Is HSCT for everyone, or not?

The HSCT zealots would want you to believe that HSCT is the solution to MS and that we the neurologists are preventing you from accessing this curative treatment. Are they correct? Or do we need evidence from randomised trials?

I saw a patient for a third opinion late last year. She was in her mid-20s and had just failed alemtuzumab with a severe spinal cord relapse 19 months into her 2-year alemtuzumab treatment protocol. The question is what do we do now? She had previously failed interferon-beta and hence fulfilled our criteria for HSCT. When I mentioned to her that the risk of premature ovarian failure (early menopause) was over 40% with aHSCT and that she would need to freeze down eggs if she wanted to optimise her chances of having children in the future she answered an emphatic no. HSCT as a treatment option was too risky for her. This risk was not around the infectious complications, but fertility. 

Please note HSCT is not for everyone based on personal circumstances. This patient then opted for natalizumab treatment as her JCV serostatus was negative. I think the latter is a very wise choice given her wish to start a family in the future. 

I have commented extensively in the past on HSCT (both non-myeloablative and myeloablative) and I would urge you to reread my earlier post after the BBC Panorama programme on the topic. 

A large number of the HSCT zealots seem to ignore the fact that HSCT does not result in a cure in many pwMS treated with HSCT and that there is an issue of HSCT-related mortality. The latter is often conveniently ignored. 

The recent study by Sullivan and colleagues quote a 6% mortality rate at 6 years in patients with severe scleroderma treated with myeloablative HSCT compared to 0% in the standard cyclophosphamide group. One could argue that mortality rates are higher in this population than in people with MS. I suspect that this may be correct, but in the Murao et al. HSCT MS meta-analysis paper there were 37 deaths, out of 281 HSCT treated patients with MS or a 13% mortality rate, from any cause (treatment-related or not); 8 deaths or 2.8% were reported within 100 days from transplant and were considered transplant-related mortality. These figures are probably within the same range as those reported for other autoimmune diseases treated with HSCT. Are you prepared to take these risks? Not all pwMS are and we need to respect their decisions. 

How effective is HSCT? In the scleroderma study below the so called event-free survival rate at 54 months was 79% in the transplantation group compared to 50% in the cyclophosphamide group. What about MS? In the metanalysis below the 5-year probability of progression-free survival as assessed by the EDSS score was 46%. Is this better than alemtuzumab, natalizumab, ocrelizumab, rituximab or cladribine? Let’s generate the evidence from head-2-head studies and find out. 

The main message from this post is that HSCT is not that safe; HSCT has many short-term complications including a relatively high mortality and although its efficacy is high it is not necessarily higher than currently licensed DMTs. So don’t believe everything the HSCT zealots tell you or ask them to show you the data. 

Please note that we at Barts-MS do offer HSCT as a treatment option, but patients have to fulfil the criteria as set by the London MS-AHSCT Collaborative Group. We are not denying people with MS access to this treatment option. 

N Engl J Med. 2018 Jan 4;378(1):35-47.

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.

METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.

RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. 

CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; number, NCT00114530 .).

IMPORTANCE: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis(MS) that fail to respond to standard therapies.

OBJECTIVE: To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.

DESIGN, SETTING, AND PARTICIPANTS: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.

EXPOSURES: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.

MAIN OUTCOMES AND MEASURES: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.

RESULTS: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).

CONCLUSIONS AND RELEVANCE: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.


About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • I think HSCT works mainly for RRMS, progressive patients can expect a few years of remission at best. Not worth it in my opinion. I really don't understand these people who spam articles about progress being made in neuroprotection and myelin repair with their ideas that the real cure is HSCT. Shouldn't we be happy that we're closer to effective treatments?

  • In the randomized trial mentioned above; what would the other arm be? What about five years of data from AHSCT vs a CD20 therapy – I think that would be insightful.

  • It's sad and self defeating to have a post with so much miss information and irrelevant information designed only to scare.

    Ironically such an openly biased article only serves to prove the zealots point.

    One ezample. Why mention a 6% mortality rate for myeloablative for severe scleroderma, when for pwMS (non meyloblative) it's nearer 0.3?

    For the provocation, for those who find it funny. It's so very cruel. That there is that little humility.

