Macchiarini Case Investigation Report PDF

Macchiarini Fallet Investigation of the activities of transplantation of synthetic trachea Karolinska University Hospital Report 2016-08-31 Glossary The following definitions are taken from the Medical Dictionary (1) or Merriam- Webster's Medical Dicti...

Macchiarini Fallet Investigation of the activities of transplantation of synthetic trachea Karolinska University Hospital Report 2016-08-31 Glossary The following definitions are taken from the Medical Dictionary (1) or Merriam- Webster's Medical Dictionary (2). When defining these sources, is the definition of our own. References 1. Medicinsk ordbok. http://medicinskordbokse/. 2. Merriam-Webster’s Medical Dictionary. http://www.merriam-webster.com/dictionary/. Ordförklaringar Forward In consultation with the Stockholm County Council decided hospital director Melvin Samsom at Karolinska University Hospital February 12, 2016 to give a mandate to an external investigators to investigate and clarify the circumstances of the surgeries with synthetic trachea which was conducted at the Hospital 2011-2013. Based on the facts investigation concluded, the investigator would give recommendations on improvements. For investigators appointed Kjell Asplund, Professor Emeritus of Medicine at Umeå University, former Director General of the National Board. He appointed a working group consisting of Nils Blom, former General Counsel at the National Board of Health and the Public Health Agency, Katarina Johansson, Chairman patient organization Network against cancer as well as Jesper Persson, chief physician of internal medicine and former head doctor at Skåne University Hospital. Pernilla Östlund, Project Manager at the Swedish Council for medical and social assessment (SBU) was hired March 1, 2016 as a research assistant. Clara Wahren, Stockholm County Council, assisted by providing administrative support. The County Council has set the premises available. We have hired two external reviewers of chapters 11 and 12, Professor Ingemar Petersson, Head of Research at Skåne University healthcare (SUS) and Professor Jack Lysholm, head of the Register Centre Norr, Umeå. Two external experts, Lars Ek, chief of pulmonary medicine at Skåne University Hospital and associate professor Jan Nyman, Chief of Oncology at Sahlgrenska Hospital in Gothenburg, have contributed their views on the two first-transplanted patients' diagnosis and forecast. Responsibility for the final report texts is however on the investigation. We have the working group consistently met with great willingness to provide material and their own interpretations the event itself. None of them we wished to interview declined. We would like to warmly thank all those who stood up for interviews and contributed material to the investigation. The inquiry report is hereby completed. Stockholm 2016-08-31 Kjell Asplund Contents Summary Contents Brief summary of the course of events........................................................4 Macchiarini was recruited to the hospital despite warning signs......6 The patients’ condition was not immediately life threatening.............8 Many inadequacies before, during and after the transplants........... 10 The scientific foundation was inadequate prior to the transplants............................................................................................... 12 The transplants should have been subjected to ethical review.......14 Macchiarini and the unit managers responsible.................................... 16 Laws and other regulations were not followed...................................... 18 Multiple problems concerning patient safety.......................................... 19 The lack of critical questions and ignorance regarding the regulations may have contributed to the course of events..............20 Complex relationship between the hospital and KI.............................22 The potential misconduct may have affected the care...................... 23 The Macchiarini case has had serious consequences for clinical research and hospital employees..........................................24 The hospital has taken some steps........................................................... 25 Patient safety and routines need to be improved................................26 Our task and its implementation................................................................. 28 4 We present here a summary of our report “The Macchiarini Case - Investigation of the synthetic trachea transplantations at Karolinska University Hospital”. The complete report is available at www.sll.se. This summary focuses on shortcomings that were exposed during the investigation and on areas where improvements may be needed. For a more intricate illustration – including issues that were properly managed – we refer the reader to the complete report. Brief summary of the course of events Paolo Macchiarini was employed at the end of 2010 as a professor at Karolinska Institutet (“KI”) and a senior physician at Karolinska University Hospital (“the hospital”). In 2011, he performed the world’s first transplant of a synthetic trachea prepared with bone marrow cells, an event that evoked extensive attention in both professional circles and the mass media. In 2011-2013, he performed synthetic trachea transplants on another two patients at the hospital, one of these on two occasions. The first of the three transplant patients died 30 months after the procedure following severe complications from the synthetic trachea. The second patient died after four months from an unknown cause. The third patient suffered very severe complications that have required continuous hospital care since the transplant in 2012. In May 2016, this patient underwent a lung, trachea and oesophagus transplant from a deceased donor at a U.S. hospital. When the unfavourable results and other circumstances surrounding the surgical procedures became clear to clinic and hospital management, Macchiarini’s employment at Karolinska University Hospital was terminated in November 2013. 