I have been forwarded a manuscript by the scandal surgeon Paolo Macchiarini, which was originally intended to present in detail all of his known 9 cadaveric trachea recipients (only 4 are recorded officially). The compilation follows exactly all the patients who are already listed on my site, with the small difference that the paper (allegedly rejected at Nature Communications) presents their clinical evolutions quite differently from reality. One of these now fully confirmed victims of Macchiarini’s research was his second patient from Barcelona, whom Macchiarini transplanted in secret; five were operated in Italy (including Keziah Shorten and the Czech patient MK). The manuscript also confirms that Macchiarini’s acolyte Philipp Jungebluth was directly involved in the transplant surgeries of these patients, despite his most probably not having a permit to practice medicine in Italy. This makes Jungebluth co-responsible for up to 13 trachea transplants, 10 of them lethal. The German doctor is currently suing me in court for alleged libel, insisting that all these patient deaths and his proven research misconduct in Sweden would never ever disqualify him from developing trachea transplants and training as thorax surgeon at the University Clinic Heidelberg, where he however doesn’t work anymore.
The first author of this lost and now found unpublished paper is Johannes Haag, Macchiarini’s other acolyte and former MD student from Hannover Medical School (MHH) in Germany. Haag is apparently still employed at the Thoraxklinik at the University of Heidelberg, where Jungebluth used to be. The manuscript, which was supposed to be Haag’s big paper, was written to deal with the fact that too many of Macchiarini’s cadaveric trachea recipients died or developed very severe complications. To this end, the team hatched an idea to do “reverse translational experiments“, where rat experiments would follow those on 9 humans, prove that the cadaveric trachea technology works in principle and it was the human patients who were making problems. This notion was to be supported also by their earlier pig study Go et al, Biomaterials 2010, where Macchiarini and Jungebluth claim, without a shred of evidence, that the large animal testing was performed before the first patient, Claudia Castillo, received a cadaveric trachea in 2008 (details here, here and here).
This is the unpublished paper’s title and its authors list:
Outcomes of tissue engineered airway transplantation using biologic
scaffolds: a translational and reverse translational report
Johannes C Haag 1 , Philipp Jungebluth 1 , Silvia Baiguera 1 , Alessandro Gonfiotti 2 , Massimo Jaus 2 , Mei L Lim 1 , Ylva Gustafsson 1 , Sebastian Sjöqvist 1 , Greg Lemon 1 , Costantino Del Gaudio 3 , Ying Zhao 4 , Rainer Heuchel 4,5 , Kielstein Heike 6 , Fatemeh Ajalloueian 1 , Alessandra Bianco 3 , Riccardo Saccardi 7 , Václav Jedlička 8 , Vítězslav Kolek 9 , Vladimir Parshin 10 , Doris Taylor 11 , Paolo Macchiarini 1
1 Advanced Center for Translational Regenerative Medicine (ACTREM), Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden ; 2 European Center of Thoracic Research (CERT), Florence, Italy ; 3 University of Rome “Tor Vergata”, Department of Industrial Engineering, Intrauniversitary Consortium for Material Science and Technology (INSTM), Research Unit Tor Vergata, Rome, Italy ; 4 Surgery Laboratory, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden; 5 Center for Biosciences and Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Stockholm, Sweden ; 6 Department of Anatomy and
Cell Biology, Martin Luther University Faculty of Medicine, Halle (Saale), Germany ;
7 Hematology Department, Careggi University Hospital, Florence, Italy ; 8 Masaryk University, St Anne’s Hospital, 1 st Department of Surgery, Brno, Czech Republic ; 9 Department of Pneumology, University Hospital, Olomouc, Czech Republic; 10 Department of Thoracic Surgery of Hospital First Moscow Medical University , Moscow, Russian Federation; 11 Texas Heart Institute, Center for Regenerative Medicine, Houston, Texas, USA
These are the individual author’s contributions, as presented at the end of the manuscript:
“J.C.H was responsible for preclinical data: performed decellularization, in vitro and in vivo studies, was assisted by M.L.L., G.L., S.S., Y.Z. and R.H., collection and analysis of data and wrote the manuscript; P.J. assisted in clinical transplantations and preclinical experiments and helped to write the report; S.B., A.G., M.O.J., V.J., V.K. and V.P. were responsible for clinical data: performed decellularization, surgery, collection and analysis of data and helped author to write the report; C.D.G. and A.B. performed image analysis; Y.G. and F.A. were responsible for cell culture and transfection; H.K. evaluated histologic samples; R.S. did bone marrow aspiration and characterization; D.T. reviewed and helped to write the manuscript; P.M. designed and oversaw all the research, performed clinical transplantations, interpreted data and helped to write the manuscript”.
