200 is manually selectable, and that optical image stabilisation is also included, here under the "SteadyShot" branding. Useful, as with a narrow screen surround there's not much of the model presented to get a firm grip on, thus camera shake can seem more pronounced.
At its top ISO setting the T90 doesn't do a bad job, the level of grain/image noise visible being comparable to that witnessed at ISO 1600 from a 10 or 12 megapixel snapper around the £120 mark, and so it proves progressing incrementally down the range.
In terms of stills quality, left on its factory settings the camera produces subdued yet natural looking colours, with a vivid option selectable for added richness. Given that previous generations of Sony's have suffered from obvious pixel fringing, here such aberrations are kept under control and, as mentioned earlier, the auto scene modes work well, particularly when the camera selects the green and blue biasing landscape mode.
It may not excel at one thing in particular but the T90 works as a general-purpose tool for occasional use for those who don't want to fuss around with settings.
Small enough to carry in a pocket at all times, the T90 suggests itself as the ideal purchase for the happy snapper wanting better quality results than a camera phone will presently provide. It looks good too, even though Sony's designers seem to be resting on their laurels rather than attempting to enhance the range further and little has changed from previous incarnations.
Incidentally, if, like we do, you feel a larger 3.5-inch touchscreen would be advantageous, then the T500 was at the time of writing available for an identical outlay.
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text:
Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: A retrospective analysis
Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: .The Lancet (Impact Factor: 45.22). 01/2013; 381(9872). DOI: 10.1016/S0140-6736(12)62114-X
Source: PubMed
BACKGROUND: Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group. METHODS: We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5-6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests. FINDINGS: Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05). INTERPRETATION: Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated. FUNDING: None.
www.thelancet.com Published online January 28, 2013 http://dx.doi.org/10.1016/S0140-6736(12)62114-X
Cardiac involvement and treatment-related mortality after
non-myeloablative haemopoietic stem-cell transplantation
with unselected autologous peripheral blood for patients
with systemic sclerosis: a retrospective analysis
Richard K Burt, Maria Carolina Oliveira, Sanjiv J Shah, Daniela A Moraes, Belinda Simoes, Mihai Gheorghiade, James Schroeder, Eric Ruderman,
Dominique Farge, Z Jessie Chai, Zora Marjanovic, Sandeep Jain, Amy Morgan, Francesca Milanetti, Xiaoqiang Han, Borko Jovanovic,
Irene B Helenowski, Julio Voltarelli*
Background Autologous haemopoietic stem-cell transplantation (HSCT) benefi ts patients with systemic sclerosis but
has been associated with signifi cant treatment-related mortality and failure to improve diff usion capacity of carbon
monoxide (DLCO).We aimed to assess effi cacy of HSCT and use of rigorous cardiac screening in this group.
Methods W
e assessed patients with diff use systemic sclerosis or limited systemic sclerosis and interstitial lung disease
who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL,
USA) or the University of São P
aulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested
with cyclophosphamide (2 g/m²) and fi lgrastim. The transplant regimen was a non-myeloablative regimen of
cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5–6·5 mg/kg). We followed patients up
to 5 years for overall survival, relapse-free survival, modifi ed Rodnan skin score, and pulmonary function tests.
Findings F
ive (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend
echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular
complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart
failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease.
Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival
was 70% at 5 years. C
ompared with baseline, we noted improvements after HSCT in modifi ed Rodnan skin scores at
1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital
capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total
lung capacity and DLCO were not improved signifi cantly after HSCT. Overall mean DLCO was signifi cantly improved
in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05).
Interpretation Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-
selected autograf
t results in sustained improvement in skin thickness and forced vital capacity. DLCO is aff ected by
baseline cardiac function. G
uidelines for cardiac screening of patients with systemic sclerosis to assess treatment-
related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be
reconsidered and updated.
Funding None.
Systemic sclerosis generally aff ects young women and is a
chronic autoimmune disease of unknown cause com pli-
cated by a combination of diff use vasculopathy, immune
activation, and tissue fi brosis.
Standard thera pies are
unable to reverse disease progression, although several
non-randomised trials involving small numbers of
patients suggest that autologous haemo poietic stem-cell
transplantation (HSCT) can improve skin and stabilise or
improve forced vital capacity.
In the only randomised
trial published to date (the American Scleroderma Stem
Cell versus Immune Suppression Trial [ASSIST]),
autologous HSCT improved both skin and forced vital
capacity, whereas disease progression was noted in
patients treated with the standard therapy of monthly
intravenous cyclo phosphamide.
Several transplantation trials for systemic sclerosis have
been complicated by treatment-related mortal ity.
Such mortality was 10% (eight of 79 patients) in the largest
reported trial to date, the European Autologous Stem cell
Tra nsp lanta tion Int ern ation al Scl erode rma ( AST IS) tr ial .