5 In August 2014, four physicians reported Macchiarini to the Vice- Chancellor of the Karolinska Institute (KI) for research misconduct. According to the reports, the Macchiarini team’s scientific articles contained incorrect clinical information. The Vice- Chancellor appointed an external investigator who found that the accusations against Macchiarini were essentially correct. However, the Vice-Chancellor decided to acquit Macchiarini of the accusations of research misconduct. In April 2015, the Swedish Medical Products Agency filed a police report against Karolinska University Hospital for violating the Medicinal Products Act. In June 2015, the Health and Social Care Inspectorate (IVO) filed a police report against the hospital for violating the Ethical Review Act. In June 2016, a prosecutor accused Macchiarini of a suspicion of gross criminal negligence causing another person’s death and gross criminal negligence causing bodily harm. The prosecutor did not rule out the eventuality that more hospital employees would be accused of suspicion of crime. Growing criticism of Macchiarini, his research and his transplants culminated in January 2016 in the TV series “Experimenten” (The Experiments). The Vice-Chancellor of KI and his closest colleagues resigned. The Personnel Disciplinary Board at KI decided to dismiss Macchiarini in March 2016. A number of investigations have been initiated due to the Macchiarini case, some with a direct focus on Macchiarini and his activities, some of a more general nature. The hospital and KI have both appointed external investigations, the hospital with a focus on Macchiarini’s clinical activities, especially the trachea transplants (this investigation), and KI with a focus on how the Institute handled Macchiarini’s academic activities. 6 Macchiarini was recruited to the hospital despite warning signs Macchiarini was recruited as a senior physician at the hospital even though there were strongly critical opinions from his previous employers. We recommend that the hospital should quality assure its recruitment process, especially concerning positions shared with KI. The employment of Macchiarini at KI and the hospital was a part of a coherent strategy to build a centre for advanced airway surgery at Karolinska University Hospital and KI. In international media, Macchiarini had received attention as a particularly innovative surgeon through the transplant of a specially prepared trachea from a deceased donor. In professional circles, he was considered to be a technically driven surgeon. He himself and his activities were described by a combination of positively charged terms, such as “translational research”, “regenerative medicine”, “stem cells”, “nanotech”, “internationally leading” and “star surgeon”. It is easy to understand that the collective concept around the recruitment of Macchiarini appeared to be very attractive and visionary. However, at a high level of management, the enthusiasm for Macchiarini appears to have been distinctly greater at KI than at the hospital. There were expectations that he would very quickly get started with trachea transplants at the hospital. The high expectations may have contributed to decisions being made too quickly when Macchiarini was hired. From the hospitals he previously worked at (in Italy, Germany and Spain), there were signals of inadequacies as a surgeon other than surgical techniques, mainly in terms of indication decisions, in other words what kinds of operations were performed on which patients. There were also several signals of cooperation difficulties that reached KI and the ear-nose-throat clinic (ENT clinic). In London, where he had research collaboration without being employed, the cooperation problems were nonetheless not considered to be insurmountable. 7 Before Macchiarini was employed, he performed a “test operation” where his Stockholm colleagues were impressed by his technical skills. The hospital took no references of its own on Macchiarini’s clinical qualifications until a very late stage in the recruitment process. The warning signs that arose then were suppressed. Pressure from KI and some time pressure appear to have contributed to Macchiarini being employed as a senior physician despite the strongly negative signals from his former clinical colleagues. Macchiarini is a thoracic surgeon, but it was decided that he would have his academic and clinical activities placed with the ear-nose-throat division (ENT unit) at KI and the ENT clinic in Huddinge (the thoracic clinic is in Solna). It is our impression that the KI management was the driver of this decision. The fact that Macchiarini was employed at the ENT clinic in Huddinge, but came to locate most of his surgical activities at the thoracic clinic in Solna contributed to unclear responsibility circumstances, which gave an independent person like Macchiarini an opportunity to move between the two clinics too freely. Even if we in this report find multiple faults in the system that may have contributed to the Macchiarini case developing as it did, we believe that this particular case cannot be taken as a reason to more generally rule out the ambition to recruit international, high-calibre talent for clinical research in Sweden. 8 The patients’ condition was not immediately life threatening There was no immediate threat to the life of any of the three transplant patients before the operations. Progressing cancer in two of the patients would very likely have led to death on the longer term. In the third patient, complications of her tracheal injury, especially severe infections, entailed a significant threat to life. Patient 1 was a 36-year-old man who had undergone surgery and radiation treatment in Iceland for a rare form of tracheal cancer in 2009. Due to clinical symptoms, a relapse into cancer was suspected. Examination showed a constriction of the trachea. An external assessment was obtained from the U.S.; the treatment possibilities were considered to have been exhausted and palliative care was proposed. The patient’s physician in Iceland then contacted Karolinska University Hospital which offered to assess the patient and potentially perform a tracheal transplant. The operation was performed at the ENT clinic