Bad times for the scandal surgeon Paolo Macchiarini and his acolyte Philipp Jungebluth. Misconduct findings led previously to retraction of an oesophagus transplant paper, with more soon to be expected, their employments in academia seem to be definitely a thing of a past. Macchiarini’s big plans of world-shattering trachea and oesophagus transplants in Russia went bust, when his grant funding was not extended and the Federal University of Kazan waved him goodbye. The master’s acolyte Jungebluth is currently suing me in court about my reporting on his own past employment, because he managed to convince the Berlin judge when passing the injunction that all his now proven research misconduct and patient abuse, which led to deaths of several patients, plus several other dishonest deeds of his, had in fact perfectly qualified him for an academic research career at the University of Heidelberg in Germany. A career he claims to have aborted entirely on his own accord, hence his (now only 1/3 successful) court injunction against me. Jungebluth, after having said farewell to his 8 years of thorax surgery training in vain, even claimed in court to be desperately wanted as thoracic surgeon by all Berlin hospitals, including the huge university hospital Charité.

Which brings us to the recent setback for the two trachea transplanters. Their publications regarding the plastic trachea operations at the Karolinska Institutet (KI) in Stockholm, which left three patients dead, were investigated by two external experts. One of the experts was Martin Björck, professor of surgery at University of Uppsala, the other was Detlev Ganten, professor emeritus of pharmacology and former CEO of the Charité. And their fresh report, submitted to the Swedish Central Ethics Review Board (CEPN), does not read like the Berlin Charité or any other medical research institution in Germany, or anywhere else for that matter, might ever consider employing Jungebluth. The central Lancet publication, describing the first plastic trachea transplant performed on Andemariam Beyene (Jungebluth et al, 2011), was slammed as based on misconduct, both ethical as well as research misconduct. It is the same Lancet paper Jungebluth presented to Berlin court as evidence of his scientific fame and excellence.

Worse, the authors were found guilty of breaching the Nuremberg Code of 1947 as well as the Helsinki declaration, which forbid unethical medical research which uses humans instead of laboratory animals for dangerous experiments. Same applies for 4 more Macchiarini publications, which were about the patient Beyene (Del Gaudio et al 2014, Ajalloueian et al 2014 as well as Badylak et al, 2012, which one of its co-author already called to be retracted), plus another KI patient, Yesim Cetir (Jungebluth et al 2013). An excuse by Macchiarini and his KI partners and supporters that this all was never research, but compassionate use surgeries, thus exempt from ethics oversight and the Nuremberg Code, was rejected outright by the two experts.

So it is peculiar that Jungebluth, a doctor who convinced a German court that his patient abuse abroad was totally irrelevant for his medical career in Germany, is accused by a retired German director of a key medical university to have done things which were forbidden to prevent a repetition of that most horrendous research by Nazi doctors in German concentration camps. I wonder how the next appeal court will see Jungebluth’s position now.

The Björck/Ganten report is next expected to be confirmed by the CEPN commission and then formulated as an official decree by the KI. I publish the expert reviewer report in full, here is the original document. I will also make available the mentioned Annexes 1-3 once I receive them.

Update 19.06.2017. Here now are the Annexes 1, 2, and 3.

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Report on potential research misconduct regarding six publications with
Dr Paolo Machiarini as the senior or corresponding author

To the Expert group on scientific misconduct at the Swedish Central Ethical Review Board (Expertgruppen för Oredlighet i Forskning vid Centrala EtikPrövningsNämnden, CEPN)

Written by professors Detlev Ganten (Berlin) and Martin Björck (Uppsala)

1. The assignment

The following assignment was defined by CEPN on the first meeting. The external experts’ assignment was to examine
1. If the six publications reported from Dr. Paolo Machiarini at the Karolinska Institutet
contain research misconduct or not. The starting point will be the report from
Professor Bengt Gerdin (BG), the accused researchers’ responses to BG’s report and
BG’s reply to the responses.
2. The external experts shall furthermore determine whether the case concerns research
or not and if required permissions existed.
3. The external experts shall also give their opinion whether the research reported in the
articles was carried out in accordance with good research practice or not.