For cancer
and auto immune diseases including systemic
pub lished guidelines recommend an echo-
cardiogram to assess cardiac reserve to establish whether
a patient can safely tolerate a transplant. However, unlike
other diseases for which haemopoietic transplantation is
done, the usual disease-related cause of death for systemic
sclerosis is cardiac complications arising from pulmonary
Published Online
January 28, 2013
See Online/Comment
*Died March 21, 2012
Division of Immunotherapy
(R K Burt MD, S Jain MD,
A Morgan NP, X Han MD),
Division of Cardiology
(S J Shah MD, Z J Chai BS),
Center for Cardiovascular
(M Gheorghiade MD), Division
of Rheumatology
(J Schroeder MD,
E Ruderman MD), Department
of Medicine, Northwestern
University Feinberg School of
Medicine, Chicago, IL, USA;
Department of Clinical
Medicine, School of Medicine
of Ribeirão Preto, University
of São Paulo, Ribeirão Preto,
Brazil (M C Oliveira MD,
D A Moraes MD, B Simoes MD,
J Voltarelli MD); Saint Louis
Hospitaux, Unité de Médecine
Interne et Pathologie
Vasculaire, Assistance
Publique Hopitaux de Paris,
Paris 7 University,
INSERM U 976, France
(D Farge MD); Saint Antoine
Hospitaux, Hematology
Department, Assistance-
Publique Hôpitaux de Paris,
Paris 6 University, Paris,
France (Z Marjanovic MD);
Division of Clinical
Immunology and
Rheumatology, Sant Andrea
Hospital, Sapienza, University
of Rome, Rome, Italy
(F Milanetti MD); and
Department of Preventive
Medicine, Northwestern
University Feinberg School of
Medicine, Chicago, IL, USA
(B Jovanovic PhD,
I B Helenowski PhD)
Page 1
www.thelancet.com Published online January 28, 2013 http://dx.doi.org/10.1016/S0140-6736(12)62114-X
Correspondence to:
Dr Richard K Burt, Division of
Immunotherapy, Department of
Medicine, Northwestern
University Feinberg School of
Medicine, Chicago, IL 60611, USA
artery hypertension and primary cardiac or pericardial
Therefore, we analysed results from two centres that
used the same mobilisation and non-myeloablative
HSCT regimen without selection or manipulation of the
graft to assess the causes of treatment-related mortality,
whether impaired cardiac function aff ects outcome, and
the appropriate screening method before transplantation
to prevent enrolment of patients with insuffi cient cardiac
reserve to safely tolerate the procedure.
Study design and patients
We undertook a retrospective analysis of all patients
treated with HSCT, either as part of a study or on
a compassionate basis, at Northwestern University
(Chicago, IL, USA) and the University of São Paulo
(Ribeirão Preto, Brazil). P
atients were enrolled in
institutional review board (IRB)-approved studies and
retrospective IRB approval was obtained to report off -
study patients. We defi
ned duration of disease as
duration from time of diagnosis of systemic sclerosis.
Patients were followed up for 5 years after HSCT.
Patients who underwent transplantation had diff use
systemic sclerosis, defi ned as cutaneous involvement
proximal to the elbow or knee with a modifi ed Rodnan
skin score
of 14 or more and internal organ involvement
defi ned as pulmonary fi brosis or ground glass on chest
CT, abnormal electrocardiograph, or gastrointestinal
track involvement. Patients with little cutaneous in-
volvement (modifi ed Rodnan skin score <14) were
eligible if they had coexistent pulmonary involvement.
Patients were excluded if they had a total lung capacity of
less than 45%, left ventricular ejection fraction of less
than 40% or pulmonary artery systolic pressure (PASP)
of more than 42 mm Hg, or positive serology for HIV or
hepatitis B surface antigen. All patients had an echo-
cardiogram and cardiac assessment. Additional cardiac
testing was done on an individual basis until imple-
mentation of a standard screening in the last 12 patients
enrolled; this screening consisted of echocardiogram
with tricuspid annular plane systolic excursion (TAPSE),
right heart catheterisation measured before and after a
500 mL intravenous normal saline bolus, and cardiac
MRI with gadolinium. Fluid bolus was contraindicated if
resting cardiac catheterisation right atrial pressure was
more than 12 mm Hg or pulmonary capillary wedge
pressure (PCWP) was more than 15 mm Hg. In Chicago,
patients were ineligible for study inclusion if they were
older than 55 years or had a disease duration of more
than 4 years.
Peripheral blood stem cells were mobilised with intra-
venous cyclophosphamide (2 g/m²) and 5–10 µL/kg
subcutaneous fi lgrastim daily started 1 day after
cyclophosphamide at the University of São Paulo or
5 days after cyclophosphamide at Northwestern
University. Peripheral blood stem cell apheresis was
done on day 10 after start of cyclophosphamide and
peripheral blood stem cells were cryopreserved without
manipulation. The conditioning regimen was
200 mg/kg intravenous cyclophosphamide given in
four equal fractions on day –5 to day –2 before stem-cell
infusion. rATG (thymoglobulin) was dosed at
0·5 mg/kg intravenously on day –5 and then either
1·0 mg/kg or 1·5 mg/kg intravenously every day on
day –4 to day –1.