in Huddinge in June 2011. There was no cardiopulmonary machine at the clinic, which meant that the patient’s life was put at risk. During the operation, it became clear that the material in the synthetic trachea was not optimal. The patient recovered, however, and after just over four weeks’ care at Karolinska University Hospital, he was able to return to Iceland for continued rehabilitation. He resumed his doctoral studies and completed his PhD in 2012. In November 2011, he was referred back to Karolinska University Hospital on the grounds of growing bronchial symptoms. He then came to be treated at the hospital on a large number of occasions between December 2011 and his death in January 2013. His general condition declined, fistulization was confirmed and he was struck by constantly recurring infections. In the autopsy, the transplanted trachea was found to have come loose. A chronic infection in the chest and a clot in the right pulmonary artery were also found. There was no remaining cancer, however. 9 Patient 2, a 30-year-old man from the U.S., had a rare form of cancer in the trachea that was diagnosed in 2009. There were no metastases. He had been treated with chemotherapy and radiation. After having heard of the first tracheal transplant at Karolinska University Hospital, he contacted the hospital through his physician for a possible transplant. He underwent the transplant with a synthetic trachea in November 2011. Microscopic analysis showed that not all cancerous tissue had been removed. After eight weeks’ care, he was able to return to the U.S. He died suddenly in March 2012. No autopsy appears to have been performed. There has been speculation regarding various causes of death, both those related directly to the transplant and those that were due to his underlying cancer. Patient 3 was a 22-year-old Turkish woman who had suffered a severe tracheal injury in 2011 in conjunction with hand sweat surgery to cut the nerve pathways from the spinal cord to the hands. Her right lung was non-functional and there was a fistula between the trachea and the pleura on the right side. She suffered from a constant cough and phlegm formation. In surgery in July 2012, Macchiarini removed the right lung and the trachea was replaced with a pipe to the large windpipe to the left lung. Two weeks later, the transplant with a synthetic trachea was performed. Postoperative complications arose and she underwent ECMO treatment (“artificial lung”) for one month. There were signs of air leakage between the trachea, oesophagus and out through the surgical wound. When the transplanted trachea began to collapse, a second transplant with a synthetic trachea was done in July 2013. The patient suffered a number of severe postoperative complications, including clot formations and kidney failure that demanded dialysis. Due to fistulization, her oesophagus had to be removed. Ever since the transplant, she has been hospitalised and required constant clean-up of the respiratory passages, but has been partially ambulatory. In May 2016, she underwent a multiple organ transplant in the U.S., including the trachea, with material from a human donor. In August 2016, she is still hospitalised, but is partially ambulatory. 10 Many inadequacies before, during and after the transplants There were clear weaknesses in how the informed consent was obtained, how the multidisciplinary conferences before the operations worked and in the continuity in the contact between patient and treating physician after the transplants. The synthetic material had inadequacies. The pharmaceutical treatment deviated from what is acceptable. Not enough information was gathered about the progression of the first transplant patient when the decisions were made to perform surgery on both of the others. Informed consent. The three patients were fully capable of making decisions. Before the operations, they were informed by Macchiarini or his colleagues. That the patients had to provide written informed consent was unconventional for Swedish medical care, but in principle a good initiative and in agreement with international guidelines. We have only been able to find that patient 1 signed an informed consent. However, the written information contained texts that neither made it possible for the patient to understand the content or refrain from the procedure. If the information had been presented to an ethical review board, it would not have been approved. The patients were not given any possibilities to discuss the operation decisions with an independent expert. Multidisciplinary conferences. Prior to the decisions to transplant, multidisciplinary conferences were held for two of the three patients. No conference was held prior to either of the transplants the third patient underwent. In our judgement, the initiative for multidisciplinary conferences was highly motivated, especially as it concerned an entirely new kind of surgical procedure with unknown risks. However, at the conferences, the crucial issues were not discussed regarding what scientific foundation there was and what risks the transplants could conceivably entail for the patients. Important expertise was missing. The conferences came to pro- 11 vide support to the transplant activities and meant that the responsibility relationships could be perceived as ambiguous. However, the ultimate responsibility for the trachea transplants being performed rested with the operating surgeon (Macchiarini). Clinical information prior to making a decision. Prior to the operations of patient 2 and especially patient 3, not enough information was gathered about the progress of patient 1, or adequate consideration was not taken to the information on hand. Synthetic material. In the four transplants, three different synthetic materials were used. There seems to have been several reasons for the material changes, including that the material was difficult to sew, it was too stiff to be able to replace the human trachea, and material failure (collapsing trachea). We believe that the material changes indicate that too little was known about the material in order for it to be able to begin to be used in patients. Moreover, the diameter of the synthetic trachea was not always optimal. Medication. In connection with the first two transplants, growth-stimulating drugs were used. For the third patient, we have not been able to find any information in the medical record that growth-stimulating drugs were applied. In other documentation received by the investigation, it looks, however, as if patient 3 had received the same kind of medication. 