As one of these authors informed me, the manuscript was sent in 2014 to the journal Nature Communications and was rejected there. Here the manuscript’s abstract:
“The gold standard for rare benign and malignant tracheal diseases is surgical resection. However, if the total length of the affected area extends over 50% in adults and 30% in children, resection is not feasible. The only solution, allotransplantation requires a complex revascularization procedure and immunosuppression. A tissue engineering approach, involving the use of 3-dimensional biologic scaffolds composed of donated allogenic extracellular matrices, would be a viable alternative to treat these patients without immunosuppression. A detergent-enzymatic method was used to decellularize allogenic human tracheal scaffolds to preserve structural, angiogenic and biomechanical characteristics of the native windpipe. Between 2008 and 2011, 9 patients were treated with these non-immunogenic scaffolds seeded with mesenchymal stromal cells. All implanted tracheae showed full integration and cellular regeneration without signs of rejection. However, in contrast to our previously performed large animal study, the intermediate and long-term clinical outcomes were affected by the development of subtotal collapse in 33% [here authors comments indicate they were not sure in how many patients the cadaveric trachea collapsed, -LS] of the patients. Re-evaluation of the tissue engineering concept using decellularized tracheae in a small animal model of immune competent rats was completed and revealed similar data to our clinical findings, regarding biochemical, histological and mechanical parameters after a 30 day period. In conclusion, tissue engineered biological tracheal scaffolds can be safely used in a clinical setting but with some risk of mechanical compromise in the intermediate and long-term post-operative course. Further improvements are required to preserve the scaffolds´ patency”.
Humans before rats
The rat experiments form here the main part of the research paper, but knowing Macchiarini’s propensity for misconduct, their scientific claims should not be taken at face value. At least the statement “All animal studied were approved by the Stockholm South Ethical Committee (Sweden) under the registration number S74-12” seems to be supported by this ethics approval I obtained from Swedish Board of Agriculture and the Karolinska Institutet (KI) registrar. This is how the authors present the rationale for their rat studies:
“Here we report lessons learned with human tissue engineered tracheal transplantation in a consecutive series of 9 patients whose tracheae were transplanted using decellularized biological scaffolds between 2008 and 2011. Since we observed long-term complications in a small number of patients, e.g. airway stenosis or collapse, which was not seen in our large animal model, we developed a small animal model in rats. We then report findings of our newly developed small animal model and compare these new data with our experience gained from human and porcine studies”.
I will hence omit the rat data (do contact me if you wish to see it) and focus below on Macchiarini’s (and Jungebluth’s) human patients, as they were presented in the article (please also use my published list as reference). The patients all are listed in a Table 2 accompanying this unpublished paper, though one of them, the 26 year-old Kazakh woman Zhadyra Iglikova, operated in Moscow, is presented as male. An oversight by Macchiarini? Or a deliberate attempt to fix the biased sex ratio, since of these 9 patients only one was a 72-year old man and one (Ciaran Lynch) was a 10 year old boy. Their supreme mathematical skills allowed Haag et al to write nevertheless: “From October 2008 to January 2011, 9 patients (aged 37.2±21.8 years; male vs. female: 3 vs. 6) underwent bioengineered airway transplantation, in Barcelona (n=2), London (n=1), Florence (n=5) or Moscow (n=1)“. So, the maximal age was 60 years then, though beside the 72-year old deceased Italian man there was also a 65-year old deceased Italian woman among the 9 patients. The minimal age was 15,4 years, which leaves Ciaran outside also.