Blood products were irradiated, cytomegalovirus-safe,
and leucocyte depleted. Filgrastim (10 µL/kg per day) was
started 5 days after stem-cell infusion and continued until
engraftment. Dependent on centre guidelines, intra venous
prophylactic cefepime or piperacillin-tazobactam was
started prophylactically or withheld until development of
neutropenic fever. Oral aciclovir or valaciclovir was started
on admission to the transplant centre and continued for
2 months after transplantation at the University of São
Paulo or 12 months after transplantation at Northwestern
University. Patients received oral daily fl uconazole and
either oral trimethoprim-sulfamethoxazole 2–3 times per
week or aerosolised pentamidine every month for
2–6 months.
Patients started hyperhydration (150–200 mL normal
saline per h) with diuretics or normal hydration at
50–75 mL per h with addition of continuous bladder
irrigation (125–150 mL normal saline per h) and intra-
venous mesna at 100% the dose of cyclophosphamide
with every dose of cyclo phosphamide, continued for 24 h.
Patients received methylprednisolone intravenously
(250–1000 mg) before rATG (at Northwestern University)
or as part of each rATG infusion bag (at University of
São Paulo; 125 mg per bag).
Figure 1: Trial profi le
143 patients with systemic sclerosis
53 excluded
39 too severe disease
10 limited skin and no
pulmonary involvement
3 confounding illness (previous
malignant disease or coronary
artery disease)
1 refused to allow blood
90 enrolled
59 on study (10 on phase 1 study,
31 on non-randomised phase 2,
18 on randomised phase 2 study)
21 on a compassionate basis (aged
>55 years or disease duration
>4 years)
10 off study after closing phase 1
but before opening phase 2 study
(met the same study criteria)
Page 2
www.thelancet.com Published online January 28, 2013 http://dx.doi.org/10.1016/S0140-6736(12)62114-X
On admission, patients were prescribed an oral calcium-
channel blocker to prevent Raynaud's phe nom ena and an
oral angiotensin-converting enzyme inhibitor or angio-
tensin receptor antagonist to prevent renal crisis. We
monitored viral loads of cytomegalovirus after transplant-
ation for 2–3 months and pre-emptively treated patients
by switching them from aciclovir to oral valganciclovir
(900 mg twice-daily) or intravenous ganciclovir (5 mg/kg
twice-daily) until they were cyto megalovirus negative.
The main outcome was treatment-related mortality
in patients who underwent HSCT. We also assessed skin
thickness by modifi ed Rodnan skin score and pulmonary
function by forced vital capacity, total lung capacity,
and diff using capacity of carbon monoxide (DLCO;
percentage predicted and corrected for haemo globin).
We administered quality of life questionnaires (short
form [SF]-36) for the last 30 consecutive patients from
one site (Northwestern University). We defi ned relapse
as any of the following criteria: increase from best
improvement of skin score by 25% or decline in forced
vital capacity by 10%, renal crisis, start of total parenteral
nutrition, or restarting of immune suppressive or
modulating medication.
Statistical analysis
We calculated overall survival and relapse-free survival
with Kaplan-Meier methods. We used two-tailed paired
t tests for comparisons within the transplantation group.
We analysed the eff ect of cardiac function and sex on
pulmonary function and skin thickness by least-square
means and standard deviations adjusted by repeated
measures across all visits (averaged over time) via a
mixed eff ects model for outcome. We used the r cor-
relation coeffi cient to determine linear relations between
variables. A correlation coeffi cient of more than 0·8 was
regarded as strong, whereas less than 0·5 was regarded
Patients (n=90)
Median age, years 42 (16–71)
Sex, female 73 (81%)
White 70 (78%)
Black 11 (12%)
Hispanic 5 (6%)
Biracial 3 (3%)
Native American 1 (1%)
Median disease duration from diagnosis to HSCT,
25 (2–156)
History of Raynauďs phenomena 83 (92%)
Median modifi ed Rodnan skin score 24 (3–47)
Diff use systemic sclerosis 72 (80%)
Gastrointestinal track disorders 81 (90%)
Gastro-oesophageal refl ux disease 51 (63%)
Patulous esophagous 52 (64%)
Gastrointestinal antral vascular ectasia 5 (6%)
Small bowel involvement 3 (4%)
Total parenteral nutrition 1 (1%)
Pulmonary function tests
Median forced vital capacity 67% (31–103)
Median DLCO (corrected for haemoglobin) 64% (19–123)
Abnormal lung involvement on imaging 73 (81%)
Interstitial lung disease 73 (100%)
Nodules or micronodules 4 (5%)
Bronchiectasis 7 (10%)
Honeycombing 2 (3%)
Oxygen dependency 2 (3%)
Previous renal crisis 1 (1%)
Abnormal electrocardiography 44 (49%)
Non-specifi c T-wave abnormalities 17 (39%)
Right bundle branch block 8 (18%)
Left bundle branch block 2 (5%)
Left anterior fasicular block 4 (9%)
Pacemaker 1 (2%)
Intraventricular conduction delay 3 (7%)
First degree atrioventricular block 1 (2%)
Prolonged QT interval 5 (11%)
Ventricular premature contractions 3 (7%)
Atrial fi brillation 1 (2%)
Supraventricular tachycardia 1 (2%)
Atrioventricular nodal re-entry tachycardia 1 (2%)
(Continues in next column)
Patients (n=90)
(Continued from previous column)
Abnormal 25 (28%)
Mild (grade 1) diastolic dysfunction 13 (52%)
Enlarged chambers 7 (28%)
Interventricular septal fl attening 3 (12%)
Pericardial eff usion >1 cm with diastolic atrial
2 (8%)
Enlarged pulmonary artery 2 (8%)
Septal bounce 1 (4%)
ANA positive (>1:40) 87 (97%)
Scl-70 positive (>10 IU) 43 (48%)
Previous immunotherapy† 84 (93%)
Data are median (range) or n (%), unless otherwise stated. HSCT=haemopoietic
stem-cell transplantation. DLCO=diff usion capacity of carbon monoxide. LVEF=left
ventricular ejection fraction. ANA=anti-nuclear antibody. *One echocardiogram was
not done; trace mitral regurgitation and left ventricular hypertrophy with no other
abnormalities were regarded as normal. †Corticosteroids (60 patients), oral
cyclophosphamide (six patients), intravenous cyclophosphamide (28 patients),
methotrexate (32 patients), mycophenolate mofetil (17 patients), penicillamine
(15 patients), azathioprine (four patients), lidocaine (11 patients),
hydroxychloroquine (fi ve patients), minocycline (fi ve patients), protein
tyrosine-kinase inhibitor (imatinib or dasatinib; four patients), TNF-inhibitor
(infl iximab or adalimumab; three patients), or colchicine (two patients).
