Updated: Retraction, and another looming misconduct finding for Macchiarini and Jungebluth

The misconduct-tainted paper on oesophagus transplants in rats (Sjöqvist et al 2014) by the fallen star of regenerative medicine Paolo Macchiarini is finally retracted by the journal Nature Communications. This happens after Swedish investigations found the authors (primarily the scandal thorax surgeon and his right-hand man Philipp Jungebluth) guilty of data manipulation and research misconduct in September 2016 and after the Karolinska Institutet (KI) shortly before Christmas publicly demanded a retraction (see my report here). Today’s retraction is a major setback for Macchiarini, since his current employment and funding at the Federal University of Kazan (KFU) in Russia depend on his experiments with oesophageal transplants in primates (see my reports here and here). That Russian project was in turn only possible because of Macchiarini’s allegedly successful experiments in rats, published in a prestige journal with “Nature” in its title. This paper’s retraction is therefore probably only the beginning of a whole looming avalanche of bad news for Macchiarini and his acolyte Jungebluth (who currently sues me in court). An expert review of their publication Jungebluth et al 2015 declares the findings of misconduct, ethics breach and patient abuse. The report however has yet to be confirmed by a commission at the Swedish Central Ethics Review Board (CEPN) and then formulated as an official decree by the KI. I publish the expert reviewer report below.

When the paper was first published in 2014, Russian media brought the headline: “Oesophagus, important for Russia“. Macchiarini’s expired Russian “Megagrant” was supplemented in the same year with an extension (see Nr 14-45-00018 here, details here), to test a tissue-engineered oesophagus on primates, before Russian patients can follow. In November 2016, Macchiarini presented his preliminary results with plastic oesophagi on baboons at a stem cell conference in St. Petersburg (p. 31 here). The next month, KFU publicly defended their new professor and his oesophagus research. However, the KFU academic Roman Deev (who is a close Macchiarini-associate, see also this comically sycophantic interview  between the two from summer 2016) started to distance himself from Macchiarini’s past achievements in regenerative medicine, when interviewed by Radio Liberty in January 2017:

“Besides, even back then it was known that Macchiarini himself doesn’t understand very much what he is talking about. When a surgeon starts talking about molecular or about cell biology, it mostly doesn’t turn out well. […] My personal view – the theoretical basis of Macchiarini’s method is insufficient. As a basic concept it is of course interesting, but its testing, its applicability are insufficient”.

Deev is rumoured to have played a key role in Macchiarini’s recruitment to KFU, several of the latter papers were published in the journal run by the former. The KI misconduct decree and the Expression of Concern for the Sjökvist et al 2014 paper was ready out then. Therefore: will any new funding follow, or in fact, will the Italian professor’s contract with KFU be renewed at the end of 2017, given that the underlying key publication in the prestigious journal with “Nature” in its name is now obliterated?

The journal Nature Communications now issued this retraction notice to the Sjöqvist et al 2014 paper “Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats”:

“This Article is retracted by the authors. Nature Communications previously issued an Editorial Expression of Concern (http://www.nature.com/articles/ncomms13310) related to this Article, following the publication of a report commissioned by The Karolinska Institute and prepared by the Expert Group for Misconduct in Research at the Swedish Central Ethical Review Board. Owing to the technical issues raised by this investigation, we, the authors, are now retracting the Article.

P.M., S.S., Y.G., S.B., M.A.B., C.D.G., A.S., K.K., H.K., P.D., A.B., R.H., D.R., C.I., B.J. and D.A.T. agree with this retraction. P.J., M.L.L., J.H., G.L., A.B.R., H.U. and Y.Z. could not be reached for comment”

The CEPN investigation found misconduct and data manipulation rather than “technical issues”, and the next paper likely to be felled by it is Jungebluth et al, Respiration, 2015. There, a human being was recruited to participate in a scientific experiment, because of his severe condition of acute respiratory distress syndrome. The patient was clinically treated by Macchiarini and likely also Jungebluth (who had no licence to practice in Sweden) in 2011 with his own peripheral blood-derived mononuclear cells (PBMCs) as well as erythropoietin (EPO). Scientifically, this therapy made little sense, and was actually very dangerous. The patient in fact died 5 weeks later, which didn’t prevent Jungebluth et al from publishing this experiment as a success 4 years later. The use of EPO was already criticized last year by the Karolinska University Hospital investigation, in regard to trachea transplant patients who were treated with it as well:

“There was no permit from the Swedish Medical Products Agency to use the growth stimulants for this purpose and in the doses provided. All three patients were struck by large clot formations and it cannot be ruled out that the drugs may have contributed to this”.