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. Patient-doctor continuity. As the operating surgeon, Macchiarini was the physician responsible for the patient and thereby responsible for the care of the patients after the operations. He appears to have initially taken this responsibility for patient 1 and possibly patient 2. But Macchiarini was active at several other hospitals. This meant that he was often difficult to get a hold of when the patients were struck by complications – the patient-doctor continuity was not maintained. This became especially clear during the very long and complicated course of care for patient 3, but was also true of later phases of the care of patient 1. 12 The scientific foundation was inadequate prior to the transplants Our collective assessment is that there was not an adequate scientific foundation for a human transplant of a synthetic trachea seeded with bone marrow cells, combined with the application of growth-stimulating drugs. The concept conflicted not only with scientific and proven experience; it was also too early to conduct a scientific study on humans. The transplantation of trachea has long been discussed as a treatment alternative if the trachea must be removed due to a tumour or severe injury or if the cartilage is so weak that the trachea is at risk of collapsing. The two main lines of research on trachea transplantation have concerned (a) trachea or other structures that are taken from deceased donors (necrotrachea, so-called biological scaffold) and (b) trachea made of synthetic material. At the time of the trachea transplants at Karolinska University Hospital, numerous animal experiment studies had been done. The results had been mixed. The Macchiarini team had reported partially successful experiments with transplants in pigs with trachea from other pigs. Other research teams had reported on the growth of tracheal epithelium on transplanted synthetic trachea, although made of a material different than what came to be used in the patients Macchiarini operated on. The survival of laboratory animals after transplant with a synthetic trachea had varied widely. In 2008, Macchiarini and co-workers reported on a transplant performed in Barcelona with a specially prepared trachea from a deceased donor. According to the report, the transplant was successful and a five-year follow- up was later published. A second transplant with a specially prepared trachea from a deceased donor was performed in London in 2010 and two years later was reported as having been successful. 13 The transplants that were performed at Karolinska University Hospital in 2011–2013 were the first in the world where synthetic trachea were used in humans. In the scientific literature, there have been strongly divergent opinions as to whether this is a way forward or not. When the transplants were performed, there were no results from experiments on whole lab animals where the specific techniques were used that were applied in the clinical transplants (the combination of the specific synthetic material, the preparation with bone marrow cells and the application of growth factors). 14 The transplants should have been subjected to ethical review A number of circumstances indicate that the transplants concerned clinical research, which according to the Ethical Review Act also refers to scientifically based development. They should have undergone ethical review. It is unlikely that the project would have been approved if so. In the debate on Macchiarini’s transplant activities, the hospital maintained that it was a matter of the medical care of severely ill individuals where other treatment alternatives had been exhausted. In accordance with this, the hospital asserted that it involved compassionate use (treatment for humanitarian reasons) and that it was not a matter of clinical research. Approval by an ethical review board was therefore not required. On the contrary, KI’s investigator Bengt Gerdin, the Swedish Research Council, the Health and Social Care Inspectorate and a number of debaters have been of the opinion that the trachea transplants involved clinical research. We have found a number of circumstances that indicate that the transplants involved clinical research, which according to the Ethical Review Act also refers to scientifically based development. In our judgement, the rules for research should have been followed – then a number of ambiguities regarding ethics permits and permits from the Swedish Medical Products Agency would have been addressed. There appears to have been a large humanitarian element (compassionate use) when the decisions were made to perform the transplants. But this does not mean that other ethical values can be set aside. Nor can it be used to justify deviations from current regulations, especially in terms of the protection of the patient and patient safety. A humanitarian element does not reduce the need for review under the Ethical Review Act. We find it to be very unlikely that the transplants would have been approved by an ethical review board based on the scientific information that was available in 2011. 15 The hospital has (like KI) maintained the opinion that the trachea transplants were not clinical research. We assess that this position, if maintained, can entail a risk of continued shifting in the application of the regulations on clinical research at the hospital. 