2. The methodology

Detlev Ganten (DG) met with CEPN in Stockholm in January 2017, Martin Björck (MB) was recruited in February 2017. Both external experts spent many hours studying the extensive documentation regarding this case. They then met with director Jörgen Svidén at a full-day meeting in Berlin on April 1st. The issues to scrutinize were defined, as well as the working strategy.
It was agreed that the report written by the two external experts (DG, MB) will be submitted to the expert group on scientific misconduct at the Swedish Central Ethical Review Board (Expertgruppen för Oredlighet i Forskning vid Centrala EtikPrövningsNämnden, CEPN) and will not be shown or discussed in detail to anyone else before it is submitted to the expert group. CEPN will then decide if this information is sufficient in order to make a decision, or if they need additional information from the two external experts DG and MB, or anybody else. The report may later become an official document, but until the decision is made by CEPN it is regarded as working material (arbetsmaterial) and not freely accessible (ej offentlig handling).
DG and MB did communicate with the responsible surgeon on Iceland, Tomas Gudbjartsson (TG) at Landspitali, Reykjavik. TG was key in the initial treatment of the first Patient at Landspitali, Reykjavik. He responded promptly to all our enquiries, provided an extensive timeline and also offered to meet with us, but we did not consider this necessary.
An important aspect of this report is the fact that the six articles/publications and their
authors are accused of scientific misconduct but the assignment does not include deciding about the individual contributions from the different authors. It should be emphasized, however, that although the corresponding or senior author Dr Paolo Machiarini (PM) has a key role, according to the Vancouver declaration, it is clear that all authors of a scientific article are responsible for the entire content of the paper.

2.1. The patients (for additional information see Annex of this report and the documentation of the PM case)

Patient 1 [Andemariam Beyene, -LS] was a 36-year old man of Eritrean origin who underwent a primary operation in Reykjavik in October 2009 for mucoepidermoid tracheal cancer. Early in 2011 a bronchial stricture developed and the patient was transferred to the Karolinska and operated on by Dr. Paolo Machiarini (PM) on June 9, 2011, receiving a synthetic tracheal prosthesis. A month following this operation, the patient was returned to Iceland for further observation. He returned regularly to the Karolinska for check-ups. He eventually developed a life-threatening oesophago-tracheal fistula. The patient died on January 30, 2014, 30 months after having received the synthetic tracheal prosthesis.
Patient 2 [Christopher Lyles, -LS] was a 30-year-old American man from Maryland who was diagnosed in June 2011 with adenoid cystic tracheal cancer. The patient made contact with Paolo Macchiarini himself, who referred him to the Karolinska for the surgical removal of the tumour and replacement with a synthetic tracheal prosthesis made of another kind of plastic than was used for patient 1. The operation was carried out on 17 November 2011 at the Karolinska. There is no formal information from the USA about what happened after this, but he was apparently admitted to hospital as an emergency a little over a month later and died on 5 March 2012, 3.6 months after his operation. No medical details are available.
Patient 3  [Yesim Cetir, -LS] was a 22-year-old woman from Ordu in northern Turkey, who received iatrogenic tracheal damage in connection with surgery for palmar hypohydrosis, probably a thoracoscopic sympathectomy. Her doctor in Turkey contacted Paolo Macchiarini. She was operated on at the Karolinska on 24 July 2012, upon which her right lung was removed in order to prepare for the insertion of a synthetic tracheal prosthesis. On 7 August 2012 she was given a tracheal prosthesis made of the same or a similar material as the one used for patient 2. Two weeks after this operation, an oesophageal fistula appeared that was treated with a stent. She was re-operated on 9 July 2013, and given a new prosthesis of the same material. Following extensive postoperative fistula-related complications, she was put in intensive care at the Karolinska, was later referred to the USA where she died in early 2017.

In this report we focused on patient #1, since he is of central importance for the content in five of the publications (1,2, 4-6). Patient 3 is important for article 3. What happened to
patient #2 and #3 is also of importance for other investigations, however.

3.2 The Publications

Publication 1
Jungebluth P, Alici E, Baiguera S, Le Blanc K, Blomberg P, Bozoky B, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011; 378: 1997-2004.

This paper features patient 1 from Iceland, reports on the result of the first transplantation of a synthetic trachea in a human. This paper is also a key reference for the other papers. The paper was submitted to The Lancet on 11 October 2011 and was accepted on November 7, 2011. The paper was published online on 24 November and in print on 10 December 2011.

Publication 2
Badylak SF, Weiss DJ, Caplan A, Macchiarini P. Engineered whole organs and complex tissues. Lancet 2012; 379: 943-952.

This is a review article that does essentially not report original new own data. It does,
however, refer to patient 1 on whom paper 1 was based, who was operated on in Stockholm on 9 June 2011. The paper was submitted to The Lancet on August 12, 2011, 64 days after the operation on patient 1 whose 8-month data was reported in the paper. This means that it was submitted before paper 1, and was available online on 8 March 2012.