    It's so self defeating, so harmful, so self serving. And only confirms the contempt I hold you in.

  • In all fairness, I think it's important to note that according to the meta-analysis of HSCT in MS patients, the progression free rate for relapsing patients was close to 80% after five years, and slightly less than 40% for secondary progressive patients. Primary progressive patients appear to have fared worse, but the study appears underpowered to draw any firm conclusions for that group.

    In a nutshell, patients with active inflammation appear to do quite well with HSCT, far better than with the highly effective DMDs. Patients whose inflammatory phase has passed, though, not so much…

    In regards to mortality rates, the high mortality rates reported in some of the studies has more to do with the chemotherapy/radiation regimens used when HSCT was first explored for use in MS, more recent data indicates that the mortality rate it using modern regimens is less than 1%.

    Please note, I am not a zealot, just stating what the science, as I can find it, shows. Would love to see some head-to-head studies done, as well as more robust studies done on progressive patients. Unfortunately, the meta-analysis did not break down SPMS patients by whether or not they still had evidence of inflammatory activity.

    • Thanks for clearing up the misinformation TWK, quoting such figures (for both mortality and PFS is beyond misleading). I have received Alemtuzumab so am far from a HSCT zealot, but I sense an underlying motive behind this post authored by someone who surely knows better.

    • Thanks for clearing up the misinformation TWK, quoting such figures (for both mortality and PFS is beyond misleading). I have received Alemtuzumab so am far from a HSCT zealot, but I sense an underlying motive behind this post authored by someone who surely knows better.

  • I had non-myelo HSCT in Moscow in March 2015. At the time the UK were rarely transplanting people, although that has finally improved. I was SPMS after 25 years mostly benign RRMS. EDSS was 6.5 on arrival in Moscow. Even though I was one of the very few, who become quite unwell afterwards back in the UK (when my wonderful GP missed diagnosing double pulmonary embolisms 😱), I would do it all again in a heartbeat. I have seen a massive improvement in balance, fatigue completely gone, bladder back to normal, swallowing now fine, walking speed gradually improving, no more cog fog. And by far the best improvement, is that I no longer need to use crutches or even a trekking pole for walking.

    But most importantly, I now have my future back. I can live my life knowing I should now only have more ongoing stability (or even more improvements!). Disease progression is a absolutely thing of the past. I truly was headed for a wheelchair and palliative care. I went from EDSS 0 to 6.0 in under a year; what had been incredibly slow RRMS progression, suddenly became incredibly aggressive SPMS. However, my MS has now stopped progressing and I am lucky to be seeing many improvements too; EDSS is now 3.5 and still improving!

    On Christmas Eve 2016 at (+21mths) I walked 700m in the dark, unaided and without stopping. New Year's Eve 2016, I was on the dance floor jumping up and down to "The Jean Genie" with the best of them! And at Easter 2017 (+24mths), I walked 2.6km along the Gold Coast foreshore in Australia with just two short 3 min rests every 850m. Latest achievement was 1.2km without resting at 27mths. I am definitely still improving even at 2.75 years! 😊

  • You have failed MS patients I know of so many bedridden on MS meds they became worse and were all part of trials .

  • There are a lot to comment on this post but the only question to pose is: is there any other way to prevent SPMS? We have patients who had HSCT more than 15 years ago and not on the very begining of their disease and are still in remission, progression free (we talk to these people thanks to internet, we talk to everyone in fact). According to this year's ECTRIMS paper, Lemtrada can only delay SPMS. Yes, there are a lot to do for RRMS and much painless things, but patients go to HSCT to prevent progression, not to avoid relapses.

    If you want to convince patients who go for HSCT -and many are newly diagnosed and DMT-free- you have to convince them about SPMS (which is the majority of their lives).

    SPMS is the question of our age and only those who dare to answer it will be relevant. (As for your question about Tysabri at the begining of the disease, IMO the thing should be Cladribine at the very beginning and then re-examination and possibly HSCT. The rest are aspirins for us. For RA Rituxan is enough, good for them).

    In real life patients monitor death rates from real life information because they just know each other, they dont need to be threatened with vague comparisons from myeloablative Scleroderma patients who are in danger of dying anyway.