The first patient on the list is Claudia Castillo, operated in June 2008, with a trachea graft which was prepared in a bioreactor in the veterinary lab of Martin Birchall. No serious complications with her bronchus transplant whatsoever are mentioned in Haag et al. In reality: Claudia’s condition progressively deteriorated, she lost a lung last year, her current fate is unknown.
The second patient is known as DD and was 55 year old at time of operation in October 2009. A source mentioned to me that she was a pharmacist or pharmacologist from Argentina, and that Macchiarini had no legal right to operate her at the Institut Dexeus in Barcelona, but did it anyway. I could not verify this information further. Interestingly, Macchiarini himself seems confused about the methodology applied on the patient DD. She received a cadaveric trachea regenerated using so-called bionic method (no bioreactor, bone marrow cells seeded directly onto the graft during transplantation), as Macchiarini explained at this lecture at the Royal Society for Medicine in July 2010 (see my article here). This method was then applied to all other 7 cadaveric trachea recipients of Macchiarini’s. In the Haag et al paper however, the authors claim instead that DD received a bioreactor-made transplant, like Claudia Castillo: “Patients 1 and 2 were transplanted using a different protocol than the others, previously extensively described elsewhere“.
For DD, Macchiarini wrote: “Airway performing excellently until 2012 (3 year after transplantation), then patient required a tracheostomy…“, allegedly unrelated to graft. That was not the truth. In his notes from the Careggi Hospital in Florence, Macchiarini admitted that the patient was emergency-operated 13 times between March 2010 and December 2011, and that the graft collapsed, “without definitive resolution”. The Haag et al manuscript was written in 2014, and suddenly DD “was conservatively and successfully treated with a vacuum assisted closure system and definitively repaired with a pectoralis major muscle flap“. In Table 2, the patient DD is presented as “alive“, though her actual fate cannot be verified.
Next falsehood in Haag et al manuscript was to claim that Ciaran Lynch’s airway “required no further stenting” 18 months after the operation in March 2010. In reality, Ciaran never lived a day without a airway-dilating stent, and Macchiarini should have known it (see this boy’s story here). Though the manuscript clearly declares that Jungebluth participated in all operations (“P.J. assisted in clinical transplantations...”), one can assume it probably does not apply to the operation on Ciaran, which took place at Great Ormond Street Hospital in London, led by Martin Elliott; also Jungebluth’s surgeon role in actually operating Zhadyra Iglikova in Moscow is not likely. But one now can rest assured that the surgeon trainee Jungebluth assisted his master Macchiarini hands-on in his two trachea transplant operations in Barcelona and the five in Florence. There is also no reason to hope that Jungebluth had a permit to practice medicine in Italy (or Spain, for that matter), in fact his lawyer insist Jungebluth solely worked as detached researcher, never involved into actual patient treatment. Well, we already knew about plastic trachea recipients in Sweden and Russia he assisted with without holding a licence, but now we also know about cadaveric trachea operations in Spain and Italy. Which would total up to 13 trachea transplant patients of his, 10 of them dead.
The first patient to receive a cadaveric trachea was the young mother from Czech republic, MK, in July 2010. Haag et al authors write “Airway performing satisfactory until April 2011, then severe systemic tumor recurrence, patient died within a month“. This is likely not true. MK was described as deceased in this abstract, submitted to a Czech 2011 conference, the deadline for abstract submission was early April 2011. And as for “performing satisfactory“, that was also not true at all: MK was, according to Macchiarini’s own Careggi notes, sent home on July 30th 2010 with mediastenitis (inflammation of chest cavity), later on a fistula (hole in the trachea) developed. Did she really die of a sudden cancer recurrence, given the very slow growing and manageable nature of her mucoepidermoid carcinoma?
Right after MK, Macchiarini and, as suggested by this newly found unpublished manuscript, also Jungebluth, operated 19-year old Keziah Shorten (her story in this article). Because her cadaveric trachea and the parallel intra-operative radiation therapy were a disastrous failure, she received in September 2011 a plastic airway replacement from Birchall in London, which then led to her death. Haag et al claim however that also that cadaveric trachea “performed well until May 2011“, despite the fact that Keziah developed a tracheo-esophageal fistula in December 2010, which was made much worse after a failed intervention in London. After a second failed intervention in February 2011, Keziah could not eat, drink or speak until her death in January 2012. Stents, which presence Haag et al categorically denied in 2014, kept her rotting airway graft open.