Publication 3
Jungebluth P, Haag JC, Lim ML, Lemon G, Sjoqvist S, Gustafsson Y, et al. Verification of
cell viability in bioengineered tissues and organs before clinical transplantation. Biomaterials 2013; 34: 4057-4067.

This paper was received on 5 February 2013, accepted on 20 February 2013 and was available online on 6 March 2013. The paper cites the results from patient 3 as an example of how the technique that had been developed for studying the viability of cells on biotechnologically manufactured organs and tissues can be used.

Publication 4
Del Gaudio C, Baiguera S, Ajalloueian F, Bianco A, Macchiarini P. Are synthetic scaffolds suitable for the development of clinical tissue-engineered tubular organs? J Biomed Mater Res A 2014;102:2427-2447.

The paper was received on 13 March 2013, again in revised form on 11 July 2013 and
accepted on 17 July 2013. It was received by the journal 21 months after patient 1 had been operated on, and submitted in revised form and accepted 25 months after this operation. This is a review article that does not report own original data, with one exception. It refers to the patient on whom paper 1 was based (patient 1) and gives information different to that in paper 1. Here mention is made of the clinical condition at 12 months, which it describes in positive terms: “After 12 months, an almost normal airway and improved lung function were assessed.”

Publication 5
Philipp Jungebluth and Paolo Macchiarini (2014). Airway transplantation. Thorac Surg Clin 24(1): 97-106

This paper was submitted on 4 August 2013. It was available online on 27 November 2013 and in print in February 2014. It is a review of the clinical need to replace the main airways with a graft, of surgical and technical developments up to that point, and of what the authors deem to be promising paths of future developments and needs.

Publication 6
Ajalloueian F, Lim ML, Lemon G, Haag JC, Gustafsson Y, Sjoqvist S, et al. Biomechanical and biocompatibility characteristics of electrospun polymeric tracheal scaffolds. Biomaterials 2014; 35:5307-5315.

The paper was received by the journal on 13 January 2014, accepted on 7 March, and was available on 3 April 2014. Patient #1, who is mentioned in the text, died on 30 January 2014, i.e. before the paper was accepted. This paper gives an account of a new technique for evaluating the biocompatibility of synthetic polymer tracheal prostheses. The introduction, states that patient 1 has been operated on, with the outcome described as follows:

“…However, due to the stiffness of the scaffold, an abnormal granulation tissue formation developed within the post-operative course. Moreover, it led to chronic fistula at the distal anastomotic sites of the left main bronchus, which required endoscopic interventions…”

3. The issues

The following four issues were identified, and will be commented on.
3A. Research or health care?
3B. “Compassionate case” waiving ethical approval?
3C. Was the research performed after ethical approval?
3D. Do the six scrutinized publications contain incorrect information to an extent that it should be regarded as research misconduct?

3A. Research or health care?
The first question is if the treatment given is research or exclusively health-care? The
assignment did not include analysing the possible unethical behaviour regarding delivering experimental health care. The external reviewers found this issue to be answered in a clear way: The given treatment of the patients was definitely not a modification of an established surgical method, but a new methodology. It included new scaffolds, with novel stem cell lining. The first author, Paolo Machiarini (PM), was mainly recruited as a researcher to the Karolinska. The plan to publish the results was evident and clear from the beginning of the project and consequently several reports were published by the authors with claims of novelty.

We conclude from all evidence available to us: the results reported by PM and his collaborators is clearly research.

3B. “Compassionate case” waiving ethical approval?
It has been claimed that this novel treatment could be labelled “compassionate use” in
patients who were in immediate need of life-saving treatment. The old Viking rule of “need brakes law” (In Swedish: Nöd bryter lag) could then have been applied. The external reviewers do not agree that such a situation prevailed when treating the first patient in June 2011. The patient was referred from Iceland after lengthy administrative and clinical considerations, and the operation was not performed as an emergency. Furthermore, it was not proven that the patient had a tumour recurrence before he was treated, although it was suspected and later verified in the specimen that was removed during the operation.

We conclude from all evidence available to us: an emergency situation did not prevail and the rule “compassionate use” cannot be applied in this case.