Table 1: Patient demographics
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as weak. We did all analyses with Graphpad Prism 5
software (Graphpad, CA, USA).
Role of the funding source
There was no funding source for this study. The
statisticians (BJ, IBH), corresponding author (RKB),
study nurse (AM), and research fellows (XH and SJ) had
full access to all the data in the study and had fi nal
responsibility for the decision to submit for publication.
Between November, 2002, and July, 2011, we included
59 patients at Northwestern University and 31 patients at
the University of São Paulo (fi gure 1). 59 patients were in
IRB-approved studies (28 from Northwestern University
and 31 from University of São Paulo) and retrospective
IRB approval was obtained for 31 patients. Table 1 shows
demographic characteristics of 90 patients who were
off ered au tologous HSCT.
Median day of engraftment (absolute neutrophil count
>1000 cells per µL) was day 9 (range 8–11). 63 patients
(70%) developed fever of more than 38°C, which was
blood-culture negative in 59 patients (two patients had
Klebsiella pneumoniae infections, one had Pseudomonas
aeruginosa infection, and one had Acinetobacter baumannii
infection). On admission, fi ve patients had positive rectal
or nasal surveillance cultures for colonisation with
vancomycin-resistant enterococcus. Five patients de-
veloped Clostridium diffi cile toxin-positive diarrhoea
during hospitalisation.
14 patients had a volume overload of more than 5 kg
because of hyperhydration (200 mL per h of normal
saline) during the conditioning regimen. Af
ter the fi rst
20 patients were treated, hydration during conditioning
was decreased to 50–100 mL/h, supplemented with
intravenous mesna infusion and intravesicle bladder
irrigation (150 mL/h of normal saline) with no further
episodes of volume overload. One patient developed
transient acute tubular necrosis (confi
rmed by renal
biopsy) from the combination of diuretics and angio-
tensin-converting enzyme inhibitor. Another patient
developed transient renal crisis during transplantation
mandating temporary dialysis. One further patient had
paradoxical emboli from a patent foramen ovale and
needed distal amputation of three toes.
No patients developed fungal or cytomegalovirus
infections. Two months after discharge home, one
patient developed West Nile virus encephalomyelitis with
prolonged but continuing recovery. No patients developed
leukaemia, myelodysplasia, or cancer.
One enrolled patient declined treatment and one
patient received treatment but did not return for follow-
up. Five patients (6%) had treatment-related deaths. Four
treatment-related deaths were from cardiac events, with
one sudden cardiac arrest during mobilisation and three
sudden cardiac arrests during transplant ation (one
because of constrictive pericarditis and two secondary to
heart failure). One death was secondary to septic
neutropenia in a patient not on pre-emptive broad-
spectrum antibiotics.
For 88 patients with follow-up, 5 year overall survival
was 78% and relapse-free survival was 70% (fi gure 2).
Eight (62%) of 13 patients who relapsed subsequently
died of their disease despite reinstitution of immuno-
therapy. Deaths related to relapse were related to
cardiopulmonary causes for six patients (three deaths
~2 years after transplantation and three deaths 3–4 years
after transplantation) and were related to renal crisis for
two patients (3 months and 4 months after trans-
plantation). The initial presentation of relapse was renal
crisis in four patients (3, 4, 12, and 18 months after
Modifi ed Rodnan skin scores improved after trans-
plantation (fi gure 3). Compared with the mean score
before transplantation (24·1), mean scores had improved
by 6 months (16·5; p<0·0001), 12 months (12·9;
p<0·0001), 24 months (12·2; p<0·0001), 36 months (11·1;
p<0·0001), 48 months (10·3; p=0·0001), and 60 months
(8·9; p=0·0003).
