Retraction Watch has obtained copies of a misconduct complaint filed against surgeon Paolo Macchiarini, who is currently under investigation by the Karolinksa Institute in Stockholm for allegedly downplaying dangers of an experimental surgery, along with other misconduct accusations. We’re posting them here to allow researchers and clinicians to review and perhaps comment on them.
The complaint was from four surgeons at Karolinska Hospital, and was filed in August, as The New York Times reported last month. You can read the full complaint here. An excerpt:
In the six articles listed below, the implantation of synthetic tracheal grafts is depicted as a viable treatment option for patients with non-resectable tracheal pathologies and is associated with negligible complications. The three patients who have undergone synthetic tracheal implantation at Karolinska University Hospital have all suffered from serious complications which have not been reported in these six publications. It is our opinion that these six articles neglect to address the morbidity associated with these procedures and omit the majority of complications which these patients have endured. Furthermore, the claim in these six articles that a synthetic trachea transplant can develop into a functional airway is unsubstantiated by the findings in the patients’ medical records. During the analysis of the six articles listed below, we have found that all six articles contain falsified data or that crucial data has been omitted or neglected.
…
These questions should have been addressed at the time of application for ethical permission to perform medical research on human subjects. However, inquires we have made to the Regional Ethical Review Board have revealed that no such application has been applied for or approved. Had such an application been filed, then it is questionable if ethical permission would have been granted because of the lack of evidence in a large animal model. Furthermore, the tracheal transplant procedures cannot be considered to be examples of immediate or compassionate use since all three patients were operated electively and the procedures were planned months in advance.
As supporting evidence, the four doctors also produced an analysis of six of Macchiarini’s papers. Each one lists inconsistencies and inaccuracies, including:
- Inquires have been unable to identify any application for synthetic tracheal transplantation filed at the Regional Ethical Review Board.
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Unapproved informed consent form signed 17 days after the transplantation.
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Serial fabrication and omission of biopsy findings.
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Serial fabrication and omission of bronchoscopic findings.
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Fabrication and omission of clinical status.
The documents also include de-identified medical histories of patients who underwent the procedure, along with papers drawn from those cases, and other such cases and papers, all of which refer to the original complaint.
When Nature spoke to Macchiarini last month about these allegations, he declined to comment on most issues but did speak up regarding the accusation that only one patient of three signed an informed consent form, and that was dated 17 days after the procedure. From Nature:
“Of course there was consent. We would never have proceeded with the transplants if there wasn’t.” He adds: “I do not know why the form is dated 17 days after the procedure and can only assume it is some kind of clerical issue.” The patient “signed it in my presence, prior to the operation”. He adds that “there was absolutely no ethical breach”.
The rest of the documents obtained by Retraction Watch include:
- An amendment to the request for an investigation
- Tables that accompany that amendment
- Other cases and papers that refer to the amendment.
Unlike new drugs or to a lesser extent the introduction of new protheses (e.g. hip joints) surgeons can introduce new procedures with almost no controls other than the disapproval of their colleagues as has been demonstrated here. there is nothing intrinsically wrong with surgeons modifying their procedures and the vast majority are hoping to improve outcome. However the problem is that the many procedures are introduced without proper planning or measurement, such as standardised measures of quality of life before and after, assessment of function or patient satisfaction. Randomised trials of surgical procedures are notoriously difficult to carry out for any number of reasons and are relatively rare as a result. When they are successfully carried out they can be very surprising clinically and also potentially have a deleterious effect on the surgical prosthesis industry as a recent study on surgery for ‘heel’ trauma reported . (BMJ 2014;349:g4483). Over regulating the introduction of new surgical techniques can be very counter productive but if you are going to change what yo do try to measure your outcomes objectively otherwise new procedures will be detrimental as seen in your report or useless and potentially harmful
I was surprised that TGF beta3 from R&D systems, which are expressly labelled as not for human use, was given to patients. There are companies producing these proteins specifically for human use and clinical trials! So this isn’t down to the fact the treatment is experimental.
Well.. it wasn’t given to the patients.
It was used for conditioning the cells.
In the same way, DMEM cell growth media wasn’t given to the patients either.
Seems like the four accusing doctors “missed” that point. What else is missed?