3C. Was the research performed after ethical approval?
Before January 1st, 2004, ethical review was not compulsory according to Swedish law, but from that date all research on patients needed to be scrutinized by one of the Regional Ethical Boards (REPN), and this project was not. Formally speaking, it is quite clear that no formal ethical application was written, or approval was given, prior to the experimental, first-in-man operation, followed by two other operations on patients #2 and #3. This was very unfortunate, since a formal ethical scrutiny would probably have identified a need of further animal research before the treatment had been tested first-in-man.
The article #1 that was later published in The Lancet (in December 2011) was first submitted to the New England Journal of Medicine (NEJM). In the response from the NEJM to PM, forwarded to all the co-authors in an e-mail on October 6, 2011, reviewer #1 comments the following:

“2) Animal work
No papers are discussed from animal work performed by the author’s group or other groups to support the success and long-term outcome of this experimental technique prior to translation into clinical practice? Are these data available? Or was permission granted by the IRB at Karolinska Institute in the absence of these experimental data?”

In the light of this concise comment, and in the historical light of the Nuremberg Code (1947), as well as the following Helsinki declarations, it is surprising that neither PM nor any of the coauthors reacted to the fact that the review of the paper highlighted that the experimental treatment had taken place without prior ethical approval. The correct reaction on such a comment should have been to conclude that this research should not have been performed in the first place and certainly was unpublishable, since there was no ethical approval of a novel experimental treatment, in particular since it had taken place without prior necessary animal experiments.
In PM’s response to BG’s report this issue is discussed. An e-mail correspondence is annexed in Appendix #2 in PM’s response [here, -LS] ). The e-mail correspondence with a scientific secretary shows that the research group was well aware of the necessity of a formal application. The answer from the scientific secretary was not quite appropriate, and shows that the system how to respond to requests needs to be improved, if that has not already taken place. An individual member of a Regional Ethical Committee should refrain from answering to such questions. Although the response may not have been sufficiently clear, the continued research without formal ethical approval could not be justified by this e-mail correspondence.

We conclude from all evidence available to us:
the research was performed without necessary ethical scrutiny and approval. This is in conflict with Swedish law and International declarations on Ethical Research conduct.

3D. Do the six scrutinized publications contain incorrect information to an extent that it should be regarded as research misconduct?
This issue was the most complex to analyse. The analysis has focused on the patient 1 who was referred from Iceland to Stockholm for treatment, and is summarised in Appendix 1 [here, -LS], since this patient is mentioned in papers 1,2 as well as 4-6. We have compared the information in the six articles with information supplied by the responsible surgeon on Iceland, Tomas Gudbjartsson at Landspitali, Reykjavik. The summary supplied by him is annexed to the report as Appendix 2 [here, -LS] . The response from the New England Journal of Medicine, explaining why the first scrutinized article (later published in The Lancet on December 10, 2011) was rejected on October 6, 2011, is also given as Appendix 3 [here, -LS].
Regarding article 3 it focuses in pre-clinical work, but there is also a long description of patient 3. She operated on in August 2012, and two weeks later an oesophageal fistula appeared that was treated with a stent. She was re-operated on 9 July 2013, and given a new prosthesis of the same material. Following extensive postoperative fistula-related complications, after years of intensive care, she died in early 2017. The article states (on page 4065) that:

“ The intermediate post-operative outcome (5 months) has shown a patent and non-contaminated graft without any signs of inflammation.”

The oesophageal fistula and reoperation are not mentioned. In his reply to BGs report PM gives no acceptable explanation to why the authors left out information on these early and serious complications, when reporting on this experimental operation.

We conclude from all evidence available to us:
As can be seen from the analysis in Appendix 1 [here, -LS], publications 1-4 and 6 have NOT been carried out in accordance with good research practice. All five publications contain biased information and lack critical thinking. This is even more important when new technology is investigated, which was the case in this first-in-man report. To bias information in order to make a novel treatment seem more favourable than what is true is a serious scientific misconduct. It may inspire other doctors and researchers to repeat the experiment, with potential serious consequences for a large number of patients. Globalisation and fast communication in the modern era has increased the magnitude of this potential negative effect, which should make researchers even more careful in not drawing fast and firm conclusions without sufficient data.

Uppsala and Berlin, May 31, 2017
Martin Björck, MD, PhD
Professor of vascular surgery
Uppsala University, Sweden
Detlev Ganten, MD, PhD
President, World Health Summit
Professor of Clinical Pharmacology, Emeritus
Charité – Universtitätsmedizin Berlin, Germany

 

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Update 30.11.1977. Swedish media reports:

“Central Ethical Review Board considers Paolo Macchiarini cheated in his research on synthetic trachea.”

 

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Dear readers, I am being persecuted in German courts with baseless injunction trials by Philipp Jungebluth and Macchiarini’s former collaborators Heike and Thorsten Walles. If you would like to support my court litigation financially, donation amount doesn’t matter, please go to my Patreon site or contact me. -LS