16 Macchiarini and the heads of department were responsible As the operating surgeon, Macchiarini had a direct responsibility for the transplants being performed. A head of a clinical department has the responsibility for patient safety at his/her clinic. The participants in the multidisciplinary conferences that preceded the transplants had some professional shared responsibility. The head of the ENT clinic had the formal responsibility for Macchiarini’s employment as a senior physician. He took several well-motivated steps to support and control Macchiarini’s establishment at the clinic, but these steps proved inadequate for such a difficult-to-manage employee. The head of the department had the formal responsibility for these inadequacies. In the time that Macchiarini was employed at the ENT clinic, he came to carry out three of the four transplants and the majority of his other operations at the department of thoracic surgery. There were inadequacies in the coordination between the departments, which contributed to ambiguous responsibility relationships. Decisions to perform transplants on patients 1 and 2 were made at multidisciplinary conferences. When the participants in multidisciplinary conferences supported the transplant decisions, they accepted some professional shared responsibility as consultants. This in no way discharges the operating surgeon (Macchiarini) from the ultimate responsibility for the trachea transplants being done. Macchiarini was also the physician responsible for the patients and was thereby responsible for the patients’ care after the operations. He did not take this responsibility for patient 3 or in the latter phases of the care of patient 1. The head of the department has the formal responsibility for the care provided at the department being safe for the patient and in compliance with 17 the rules. There were inadequacies here and the heads of the ENT and thoracic surgery departments accordingly have a responsibility for this. We assess that the head at the thoracic surgery department acted adequately once he fully understood the unfavourable results of the three transplants. Macchiarini was no longer permitted to operate. The ENT department wanted to extend his appointment as a senior physician when it expired in November 2013. After intervention by the hospital director and his staff, it was decided, however, to end Macchiarini’s employment at the hospital. The hospital withstood pressures from KI to extend the appointment. 18 Laws and other regulations were not followed The conclusion of the investigation based on the occurred events is that the hospital did not maintain a proper approach to the healthcare regulations. Several deviations were made from the regulations. As previously presented, we deem that the transplants of the synthetic trachea constituted clinical research. The hospital should therefore have applied the regulations of the Ethical Review Act. The lack of a research ethics review was of crucial importance to the course of events. Permits should also have been obtained from the Swedish Medical Products Agency for the use of the combination of a synthetic trachea, preparation with bone marrow cells and the use of non-approved pharmaceuticals. No such permits existed. The contacts with various permit issuing bodies were handled informally, most often over the phone. This has allowed room for divergent interpretations. We find it to be unacceptable that formally correct ways to assess the extent to which permits were needed for different parts of the transplantation concept were not used. The regulations for healthcare were partly applicable in these operations. The management system was inadequate to some extent. The regulation regarding information and consent and a second opinion were not handled satisfactorily. 19 Multiple problems concerning patient safety During our investigation, there were signs of inadequacies in the patient safety work at both of the clinics involved, possibly also at the hospital in general. The Macchiarini case may have contributed to there being a risk that patients cared for at the university hospital feel less safe. We have not had the ambition of shedding light on the whole hospital’s patient safety culture and patient safety work. Our impression is nonetheless that the hospital largely appears to have an adequate organisation and works with the tools and models that are needed for suitable patient safety work. However, the Macchiarini case has exposed inadequacies in the management and governance of the activities. No risk analysis was done before the procedures and there was no systematic follow-up. In our opinion, patient safety must be put first when new methods are introduced. We are aware that “lex Maria” is not primarily focused on events in healthcare of the nature in uestion here. But we nonetheless believe that a report under lex Maria should have been filed, in any case after the operation of the third patient. A report had in all certainty led to the hospital conducting an event analysis. Even if Macchiarini had already been forced to stop his transplant activities, an event analysis could have identified more general patient safety problems. One might say that our investigation constitutes an unconventional form of event analysis. Based on our interviews and the measurements of patient safety culture carried out by the hospital, there are numerous indications of inadequacies in the patient safety culture at both of the departments we examined, above all at the thoracic surgery department (even if these measurements should be judged with caution due to a low response rate in the questionnaires). 