    Also no one that I know of names it a cure, patients in general are actually quite realistic in their expectations. They know that they go and they may fail.

    Patients pay from their pockets to find some relief because they've seen it all already and you are talking about sledge hummers and nuts. Its a little offensive.

    • I don't agree with your interpretation of the data regarding lemtrada's potential effects on the on-set of SPMS. The data from the phase II and phase III trials shows a very low rate of conversion to SPMS. The paper that I think you are referencing from ECTRIMS is "Alemtuzumab-Treated Patients With Relapsing-Remitting MS Show Low Rates of Conversion to Secondary Progressive MS: 6-Year Follow-up of CARE-MS I and II." The paper reports that 2.5% of patients across the two phase III trials progressed to SPMS over a six-year period. This is much lower than might be expected for patients with highly active disease. I do hope that we will one day have a treatment that prevent SPMS in 100% of patients – that would be a cure. Preventing SPMS in 97.5% of patients is pretty darn good though. As the extension data gets reported during the next few decades, I hope that this effect will maintain itself, in line with the hypothesis that early and effective treatments might have an impact on long-term prognosis.

  • Why allow zealots the freedom to make these in accurate comments? Shouldn't the comments section be driven by comments based on fact? There are a lot of patients who may buy into these comments and end up losing their lives and precious time with their families following the zealot advise / comments!

  • "Or do we need evidence from randomised trials?"

    It is surprising and disappointing that most of the info you think you get about MS comes from randomised trials instead of first-line research about MS pathology (in humans, not rats) like the one Dr KS presented recently. Remember that the cause of MS is still unknown, so you should keep an open mind and not rely on drug research that generally presuppose some kind of immune malfunction or over-reaction.

    We need to know more about basic facts like the way lesions arise and evolve, the very early signs of the disease, the temporal associations of tissue damages and involved cells, the rules that decide the time and place a lesion will appear.

    You should encourage and perform more studies of this kind, instead of fundraising for highly expensive trials of limited scope. You could replicate the following study, for example, in 3D:
    "Or do we need evidence from randomised trials?"

    It is surprising and disappointing that most of the info you think you get about MS comes from randomised trials instead of first-line research about MS pathology (in humans, not rats) like the one Dr KS presented recently. Remember that the cause of MS is still unknown, so you should keep an open mind and not rely on drug research that generally presuppose some kind of immune malfunction or over-reaction.

    We need to know more about basic facts like the way lesions arise and evolve, the very early signs of the disease, the temporal associations of tissue damages and involved cells, the rules that decide the time and place a lesion will appear.

    You should encourage and perform more studies of this kind, instead of fundraising for highly expensive trials of limited scope. You could replicate the following study, for example, in 3D:

    • I have seen that in the past its "spooky"

      Looks like a battle field

      That patient is "stable" (or so the drs says)

      Imagine if he was´nt

      Unfortunately thats ours brains …. 🙁


  • I would love to see a head to head trial of HSCT vs current effective DMDs (excluding CRAB drugs), of which many are based on recycled chemotherapy drugs just at an outrageous price and with similar severe side effects to ablative HSCT.

    I would love to see a head to head trial of cost-effectiveness and efficacy (NEDA-4) but this will not happen as Pharma's DMDs would lose badly to HSCT thus surrendering their 20+ billion dollar share of the market . Current best NEDA for a DMD, I believe, is Tysabri at 48% percent and NEDA for HSCT is around 78% for RRMS.

    I read a statistic that stated that 80% of MS patients have gone bankrupt but Dr. Giovannoni believes we should support Pharma "innovation" in developed countries. I would agree with this statement if we actually had some innovation for remyelination, neurodegeneration or neurorestoration or any substantial treatments for progressive MS. It is undeniable that HSCT is much more cost effective to any healthcare system than the ridiculously expensive DMDs.

    Oh, I am not an "HSCT zealot" as, according recommendation in studies, I am not a good candidate but if I could go back in time, I would have done it in a heartbeat even with the risk to escape the life I have now for which there is no treatment. Also, please, Dr. Giovannoni, do not tell me that current DMDs also do not have their severe risks as well, including severe morbidity and mortality.