The apparent rationale for the intervention was: if the damage to the airways of this otherwise stable patient can’t be cured by standard medical care, one might just as well experiment on him with a method which was rather a poorly educated guess than a reasonable scientific approach. Of course no one thought to apply for an ethics permit for such research intervention, it was instead passed off as compassionate use care. My regular readers might be reminded in this regard by a similar attitude displayed by Macchiarini’s former colleagues Heike and Thorsten Walles in Germany (see my report here). Unlike Walles, Macchiarini at least mentioned the death of his patient in the Jungebluth et al 2015 paper, but insisted it was “possibly secondary to disseminated fungal infection and intra-abdominal sepsis”.

KI whistleblowers informed the institute about suspected misconduct and patient abuse, by submitting these 12 questions, including on the use of EPO and the rationale to experiment on a stable patient.  KI initiated an investigation and invited Macchiarini and others to comment (see this document). Macchiarini, Jungebluth and other co-authors replied (document here), where they also admitted that there was a second patient who was treated in a similar manner. They however utterly refused to discuss that case or its outcome.

KI then delegated the case in October 2016 to the Central Ethical Review Board (CEPN) of Sweden, which in turn recruited on November 25^th 2016 an external examiner, Dag Lundberg, Professor emeritus of Anesthesiology and Intensive Care at the Lund University in Sweden. His full report to the Expert group for misconduct in research, dated February 14^th 2017, is available here. It is very likely that CEPN will accept his recommendation and that KI will decide according to the CEPN findings, just as it happened with the now retracted Nature Communications paper. Therefore, another official decree of research misconduct is likely imminent for Macchiarini and Jungebluth.

Lundberg found research misconduct and ethics breach, since the authors misrepresented an experimental research approach as compassionate use case and failed to obtain a necessary ethics vote. This is how he summarised the intervention:

“The patient who received the innovative treatment was a young man who suffered life-threatening acute respiratory distress syndrome (ARDS) as the result of a burn injury. In order to temporarily compensate for the failing pulmonary function, and for the patient’s survival, advanced treatment in the form of extra corporeal membrane oxygenation (ECMO) was commenced. The patient was treated at the ECMO Centre at Karolinska University Hospital, which has extensive and well-documented experience of this type of treatment. After nine days of ECMO, the treating physicians decided to adnninister an experimental treatment. During a treatment meeting, in which Prof. Macchiarini participated (according to the medical record notes of 18 November 2011), the decision was made to administer local treatment in the lung with a suspension of peripheral blood-derived mononuclear cells (PBMC) harvested from the patient’s own blood. The treatment was administered through repeated intratracheal installations via bronchoscope. In addition, the patient was treated with erythropoietin (EPO), which was administered subcutaneously, orally and intratracheally. The treatment lasted for 23 days”.

On the day 36, the patient died of multi-organ failure. Lundberg presented his detailed criticisms of the Jungebluth et al 2015 publication, followed by this six-point summary:

“The article has a number of shortcomings, which have consequences in terms of research ethics, namely:

1. There is no clear weighing of risk versus benefit nor a detailed description of ethical considerations.

2. Ethical approval to carry out the innovative treatment has not been obtained. Strictly speaking, no approval had been given to take additional blood samples or carry out bronchoscopies outside of the regular care either. Ethical approval was obtained after the fact for a later analysis of blood samples and publication of the findings.

3. The work was first published four years after the treatment. It is unclear why that was.

4. The method description lacks information about the simultaneous intensive care treatments in addition to the ECMO treatment, such as antibiotics, diuretics and haemofiltration.

5. The article is predominately about the nnolecular biology and immunology aspects of the study. This emphasis shift indicates that the main purpose of the study was to measure changes in the function of the blood’s mononuclear cells during a critical stage in a severely ill patient, rather than saving lives. In other words, it is difficult to rid yourself completely of the impression that the patient case itself, as well as the innovative treatment, were used as a means to produce front-line results in a preclinical discipline. The fact that the majority of the 26 (sic) authors of the case study in question come from preclinical specialities gives a similar indication.

6. In light of the uncertain conditions of this unverified study, the authors draw conclusions from their results that are too definite, which can be misleading and have uncritical readers believe that the treatment is effective”.