20 The lack of critical questions and ignorance regarding the regulations may have contributed to the course of events Group thinking, bandwagon effects, a very competitive care environment, many informal leaders and deficient knowledge of and respect for rules are some of the factors that may have contributed to the course of events. In all likelihood, group thinking contributed to warning signs in connection with Macchiarini’s hiring not being taken seriously enough. Group thinking may also have contributed to Macchiarini’s clinical colleagues not raising objections or asking critical enough questions before the transplantations. The initial view of Macchiarini as a particularly successful researcher and surgeon appears to have created a bandwagon effect, which is to say that once the wagon started moving, it was important to hop on. In our investigation, we have tried to get a grasp of the environment that made the course of events in the Macchiarini case possible. Here, we present some of our observations, well aware that there are very wide variations in the care culture within the hospital. In an environment as strongly competitive as Karolinska University Hospital, culture of silence is found – people are cautious with open criticism upwards so as to not put their position at risk. Since a large share of the doctors hold extensive academic qualifications and have their KI positions linked to clinical service at the hospital, there are many informal leaders. The knowledge of and respect for the rules appear to vary within the hospital. It is not uncommon to take short-cuts through informal contacts with authorities. There are such examples in the Macchiarini case. Hospital management has had ambitions to work against a repressive culture. This work does not appear to have achieved a full breakthrough in the whole hospital. 21  Karolinska University Hospital has a long tradition of being seen as Sweden’s leading university hospital in both medical care and research, which is something that entails a risk of inadequacies and shortcomings not coming to light. There may be a need to further develop the hospital’s work on core values. 22 Complex relationship between the hospital and KI As a result of different development strategies, management commitment to Macchiarini has been greater at KI than at the hospital. In the Macchiarini case, the hospital has not been independent enough from KI. KI and the hospital have had different fundamental strategies for how they wanted the hospital to develop. While KI would have preferred to make a stake on excellent researchers and top recruitment of employees with shared positions, hospital management has strived for a system of continuous improvement with the aim of creating a credible and patientsafe organisation. Consequently, KI’s backing of Macchiarini was more wholehearted than the hospital’s at a high level of management. For better or worse, KI had extensive influence on decisions made within the hospital’s organisation, an influence that is probably greater than at other Swedish university hospitals. When Macchiarini’s research activities were criticised by those filing reports and in the media, the hospital, in our opinion, too willingly supported KI’s line in the defence of Macchiarini. 23 The potential misconduct may have affected the care Potential research misconduct concerning the first transplant patient may have influenced the care of both of the subsequent patients. Warning signals must be taken seriously. When the first report of irregularities in Macchiarini’s research were filed with KI, Macchiarini’s employment at the hospital had already been ended. In our judgement, potential misconduct in research may have possibly affected the care of the patients by the progress of the first transplant patient being described too positively. This led to the transplant of patients 2 and 3 not being called into question. It was unfortunate that focus initially came to rest on the issue of possible unlawful access to medical records instead of on the fundamental issues regarding Macchiarini’s activities at the hospital. This can be perceived as a repressive measure towards employees who point out improprieties. 24 The Macchiarini case has had serious consequences for clinical research and hospital employees Restoring the trust in the clinical research demands longterm, wholehearted efforts based on sound ethics, high patient safety and respect for the rules and regulations that exist. Many employees at the hospital have been harmed by the Macchiarini case. Targeted work-environment efforts are needed. Macchiarini’s transplant activities have damaged clinical research not only at Karolinska University Hospital, but also in Sweden in general. Restoring the confidence in the research requires long-range, wholehearted efforts. We want to emphasise that what happened around Macchiarini in no way in militates against bold and innovative clinical research. Such research presupposes ethical review and can very well be combined with a strong protection of the patient and high patient safety. It is clear that many of the hospital’s employees at various levels were harmed by the Macchiarini case. In the debate, there has been an unforgiving attitude, even bitterness, that many have been very hurt by. This can be seen as a work environment issue. It appears to us to be important that the conflicting views are toned down and a “reconciliation process” is begun. 25 The hospital has taken some steps We find four initiatives on the part of the hospital to be particularly relevant to trying to resolve the problems exposed in connection with Macchiarini’s activities: A task force will work with issues in the border zone between healthcare and clinical research A whistle-blower function has been established The chief medical officer recently gathered information on which patients Macchiarini operated on at the hospital in addition to the three transplant patients An effort to strengthen patient safety has begun at the thoracic clinic. 26 Patient safety and routines need to be improved Based on our observations, we have compiled a number of recommendations to hospital management on improvement measures. Our task included making recommendations on improvements that could reduce the risk of events similar to the Macchiarini case. Based on the observations we made, we compiled a number of recommendations. Most of them build on suggestions made by the individuals interviewed, many of whom are hospital employees. Our recommendations are focused on improvement possibilities with regard to patient safety, organisation and routines. Here, we summarise the most important of the recommendations, well aware that they may seem general in condensed form. Recruitment. The recruitment process must be quality assured and the hospital must demonstrate greater independence from KI in the recruitment of clinically practising employees. Rules and guidelines. Since there