Just read the whole thing, at least the parts that were in english. Insane. This whole thing makes the STAP cell controversy look like a minor traffic violation. The only open question now is where this Macchiarini character is going to go to jail. Italy? The US or Sweden? In Sweden you probably get your own cable.
Last I heard, he was was working in Russia.
Before going to jail one is supposed to be condemned. This has not happened yet, and possibly (probably) will never.
I’d better wait for the independent committee judgement in february (Macchiarini has been already investigated twice by Karolinska, accused by the same people, and was found not guilty), and the Italian trial (which has not started yet).
Actually the accusations are relevant, but still under revision by the independent committee. Of note, according to the documents herein attached, the poor outcome of the first patient was evident BEFORE the Lancet publication. If so, why Dr. Grinnemo (who now accuses prof. Macchiarini) is one of the co-author of the paper? If he knew at that time that data were flawed, why did he participate and signed the paper?
Second question: did prof Macchiarini go around seeking for patients to operate, or did the doctors who had in charge the patient in Iceland look for him? It is frankly unbeliavable that a patient without cancer was referred to Karolinska from a Iceland Hospital with a false diagnosis.
Last question: I believe that the clinical records and charts of these patients had been examined before planning such innovative surgery. Nobody noticed anything wrong?
There are still MANY open question!
I’d better wait to hear the entire story (not only the accusations) before telling: “The only open question now is where this Macchiarini character is going to go to jail. Italy? The US or Sweden?”
By the way: the trial in Italy has been posponed, but at least two of the supposed victims have already spontaneously declared that they had not been forced to pay anything, and the first (and only) accusator has been proved to have lied.
http://www.lanazione.it/firenze/cronaca/2012/10/10/784751-macchiarini-chirurgo-arrestato-careggi-torna-in-sala-operatoria.shtml
His Wikipedia entry is a eulogy and does not reflect any other controversy than that the treatment is not covered by insurance in US, prohibiting patients from benefitting from it.
For your information, today the medical journal of the Swedish Medical Association (Läkartidningen) reports that the “leak” of the analysis of Macchiarinis papers by Corbascio et al that RetractionWatch has published has been reported to the police by the Karolinska University Hospital. There is an ongoing investigation as to whether the extraction of data from the patents’ medical records (ostensibly performed by Corbascio et al), and subsequent publication in the analysis, as well as leak of the analysis to RetractionWatch constitutes an illegal act of data breach. The article in Läkartidningen does not mention RW, only a “foreign blog specialising in research fraud and retracted articles”, but I assume they mean RW.
Article (in Swedish, you can use Google Translate):
http://www.lakartidningen.se/Aktuellt/Nyheter/2015/01/Lackta-patientuppgifter-polisanmalda/
Sad and ironically tragic that whistleblowers are facing lawsuit in the midst of a huge debate on freedom of press and freedom of speech.
very unlikely that one could perform such a transplantation at the university hospital with so many people involved without any permission and consent…especially as a guest surgeon…this sounds absurd…cheers peter
An external reviewer says Macchiarini has committed misconduct and the Swedish “Läkemedelsverket” has handed matters over to the police.
http://www.svd.se/nyheter/inrikes/utredare-ki-kirurgen-fuskade-i-forskningen_4573664.svd
As noted in the post:
http://www.nytimes.com/2014/11/25/world/leading-surgeon-is-accused-of-misconduct-in-experimental-transplant-operations.html?_r=0
Case 3 (in the PDF report), if true, is a shocking story. Hard to read it without horror.
One of the allegations against Macchiarini is that he performed an unnecessary surgery to the first patient who received an artificial trachea
Finally we can read the reply of prof. Macchiarini
FROM THE ALLEGATION:
“Lack of Verification of Malignancy, which was the Postulated Indication for Transplantation in Case 1 (transplanted Jun 9, 2011).
The reoccurrence of the malignant tumor in the trachea (mucoepidermoid cancer), which was postulated to be the indication for the transplantation of the synthetic trachea, cannot be verified in the patient’s medical records from either Landspitali, Reykjavik or from Karolinska University Hospital pre-, peri-or postoperatively.