Forced vital capacity also improved after transplantation
(fi gure 3). Compared with a mean forced vital capacity
before transplantation of 66·2%, patients had improve-
ments at 6 months (70·8%; p=0·0009), 12 months (71·1%;
Figure 2: Overall survival (A) and relapse-free survival (B) after haemopoietic
stem-cell transplantation
Overall survival (%)
Relapse-free survival (%)
Time (months)
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p=0·009); 24 months (72·6%; p=0·02), and 36 months
(76·1%; p=0·004), but these improvements were not
signifi cant at 48 months (73·4%; p=0·11) or 60 months
(73·0%; p=0·26). Total lung capacity and percentage
DLCO corrected for haemo
globin did not change for the
entire group (fi
gure 3). Compared with mean DLCO values
before trans plantation (68·2%), values after transplantation
did not diff er at 6 months (64·9%; p=0·41), 12 months
(66·5%; p=0·56), 24 months (72·8%; p=0·82), 36 months
(68·3%; p=0·27), 48 months (64·5%; p=0·48), and
60 months (64·5%; p=0·67).
We noted at best a weak correlation (r<0·5) between
DLCO values after transplantation and modifi ed Rodnan
skin score, age, and duration of disease before trans-
plantation (table 2). We identifi ed an intermediate
correlation (r=0·5–0·8) between baseline DLCO values
and DLCO values after transplantation, but baseline
DLCO, forced vital capacity, and modifi ed Rodnan skin
scores had weak correlation with change in DLCO after
transplantation (table 2). The only baseline factors that
correlated signifi cantly with DLCO outcome after trans-
plantation were baseline echocardiogram or electro-
cardiograph abnormalities (table 3, fi gure 4). DLCO
values after transplantation were improved if the base-
line electrocardiograph or echocardiogram was normal
(p=0·05 for electrocardiograph and p=0·005 for echo-
Cardiac assessments before transplantation evolved
during the study from echocardiogram and cardiac
assessment (for 90 patients) to include echocardiogram
with TAPSE and right heart catheterisation (for
23 patients and 39 patients, respectively), and fi nally a
consistent approach of echocardiogram with TAPSE,
right heart catheterisation without and with fl uid
Figure 3: Modifi ed Rodnan skin score and pulmonary function tests before (0 months) and after haemopoietic stem-cell transplantation
Vertical lines show standard error at each time point. mRSS=modifi ed Rodnan skin score. DLCO=diff usion capacity of carbon monoxide.
Number of patients
89 66 58 42 27 17 12
88 65 58 40 28 14 11
Forced vital capacity (%)
Number of patients
0 6 12 18 24 30 36 42 48 54 60
82 59 54 41 28 14 11
Time (months)
Total lung capacity (%)
0 6 12 18 24 30 36 42 48 54 60
75 62 53 42 27 15 11
Time (months)
1 year
after HSCT
Duration of disease since diagnosis vs DLCO
–0·34 –0·47
Patients age vs DLCO
–0·25 –0·08
mRSS vs DLCO before transplantation
0·26 0·43
FVC vs DLCO before transplantation
0·58 0·63
DLCO before transplantation vs DLCO after transplantation
mRSS before transplantation vs change from baseline in DLCO after transplantation
FVC before transplantation vs change from baseline in DLCO after transplantation
DLCO before transplantation vs change from baseline in DLCO after transplantation
Duration of disease vs change from baseline in DLCO after transplantation
Age vs change from baseline in DLCO after transplantation
Data are linear correlation coeffi cients (r>0·8 is strong correlation, r<0·5 is weak correlation). HSCT=haemopoietic
stem-cell transplantation. mRSS=modifi ed Rodnan skin score. DLCO=diff using capacity of carbon monoxide
(% predicted, corrected for haemoglobin). FVC=forced vital capacity (% predicted). NA=not applicable.
Table 2: Correlation coeffi cient (r) between pretransplantation parameters and DLCO before or after
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challenge, and cardiac MRI with gadolinium for the last
12 patients assessed (table 3).
Table 4 shows the information for the last 12 patients
enrolled provided by echocardiogram, cardiac
catheterisation without and with fl uid challenge, and
cardiac MRI. Patients without signifi cant pulmonary
artery hyper tension tolerated fl uids without signifi cant
increase in PASP. By comparison, after infusion of
500 mL normal saline, patients with underlying
pulmonary artery hypertension had a striking increase in
PASP, mean pulmonary pressure, and pulmonary
vascular resistance. In these patients, cardiac MRI
showed signifi cant indentation of the right ventricle into
the left ventricle via the common interventricular
septum—ie, diastolic septal fl attening or D-sign.
In patients without pulmonary artery hypertension, fl uid
challenge with 500 mL normal saline could also provoke
left ventricle compromise, shown by increase of PASP,
mean pulmonary pressure, and PCWP without an increase
in pulmonary vascular resistance (table 4). These patients
also usually show diff use gadolinium enhancement on
cardiac MRI and a history of palpi tations, recurrent atrial,
ventricular premature contrac tions, or recurrent, multi-
focal, non-sustained ventricular tachycardia.
Quality of life before transplantation and at last follow-
improved signifi
cantly in total score and in all scales
and dimensions apart from emotional role limitation and
mental health score (table 5).