The external examiner Lundberg then explained why “the initiatives carried out in the case constitute research rather than pure health care” and presented his arguments that “misconduct has taken place”:

“The responsible researchers have, presumably due to gross negligence:

1. Failed to document a risk/benefit analysis and the associated ethical considerations prior to making the decision to start the innovative treatment.

2. Failed to contact the regional ethical review board, despite reasonably having time for an informal consultation.

3. Used a severely ill patient, without ethical approval, as a means to carry out advanced preclinical research.

4. Carried out the innovative treatment, despite its insubstantial theoretical foundation and insufficient knowledge from adequate animal testing. Extrapolated a hypothesis in several steps regarding a potentially beneficial anti-inflammatory effect from the treatment with no scientific evidence. It was thus assumed that mononuclear cells from the blood have the same effect as stem cells from bone marrow and that local intratracheal installation is equivalent to intravenous administration.

5. Failed in the article to account for parallel conventional clinical treatment and discuss the possibility that such treatment could provide an explanation for the temporary improvement in the patient’s status.

6. Considering the minor evidentiary value of the unverified study, strongly exaggerated the significance of the achieved results, which could evidently mislead a less critical reader.

7. Neglected the established ethical publication practice by including 26 authors: an unreasonable number, considering the contributions of the individual researchers and the insubstantial scientific value of the publication.

8. Denied all ethical responsibility in their statements, relaying the blame by systematically and categorically referring to other clinically active colleagues. This does not strengthen their case.

Lundberg also criticised the “unbridled enthusiasm for stem cell treatments”, combined with “the express support of the Karolinska Institutet management” towards Macchiarini as well as the “elitist attitude” in medical academia which “led to the notion that the number of publications is more important than the quality of each article”.  He concluded on Jungebluth et al 2015:

“The innovative treatment that was carried out is to be considered research, and the matter, despite the existence of certain generally mitigating circumstances, can be considered a case of misconduct in research”.

The full Lundberg report is available here. It is now with the CEPN expert group for misconduct in research, and its decision (based on Lundberg report) will in turn be relayed to KI for final judgement. More investigations on Macchiarini’s and Jungebluth’s publications are ongoing at KI and CEPN. Of course, also the publications on trachea transplants in humans are currently under a CEPN investigation, which is performed by a Swedish surgeon from the University of Uppsala and a German pharmacologist of the Charité university hospital in Berlin (names known to me). Hopefully, the results will be announced soon, and hopefully the journal The Lancet will follow the recommendations (which is by no means self-evident). The Swedish state prosecutor also indicated to charge Macchiarini and his partners (thus probably Jungebluth) with manslaughter of the three KI patients transplanted with plastic tracheas.

The last survivor among these 3 patients, Yesim Cetir, died  on March 19^th, four and a half years after she was operated by Macchiarini and Jungebluth. 8 out of 9 plastic trachea recipients are now dead, the last one, Dmitri Onogda, was lucky to be still alive because his plastic transplant could be removed as soon as it started to collapse.

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Update 21.06.2017. CEPN has now rejected Lundberg’s decision that the clinical interventions described in Jungebluth et al, Respiration, 2015 constitute research, and thus decided they cannot be research misconduct, as reported by Swedish press. As explanation (see this English-language CEPN decision), e.g. the 23 bronchoscopies performed on that dying patient were seen as likely medical care on the patient. CEPN failed to coherently explain how so, especially since even they admit that the 26-head strong researcher team used this bronchoscopy data for research purposes. Karolinska Institutet now has to make the final decision. In any case, no judgement was made yet on the medical ethics of the intervention.

Update 30.01.2018. Now Karolinska rejected the recommendation of CEPN regarding Jungebluth et al, Respiration, 2015 and found misconduct. A retraction was requested by KI in this full report (in Swedish and in English) and in a public announcement:

“Karolinska Institutet’s vice-chancellor Ole Petter Ottersen reached the decision to find Paolo Macchiarini, Philipp Jungebluth, Bernhard Holzgraefe and Håkan Kalzén guilty of scientific misconduct. The case relates to the article “Autologous peripheral blood mononuclear cells as treatment in refractory acute respiratory distress syndrome”, published in 2015 in Respiration.

The article is a case study of a patient suffering from acute lung damage who, in 2011, received ECMO treatment at Karolinska University Hospital and thereafter experimental treatment. […]

According to the Vice-Chancellor’s decision, Respiration should be notified with a request that the article be immediately withdrawn.

None of the researchers who have been found guilty of scientific misconduct are employed by Karolinska Institutet and therefore they will not be subject to any disciplinary measures under employment legislation”

 

 

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