The patient underwent a complicated surgical procedure of the newly diagnosed tracheal tumor on Oct 29, 2009 at Landspitali, Reykjavik, Iceland. Histological analysis demonstrated a low differentiated mucoepidermoid cancer. Initially, postoperative radiation therapy was planned, but had to be postponed because of miliary tuberculosis (TB). Treatment for the TB was initiated in January and continued until July of 2010, after which radiation therapy was started. Early in the spring of 2011 the patient developed respiratory symptoms believed to be tumor reoccurrence. Clinical investigations were initiated on Iceland where biopsies of the trachea were performed on Feb 11, 2011, four months before the transplantation on Jun 9, 2011. These biopsies did not yield any signs of malignancy, but only inflammatory granuloma (Appendix 1). After assessment by Prof Macchiarini, the patient was transferred on May 24, 2011 to the Departments of Ear, Nose and Throat (ENT) at Karolinska University Hospital for further investigations and “…planned major surgery in approximately two weeks.” (May 24, 2011, Admission notes, Departments of ENT, Appendix 2). The patient flew on a standard international flight to Stockholm to undergo these investigations and surgery and therefore the procedure has to be considered an elective procedure.
Computer tomography of the chest from May 24, 2011 (CT report, Appendix 3) could not verify if the changes in the patients’ trachea were of malignant origin. A PET-(18-
1
FDG) examination performed on May 25, 2011 (PET report, Appendix 4) showed signs, which may be consistent with a tumor. However, 18F-FDG is not a cancer specific marker and false positive results may also be detected under various circumstances including active inflammation and granuloma, infection from for example tuberculo-lymphoadenopathy, active fibrotic injury, and radiation induced fibrosis or hyperplastic lymphadenopathy in the absence of malignancy (Appendix 5a, b, c). Two weeks before the planned transplantation two tracheal biopsies where performed at Karolinska University Hospital (May 26, 2011, Biopsy reports, Appendix 6a, b) as well as a bone marrow biopsy (May 27, 2011, Biopsy report, Appendix 6c). None of these biopsies verified the presence of any type of malignancy. Despite these negative histological findings surgery was performed June 9, 2011.”
Macchiarini’s reply:
“Firstly, the initial operation in Iceland in 2009 only partially excised the tumour (see description published in Am J Resp and Crit Care Med 2011, 183, 681-682, Appendix 14). The tumour material was at that point confirmed as malignant, and as it had only been partially excised, its return was expected. The return was indeed reported in the above article (“Control bronchoscopy 7 months after the operation revealed a small residual tumour”).
Bronchoscopies, CT and PET scans all confirmed the presence of a mass in exactly the same position as the original tumour, with a strong signal. A multidisciplinary conference on 27th May 2011 attended by more than 15 senior physicians (notes in Appendix 7 – entries 8 & 9), as well as a second opinion obtained from Harvard University both concluded that a recurrence of the tumour was the most likely diagnosis, and that surgical intervention was required to prevent asphyxiation of the patient, who was already suffering dyspnea from its intrusion into the airway. The need for a non-conventional surgical procedure would have been the case whether the mass was malignant or not, given its progressive growth into the airway.
The biopsies taken for PAD testing on the 27th May were specifically taken outside of the margins of the mass in order to ascertain the size of complete resection needed, and to manufacture the bioengineered scaffold to the exact length and shape required. As such, a negative result on those was hoped for, and expected. A biopsy of the suspected tumour was not taken at this point, as the previous surgery on the tumour had cause unexpected massive and near-fatal bleeding, which necessitated intra-operative initiation of veno-arterial extra corporeal membrane oxygenation to keep the patient alive. The risk of this complication re-occurring outweighed the benefit of a biopsy of a mass which needed resection no matter the results of the biopsy.
Surgery was planned, and the surgical notes by Dr. Jan Liska of 9th June 2011 (Appendix 7 – entry 10) reveal that the surgical specimen was indeed sent to the pathology lab for biopsy from the operating theatre. Like Professor Gerdin, however, we have no notes of the result of analysis of the suspected tumour itself, only confirmation by Dr. Anna Januszkiewicz, the anesthetist responsible of the operation, to the surgeon (myself) that the entire mass had been successfully resected (Appendix 7 – entry 11).
Andemariam video 1 year
https://www.dropbox.com/s/u0mimrpcpiq2z1f/Trachea%20implant%20-%20one%20year%20later-1.mp4