HSCT was associated with treatment-related mortality in
fi ve (6%) of 90 patients in our study, which is about half
the rate (eight [10%] of 79 patients) in the European
multicentre ASTIS trial.
Treatment-related mortality in
our study was predominantly related to cardiac events
(four of fi ve deaths). We attribute the reduced mortality in
our study compared with ASTIS to recognition that
echocardiogram and resting right heart catheterisation
might be insuffi cient to assess cardiac risk in patients
with systemic sclerosis (panel). The ASTIS trial
echocardiogram whereas cardiac catheterisation was only
required for patients with pulmonary artery hyper tension
suggested by an echocardiogram. However, pulmonary
artery hypertension determined by echo cardio graphic
calculation of PASP can signifi cantly overestimate or
underestimate invasive PASP because of image problems,
Doppler alignment, or violation of viscosity assumptions
in the modifi ed Bernoulli equation used to calculate
echocardiographic PASP.
Normal echocardiogram
or electrocardiograph or
female sex
Abnormal echocardiogram
or electrocardiograph or
male sex
p value*
Group: echocardiogram Normal 71·3% (3·1) Abnormal 56·7% (3·8)† 0·0045
Group: electrocardiograph Normal 73·3% (4·6) Abnormal 62·0% (3·0)‡ 0·045
Group: sex Female 66·3% (2·8) Male 64·5% (4·9) 0·75
Group: echocardiogram Normal 70·8% (3·2) Abnormal 68·4% (2·4) 0·58
Group: electrocardiograph Normal 73·6% (4·6) Abnormal 68·2% (2·1) 0·28
Group: sex Female 66·1% (2·5) Male 66·3% (3·1) 0·95
Total lung capacity
Group: echocardiogram Normal 80·3% (3·4) Abnormal 78·8% (2·3) 0·70
Group: electrocardiogram Normal 81·9% (4·4) Abnormal 78·7% (2·1) 0·51
Group: sex Female 75·8% (2·4) Male 75·2% (3·0) 0·80
Group: echocardiogram Normal 16·1 (1·7) Abnormal 18·2 (1·3) 0·33
Group: electrocardiograph Normal 16·1 (2·4) Abnormal 17·8 (1·1) 0·51
Group: sex Female 17·0 (1·4) Male 16·4 (2·1) 0·77
DLCO=diff usion capacity for carbon monoxide (% predicted, corrected for haemoglobin). FVC=forced vital capacity
(% predicted). mRSS=modifi ed Rodman skin score. *Least-square means (SDs) adjusted by repeated measurements
across all visits (before and after transplantation) averaged over time via a mixed eff ects model. †Abnormal
echocardiogram was diastolic or systolic dysfunction, enlarged chambers, left ventricular ejection fraction <50%,
interventricular diastolic fl attening, pericardial eff usion >1 cm with diastolic atrial indentation, enlarged pulmonary
artery, or septal bounce. ‡Abnormal electrocardiogram was non-specifi c T-wave abnormalities, bundle branch or fasicular
block, conduction delay, pacemaker, prolonged QT interval, ventricular premature contractions, or arrhythmias.
Table 3: Eff ect of cardiac function and sex on lung and skin disease in patients with systemic sclerosis
Figure 4: DLCO corrected for haemoglobin before and after HSCT, by normal
or abnormal echocardiogram or electrocardiograph before transplantation
Abnormal echocardiogram was diastolic or systolic dysfunction, enlarged
chambers, left ventricular ejection fraction <50%, interventricular diastolic
fl attening, pericardial eff usion >1 cm with diastolic atrial indentation, enlarged
pulmonary artery, or septal bounce. Abnormal electrocardiograph was
non-specifi c T-wave abnormalities, bundle branch or fasicular block, conduction
delay, pacemaker, prolonged QT interval, ventricular premature contractions, or
arrhythmias. HSCT=haemopoietic stem-cell transplantation.
Normal echocardiogram before HSCT
Abnormal echocardiogram before HSCT
0 6 12 18 24 36
Time (months)
Normal electrocardiograph before HSCT
Abnormal electrocardiograph before HSCT
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Right heart catheterisation is regarded as the gold
standard to rule out pulmonary artery hypertension
is recommended for early detection of pulmonary artery
hypertension in patients with systemic scler osis.
Nevertheless, PASP obtained via resting right heart
catheterisation can be falsely reassuring for patients with
systemic sclerosis. As shown in table 4, pulmonary artery
pressure can be volume dependent in patients who have
systemic sclerosis because of ab normal stiff ening of
pulmonary arteries or myocardium. At the time of
measurement, patients are relatively volume depleted
because they have had no oral hydration since the previous
night in preparation for the procedure. In our study, fl uid
challenge unmasked patients with volume dependent
pulmonary artery hypertension manifest by increase in
PASP, mean pulmonary pres sure, and pulmonary
vascular resistance and patients with pulmonary venous
hypertension because of left ventricle compromise in
which pulmonary artery and PCWP increased without an
increase in pulmonary vascular resistance.