are many indications that the knowledge of rules and guidelines is limited in many places within the hospital, extensive training efforts are necessary. It is particularly important to invite the Swedish Medical Products Agency to clarify what rules apply within its field. Patient safety. Patient safety must be central. Systematic review of the scientific foundation, risk analysis and systematic follow-up should be regularly done when new methods are introduced in medical care. The staff for quality and patient safety should be given expanded and clearer responsibility for issues of patient safety being put first and for ensuring that the hospital follows and adapts to the research in the patient safety field. There have been indications that the patient safety culture at the department of thoracic surgery has not been satisfactory. Improvement efforts are under way. Hospital management should carefully monitor this work. 27 Clinical decision-making. The working method of the multidisciplinary conference should be quality assured. Group thinking should be prevented, the responsibility for the decisions made needs to be clearer and considerations and decisions must be well documented. The unit manager has a responsibility for continuity in care, which is something that must be emphasised. This responsibility becomes especially important to maintain with regard to highly specialised care where the expertise is concentrated to one single person or a limited number of people. Clinical research and introduction of new untried methods. In the hospital and KI work that has begun on internal guidelines for new untried methods, particular importance should be placed on ensuring compliance to the Ethical Review Act and the regulations on clinical studies. Several of the investigation’s recommendations aim to strengthen ethics when new methods are introduced to medical care and thereby preserve the respect for the clinical research. Special ethical expertise should be tied to the introduction of new methods to medical care (the ethics committee currently at the hospital has a different focus). The room for individual employees to begin applying new untried methods without external review must be minimised. Employees. Several recommendations aim to reduce the room for such independence that can lead to inadequate patient safety. Hospital management should continue the work to counter repressive elements, not least in the patient safety work. The hospital should also address the conflicts and work environment problems that the Macchiarini case has created. 28 Our task and its implementation In February 2016, the Director of Karolinska University Hospital commissioned an investigation with the directive to answer the following questions surrounding Macchiarini and the trachea transplants he performed at the hospital: Under what circumstances and under what conditions was Paolo Macchiarini hired at the hospital and what were the circumstances surrounding the termination of his employment. What did the decision-making process and documentation look like prior to the decisions to operate? Was the choice of measures correct based on available knowledge, applicable legislation and guidelines? This pertains to both the surgical procedures and the subsequent care. What ethical assessments were made before the operations and later during the course of illness? What guidelines and other steering documents existed at the time the operations were performed and were they complied with? What roles did decision-makers at various levels in the hospital have regarding the decisions on the operations and care? What later steps were taken due to Macchiarini’s activities? Have there been other circumstances of direct relevance to a specific assessment of Macchiarini’s activities at Karolinska University Hospital? The task also included making improvement recommendations based on the facts that came forth in the investigation. The task was assigned to Kjell Asplund, Professor Emeritus in Medicine at Umeå University, Chairman of the Swedish Council on Medical Ethics (Smer) and former Director-General of the National Board of Health and Welfare. To help him, he appointed a workgroup consisting of Nils Blom, former Senior Legal Counsel at the National Board of Health and Welfare and the Public Health Agency of Sweden, Katarina Johansson, Chair of the patient organisation Network against Cancer, and Jesper Persson, Senior Physician and former Chief Medical Officer 29 at Skåne University Hospital. Pernilla Östlund, with the Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) as her ordinary place of employment, served as the investigation secretary. The focus of the investigation was on patient safety issues in a broad sense. We examined the circumstances surrounding the three patients’ trachea operations and shed light on issues concerning the patient safety culture that existed in connection with the three patients’ operations and continued care. Processes, documentation and decisions were checked against the steering documents and guidelines that applied during the period in question. To be able to learn lessons from the Macchiarini case, we strived to describe not only what happened, but also attempted to gain insight into how it could happen. There was a clear risk that our analyses and assessments would be characterised by hindsight. We therefore, to the furthest extent possible, worked based on the state of knowledge and regulations that applied at the time that various decisions were made in the Macchiarini case. A large amount of written materials were gathered during the investigation, including: the medical records of the three patients other documented considerations and decisions scientific publications local steering documents steering documents from authorities and national and international professional organisations relevant legislation correspondence the hospital’s patient safety reports and quality reports 2011-2014 the hospital’s patient safety culture measurements 2010-2013 During the investigation, more than 60 people were interviewed. Most of them had a direct connection to Macchiarini’s activities at the hospital. 