  • To the MD's[1,2..n] and Barts Blog: your churlish, immature and insensitive post and initial tone doesn't seem all that funny any more does it?

    Just read your post, rad the backlash, read the positive experience, read the regret.

    This post is foretelling your future climb down and distancing yourselves from such radical and frankly ignorant views on HSCT.

    • Don't worry our hides are like an unexfoliated rhinoceros 😉 We understand you're a persisatent evangelist for HSCT but I'm afraid sliced bread still maintains prime position. No-one here is against it and for some (note some) it is a viable a good option, particularly aggressive RRMS but for many it isn't.

    • bearms… thank you for verbalising exactly how many of us feel. The future climb down beckons more strongly every day.

  • Safer HSCT on horizon. So we are all right!

    • This agent is at phase I for cancer, IF it works it will take a while to be applied and I guess it will not be affordable by any means.

  • Interesting comments. I am halfway through the Gary Taubes' book "The case against sugar"; he makes the point that repeatedly in the history of medicine hypotheses are accepted as fact long before definitive evidence informs the discussion. The hypotheses then get accepted and get embedded in medical literature as beliefs. It then takes someone a generation or two later to undo the damage.

    The lesson from the sugar story is to be patient and let the scientific process run its course. At the moment the position that HSCT is the most effective DMT/treatment strategy and that it can cure some people of MS is still a hypothesis. What we need is randomised trials and evidence to support the acceptance of this hypothesis as fact.

    The reason for doing this post is to make the case that we need to learn from diseases such as scleroderma; i.e. to do randomised controlled trials.

    • I totally agree with you ProfG. At the moment all we have is observational studies and one randomised trial that was aborted early due to poor recruitment. The poor recruitment happened because the Italian neurologists 'believed' that HSCT was superior to mitoxantrone and felt the trial was unethical. This is an example of a belief becoming dogma.

      I think this post is important and relevant to the debate. I note that it is always a small group of people who come back to the blog over and over again to make the case for HSCT based on ancedote and observational studies. I suspect you will never change their minds even if a trial shows that licensed DMTs are as effective as HSCT.

    • "… to be patient"

      Patients can't be patient, this is a fact that should always be taken into account. You would now. It's the difference between first and second degree knowledge. Experiencing the symptoms is simply unimaginable by non-patients.

  • As a current HSCT patient (harvesting next week), I can only agree with both Giovannoni and Mousedoctor about patient profile and hsct outcome.

    To see hsct as a cure is super dangerous, as some people go straight looking for it

    I can't understand how new dx people are fundraising for HSCT in Russia/Mexico with EDSS 0. 0!!!!!!

    • In Germany they use Lemtrada as a first line treatment-first DMT, why not HSCT too? The more you wait for EDSS to built the less are the chances to live a normal life.
      From a phychological aspect, I guess it is fear of the unknown but also you can see that other patients act like boiling frogs ("for now I can deal it" -until you are boiled without noticing it).

    • They are fundraising at 0.0 EDSS in order to STAY that way! In Moscow their main international patient liaison staff member, is a former HSCT for MS recipient. She was treated at 20yrs old when relatively newly diagnosed. She now has NO sign of MS at all, is incredibly active and holds down a very stressful job (dealing with all us 6.5 EDSS people who were not able to access HSCT in our own countries). HSCT is better when performed as soon as possible after diagnosis.

      We live in the age of social media now and that is not going to change. Our Forum of POST HSCT patients is now 1248 strong. They are the 21st century version of clinical trials…

    • "We live in the age of social media now and that is not going to change."
      With respect,with so much of the web etc, there's no way to determine fact from fiction, that's what clinical trials are for.

    • We can't wait for the clinical trials. We are dying out here. We do the best we can while the Neurology profession fannies about shrieking "charlatans".

      A friend of mine with MS committed suicide a couple of months ago. He had been told by his LONDON Neurologist that nothing could be done for PPMS. So he silently suffered for 3 years and then gave up in the worst possible fashion. If only he'd been told by his Neuro to research HSCT.

    • So Barts, so neuros, so mouse Drs – whats your response to that?

      What futile, ineffectual, self-serving, status quo, soundbite are you going to make yourselves feel better with?