Because patients with systemic sclerosis might not
notice cardiopulmonary symptoms at rest but have
symptoms only with exertion or volume loading, volume
confrontational testing might be required to diagnose
Echocardiogram Right heart catheterisation Cardiac MRI/arrhythmias
Summary LVEF PASP PASP
PASP (mPAP)
after 500 mL
normal saline
PCW PCW after
500 mL
normal saline
PVR PVR after
500 mL
normal saline
Eligible for HSCT
Patient 1 Normal 65% 35 26 (18) 35 (25) 7 13 148 143 Normal
Patient 2 Normal 65% 30 23 (18) 25 (21) 10 15 89 65 Normal
Patient 3 Normal 55% NR 27 (20) 34 (29) 11 18 93 85 Normal
Patient 4 LVH 65% 22 19 (14) 25 (21) 3 5 95 179 Patchy myocardial enhancement, LVH, LADB
Patient 5 Normal 60% 24 16 (11) 22 (18) 5 11 69 86 Normal
Patient 6 Grade 1 diastolic dysfunction 55% 23 27 (19) 36 (30) 10 19 105 NR Normal
Patient 7 Normal 60% 34 30 (22) 46 (38) 12 25 119 198 Patchy left ventricular myocardial enhancement
Denied HSCT because of PAH
Patient 8 Septal fl attening 65% 27 42 (27) 51 (34) 14 7 110 225 D-sign, interventricular septal diastolic
fl attening, atrial premature beats
Patient 9 Grade 1 diastolic dysfunction 55% NR 38 (28) 51 (39) 14 19 175 240 D-sign, interventricular septal diastolic fl attening,
enlarged right ventricle, inferior infarct
Denied HSCT because of right or left ventricle dysfunction
Patient 10 Grade 1 diastolic dysfunction 46% 40 31 (23) 42 (31) 9 16 174 158 LVEF 40%; systolic hypokinesis and diastolic
Patient 11 Septal fl attening 55% 26 31 (24) NP NP NP 119 NR LVEF 39%; D-sign, notably enlarged right
ventricle; diff use left and right ventricular
enhancement; frequent PVCs, low QRS voltage
Patient 12 Normal* 55% 23 13 (8) 21 (14) 3 7 61 81 LVEF 45%; right ventricular ejection fraction
30%; diff use left and right ventricular myocardial
enhancement; right ventricular dilatation,
non-sustained multifocal ventricular tachycardia
LVEF=left ventricular ejection fraction. PASP=pulmonary artery systolic pressure (mm Hg). mPAP=mean pulmonary artery pressure (mm Hg). PCW=pulmonary capillary wedge (mm Hg). PVR=pulmonary vascular
resistance (dynes·s·cm
⁵). HSCT=haemopoietic stem-cell transplantation. NR=not reported. LVH=left ventricular hypertrophy. LADB=left anterior divisional block. PAH=pulmonary artery hypertension. NP=not
performed. PVCs=premature ventricular contractions. *Echocardiogram reported as normal but after obtaining results of cardiac MRI, reassessment of echocardiogram reported as inferior hypokinesis.
Table 4: Echocardiogram, right heart cardiac catheter parameters before and after fl uid challenge, and cardiac MRI in 12 consecutive patients with systemic sclerosis referred for HSCT
Scale Dimension Total SF-36
Physical role
Body pain General health
Vital energy
role limitation
Before HSCT 28 23 45 38 39 47 58 74 35 51 44
Last follow-up after HSCT 58 53 62 52 52 69 71 76 55 64 62
Diff erence (SD) 30 (31·47) 30 (47·20) 17 (26·47) 14 (46·98) 13 (27·84) 22 (35·12) 13 (46·84) 2 (11·70) 20 (27·69) 13 (23·36) 18 (20·25)
p value <0·0001 0·001 0·001 0·105 0·024 0·002 0·129 0·308 <0·0001 0·005 <0·0001
SF-36=short form 36. HSCT=haemopoietic stem-cell transplantation.
Table 5: Quality of life by SF-36 before and after HSCT
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and assess the severity of pulmonary artery hyper tension
as has been reported in assessment of portopulmonary
hypertension in recipients of liver transplants.
Our data
for cardiac catheterisation with and without fl uid con-
frontation argue for reconsideration of the presently
published cardiac guidelines about assessment of cardiac
risk in patients with systemic sclerosis.
However, a
confrontational fl uid challenge might, itself, be dangerous
in patients with little cardiac reserve.
Thus, we excluded
fl uid challenge in patients with resting cardiac catheter-
isation right atrial pressure of more than 12 mm Hg or
PCWP of more than 15 mm Hg.
Cardiac MRI is helpful for assessment of ventricular
volumes, function, wall motion, and myocardial fi brosis
or infl ammation in patients with systemic sclerosis.
Pulmonary artery hypertension-induced displacement
of the common interventricular wall into the left ventricle
(diastolic septal fl attening or D-sign) decreases left
ventricular compliance and impairs left ventricular
fi lling, thereby potentially increasing left atrial pressure
and causing pulmonary oedema in the setting of
hyperhydration. Myocardium scar detected by late
gadolinium enhancement of myocardium on cardiac
MRI is an indication of poor myocardial reserve,
increased risk of arrhythmias,
and left ventricle dys-
function as uncovered by fl uid challenge during cardiac
catheterisation. Patients with systemic sclerosis compli-
cated by either pulmonary artery hyper tension or
myocardial fi brosis are volume sensitive and fl uids might
precipitate cardiac failure. One death in our study was
due to constrictive pericarditis, which is another
complication that is exacerbated by fl uids and that, in
retrospect, might have been identifi ed by pericardial
enhancement or septal bounce on cardiac MRI or cardiac
catheterisation with rapid fl uid challenge.