The Italian patient GM received a cadaveric trachea graft to replace her left bronchus, in September 2010. For Haag et al, a success after some complications: “at 1 year follow-up, the patient has recovered with normal quality of life“. Well, maybe Macchiarini sees this relatively, given that his several other patients died. This patient namely suffered “serious permanent brain damage”, in addition to losing her her left lung, the latter Haag et al at least admitted (“developed 60 days from the bronchial transplantation (patient No. 6 [GM,- LS]) an aorto-bronchial fistula located at the proximal (tracheo-bronchial) anastomosis requiring an emergency left carinal pneumonectomy and aortic suturing“. Her current status is unknown, unless you trust Haag et al who claim she is alive and well.
The next Italian patient, MM, 65 years old, was operated in October 2011. Complications are described in Haag et al, but: “functioning airway until September 2012, then patient died of sudden massive upper gastrointestinal bleeding, unknown relation to transplant” is hardly credible, since Macchiarini himself wrote in his Careggi notes that the graft became infected and then necrotic.
In December 2010 Zhadyra Iglikova was operated in Moscow, in a kind of a show transplant surgery which Macchiarini performed together with Vladimir Parshin (see this article). In Haag et al, she was turned into a male, likely to fix the skewed sex ratio. Naturally, as of 2014, her “airway performing satisfactory“. Only that this is also not the truth, in fact Macchiarini never bother to check on this Russian patient. As a Russian clinician and journal editor summed up next year: “graft’s stenosis due to scarring and granulation tissue formation without signs of preservation of native tracheal structure and function”, Dzemeshkevich 2015.
The last cadaveric trachea recipient was a 72-year old Italian man, who died so fast (less than one month after operation in January 2011) that even Macchiarini could not present his clinical evolution as a success. But of course they wrote that this patient’s “neotrachea was biomechanical and histological normal at autopsy“, official cause of death: “pulmonary embolism“. Obviously, here a feeble patient failed his excellent doctors.
Haag et al conclude:
“To date, 9 patients, affected by malignant disease, tracheo/bronchomalacia or fistulas affecting the airway have been transplanted with biological tracheal scaffolds. In all cases, the implanted scaffolds developed native airway characteristics with complete lining of respiratory epithelium and recellularization of perichondral and cartilage areas. “
One wonders where was the evidence for that miraculous regeneration, since all we got objectively confirmed were the rotting, fistula-prone and collapsing trachea grafts. The German anatomy professor Heike Kielstein, who according to Haag et al preformed the histological analyses, did not reply to my inquiry. A particularly cynical and hair-raising statement in Haag et al this anatomy specialist signed as co-author is this:
“In patients, we saw a very rapid recellularization speed of the implanted scaffolds. Internal bleeding occurred after 1 week suggesting neovascularization of the graft”.
So internal haemorrhage around the rotting graft was bizarrely re-interpreted as dead tissue actually coming alive, with blood vessels growing into it from nowhere. We now also learn from Haag et al that Macchiarini used to wrap these grafts into patients’ own fat tissue, with idea to promote the vascularisation of the dead tracheas:
“To support the avascular tracheal scaffold, the omentum major was prepared through a median mini-laparotomy and wrapped around the construct in the mediastinum”.
When bronchus transplantation was performed, with Claudia Castillo and patient GM, a muscle wrap was used:
“After the distal anastomosis was complete, the transplant was wrapped with a pedicled intercostal muscle, prepared at the time of thoracotomy”.
This is basically the technology Birchall now uses for his ongoing clinical trials INSPIRE and TETRA (see my reports here, here and here), to distinguish himself from Macchiarini’s past failures described in Haag et al. The omentum and muscle wrap shall, according to Birchall, assure vascularisation in his future patients. Hopefully it is not only me who notices the inconsistency here.
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