      Go home. Go to bed, Without MS. See your family and friends. All the while perpetuating and promoting the very stance and treatments which exacerbate pwMS pain, or delay vital treatment.

    • I guess the reply to that is a doctor can't recommend a treatment that has not been approved, thats the job.
      Well, a great doctor, one that does not only do "his job", would say, we have these trials, they have a 50% success for progressive patients, we dont have anything else we can do, you might win, you might lose.
      Those doctors who get in the shoes of their patients and risk their own reputation for them, those are who are truly remembered. And thankfully we have seen some of those in HSCT-MS patients.

    • Bearms you should be careful peddling HSCT as a cure. The data does not support this position. I am aware of one person who has committed suicide after suffering a rebound post spending his family's savings on HSCT abroad.

    • I'm afraid nothing will change Bearms HSCT zealotry or Mindy Watt's either it appears, including the sad case you mention.
      Let's see what the Norwegian study mentioned up thread reports.

    • This will have no effect. Self promoting, self obsessed individual whose deluded in thinking his/her people's champion by deriding/undermining people actually trying to cure this henious disease. I implore barts again to silence this idiots (bearms) voice before more people follow his I'll informed advice.

    • "I am aware of one person who has committed suicide after suffering a rebound post spending his family's savings on HSCT abroad. "

      Isn't that the reason why we want it an official treatment for MS? To protect patients from bankruptcy?

      The patient committed suicide because he had PPMS, and his chances were 50-50%, he was one of the unlucky ones unfortunately. The treatment only gives chances that nothing else does. Be careful who you blame and for what.

    • All the more reason, if that is correct to determine definitively if HSCT really is a viable treatment for PPMS (and also SPMS).

    • "Isn't that the reason why we want it official" IT FAILED SADLY FOR THIS INDVIDUAL. HOW IS IT GOING TO MAKE IT MORE EFFECTIVE by making it official??????????

  • Prof G you mentioned in one of your previous responses (I can't find it) that if you personally had MS you would want to be treated with HSCT. Is this still your position?

  • Well, even if Pharma does not support HSCT, the conficts of interest will move things forward. Trials are happening in all autoimmunes, the procedure is getting safer, the know-how is building, media take notice, heamatologists are more and more interested in the procedure and new clinics with good reputation are offering the treatment because the mortality rates are low and patients are satisfied (London has a private clinic too).
    All you can do is what Dr. Burt does: inform patients that they can die from the treatment (about 0,3% do die). The rest should lie on patients choice.

    • Not everyone can afford his rates, so they go elsewhere.
      HSCT is not one procedure but can be many different variants

  • Given that if you are PPMS in the UK you are offered no treatment, HSCT looks a reasonable option. Carry on waiting while Neuros argue for more 'Trials'…. which tend not to include PPMS'ers….. i think not! My husband aged 66 EDSS 7 had HSCT in Mexico in April 2016! Ask him now if he has MS and he will tell you NO! he is left with what MS did to him 🙁 Yes he is still EDSS 7, but no worse and lots of other benefits! Worth a risk to his life? When i asked him that question he said "what life?" Surely it is up to the individual to make their own decision? Only regret here is that we didnt find out about this sooner!

    • Happy for your positive experience, but this anecdote and not a substitute for trials, we have been here recently with CCSVI.

  • Patients want the Swedish HSCT protocol to be applied in all countries, an official treatment option under the national health system.

  • You need to quote DMT progression free survivak rates from real treatment not miicro studies of a couple of hundred people.
    Thousands have had DMTs so get the data. Start acting like scientists rather than playing roulette with someone else's chips.

  • Does alemtuzumab, natalizumab, ocrelizumab, rituximab or cladribine work for or are they prescribed for progressive MS? Isn't Murao's trial including progressive MSers? Interesting

    • We are trying to get a trial on cladribine off the ground for people in wheel chairs. Just finished off the paper on our experiences so far.

  • OK the firework has gone off and so I'm now calling it a day.

    I can't be bothered to sort out what is spam, what is not, what may be a subliminal advert, what is not, what is an out and out insult and what is not. Whta is really valid point and what is not.

    Until the next time ProfG pushes some buttons for some and informs for others.

    Best wishes

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