In three patients, the fi rst manifestation of relapse
was renal crisis after the transplantation. None of the
patients who developed renal crisis had been maintained
on angiotensin blockade. We currently recommend
that patients start an angiotensin-converting enzyme
inhibitor or angiotensin receptor blocker on admission
and indefi nite continuation after discharge from the
transplant centre.
Factors that reduce DLCO include: anaemia, lung
disease that impairs alveolar gas exchange or results in
uneven distribution of air, intrapulmonary or intracardiac
shunts, and cardiac insuffi ciency.
Because heart failure
can diminish DLCO
and systemic sclerosis involves
the heart, in retrospect, our fi ndings that abnormal
baseline echocardiograms correlate with a decline in
DLCO after transplantation that does not return to
baseline for at least 2 years is not surprising (fi gure 3). By
comparison, normal baseline echocardiograms cor relate
with improved DLCO after transplantation.
Because our study was non-randomised, our patients
might have been at a later stage of disease where skin
thickness and quality of life can improve without
intervention. However, our results are consistent with
those from our previous randomised trial in a smaller
subset of patients in which skin score, forced vital capacity,
and quality of life improved equally in the transplantation
group but declined in the control group.
Moreover, no
other type of therapy or natural history study has reported
improvement in pulmonary func tion—ie, in forced vital
capacity or DLCO. Furthermore, we noted no correlation
between duration of disease before transplantation and
improvement in DLCO after transplantation. Conversely,
DLCO values after transplantation correlated with cardiac
structure and function before HSCT.
In conclusion, previous reports of high treatment-
related mortality might suggest to physicians that HSCT
should be reserved as salvage therapy. However, this
bias would result in a self-fulfi lling prophecy of high
transplant-related mortality, especially without appro-
priate cardiac assessment before HSCT. Our fi ndings
suggest that cardiac screening guidelines for systemic
sclerosis should incorporate not only echocardiogram
but also confrontational right heart catheterisation,
including a fl uid challenge test and cardiac MRI to
appropriately assess procedure risk. We also showed that
DLCO can improve after transplantation if baseline
cardiac function and electrocardiograph fi ndings are
normal. Systemic sclerosis-related cardiac involvement
before an HSCT is an important variable in determining
both treatment-related mortality and DLCO after
transplantation. HSCT can be considered as upfront
therapy if baseline cardiac assessment is favourable.
Panel: Research in context
Systemic review
We searched PubMed without language restriction for original research articles published
between June 25, 1997
, and May 1, 2012, with the terms "stem cell transplantation" and
"systemic sclerosis". We identifi ed no distinct large phase 2 non-randomised studies or
phase 3 trials with long-term follow-up that used the same regimen as our study. The only
completed randomised trial reported to date
was strongly in favour of transplantation
and was stopped early after 19 patients. We identifi ed no distinct phase 2 or phase 3
studies that identifi ed risk factors for transplantation, focused on extensive cardiac
assessment before transplantation, or documented improvement in diff using capacity of
carbon monoxide (DLCO) after transplantation. Two randomised trials have yet to be
concluded, the European Autologous Stem cell Transplantation International Scleroderma
(ASTIS) trial
and Scleroderma Cyclophosphamide versus Transplant (SCOT) trial; ASTIS
has reported a treatment-related mortality of 10% (eight of 79 patients).
Previous studies showed improvement in patients' skin scores and forced vital capacity
after haemopoietic stem-cell transplantation (HSCT) but transplantation based on
published guidelines for baseline cardiac screening have shown no improvement in DLCO
and a number of deaths. To our knowledge, our study is the fi rst to show a benefi t of
extensive cardiac screening at baseline and that pretransplantation cardiac structure,
function, and electrophysiology aff ect DLCO after transplantation. These fi ndings argue for
early referral of patients for transplantation before onset of cardiac or pericardial-related
compromise in heart function and for reassessment of present cardiac screening
guidelines for systemic sclerosis.
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All authors contributed to review and proof of this report. RKB designed
the protocol, wrote the report, and was responsible for the conduct of the
trial in Chicago, IL, USA. RKB, SJ, and AM were responsible for
treatment and care of patients in Chicago. SJS and MG were responsible
for baseline cardiac consultation. JS and ER were responsible for
baseline rheumatology consultation. JV, MCO, DAM, and BS were
responsible for conduct of the trial and care of patients in São Paulo,
Brazil. SJS and ZJC assessed all echocardiograms. XH and SJ collected
data and reviewed records. IBH and BJ did statistical analysis.
Confl icts of interest
We declare that we have no confl icts of interest.
We dedicate this manuscript to the memory of our colleague and friend,
Professor Julio Voltarelli MD, PhD (Dec 17, 1948–March 21, 2012).
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