30 We also interviewed representatives of authorities, labour unions, patient organisations, individuals who were especially active in the public debate surrounding Macchiarini and people who had more general information in issues concerning new untried methods in medical care. Opinions from Macchiarini were shared with the investigation through an extensive interview, e-mail correspondence and written materials that he sent to the investigation. During the investigation, four external reviewers were brought in; two made prognosis assessments of patients 1 and 2 and two others reviewed chapters 11 (Analysis and summary assessments) and 12 (Recommendations). Other investigations are addressing issues surrounding Macchiarini’s activities at KI and the accusations of misconduct in the Macchiarini team’s research. 31 32 Report Chapter 1 1. The Committee's mission and work 1.1 The mission and the mission's content The management of Karolinska University Hospital (also known as hospital) have wanted to investigate the events before, during and after the luftstrupstransplantationer performed on three patients at the hospital. Hospital Director Melvin Samsom decided 2016-02-12, together with Head doctor Professor Nina Nelson Follin at the headquarters of Quality and Patient Safety and after consultation with the Stockholm County Council, to appoint an external investigation. The contract was awarded Kjell Asplund, professor emeritus, president of the National Council on Medical Ethics (Smer) and earlier Director General of the National Board. The assignment was to investigate: Under what circumstances and conditions Paolo Macchiarini employed at the hospital and what the circumstances were surrounding his employment was terminated. How the decision making process and the documentation for the operating decisions looked. If the choice of action was correct on the basis of available knowledge, existing legislation and guidelines. This pertains to surgical interventions that subsequent care. What ethical assessments conducted for operations and later in the disease. What guidelines and other policy documents that existed at the time of implementation of operations and if these were followed. What is the role of decision-makers at various levels within the hospital have had when it comes to decisions concerning the operations and management, and the measures taken following the Macchiarinis activity. If there were other circumstances directly relevant to a specific assessment of Macchiarinis operations at the Karolinska University Hospital. Based on the facts that emerged from the investigation would formulate recommendations on improvements. 1.2 Project The investigator has appointed its own working group consisted of: Nils Blom, former general counsel at the National Board of Health and the Public Health Agency Katarina Johansson, patient representative, chairman of the Network Against Cancer  Jesper Persson, former head doctor at Skåne University Pernilla Ostlund, research assistant The group has been through Stockholm County Council had access to administrative resources equivalent 20 percent of full time. Stockholm County Council has funded a study and the set premises Working disposal. 1.3 The inquiry's main focus The focus was on patient safety issues in a broad sense. The study was based on a examination of the circumstances surrounding the three patients who underwent luftstrupstransplantationer, but have also highlighted questions about the patient safety culture prevailing in connection with the three patients' surgeries and continuing care. Processes, documentation and decisions have been checked against the policy documents and guidelines in force during the period in question. 1.4 Limitations The assignment is limited to Macchiarinis luftstrupstransplantationer at Karolinska University Hospital. This means that the following issues have been outside of our mission: Macchiarinis operations at the hospital regarding other than the three luftstrupsoperationerna Macchiarinis operations at other hospitals questions about Macchiarinis employment at Karolinska Institutet (KI) issues relating to possible misconduct in research issues relating to the KI management's handling of Macchiarinifallet. These issues mentioned in our report if they were of direct relevance to the assessment of Macchiarinis transplant operations at the Karolinska University Hospital, but we have not had the ambition to analyze them more closely. 1.5 Relation to other investigations It has added several other investigations for the direct or indirect view Macchiarinifallet. The investigation closest to this, "the Karolinska Institute and Macchiarini case An external audit in 2016 ", led by Sten Heckscher with the task of investigating certain matters concerning Macchiarini from a CI perspective. Inquiry appointed by the Senate, KI University Board. We have had regular contact with Heckscherutredningen to clarify our boundaries and avoid duplication of efforts and cooperate in cases where it has been possible. We have had, among other some joint interviews and shared some written material that has been of interest to Both investigations. Other investigations: - Investigation of Research Misconduct. The Government set this inquiry in October 2015. It will, inter alia, examine the need for a new organization for independent investigations research misconduct. It will be ready on 25 November 2016. Investigators are Margareta Fahlgren, Professor of Comparative Literature. - Review of the regulatory frameworks for research ethics and the interface between clinical research and health and medical care. This investigation was launched by the government in June 2016, Gudmund Toijer as investigators. The inquiry will report to the Education Ministry by 31 August 2017. - Ethical aspects of the use of untried new methods of care. The project has been initiated by the National Council on Medical Ethics (Smer) and is about the ethical problems that may arise in the boundary between health care and research, and the need clearer regulations or guidelines. Smers report is expected to be completed in autumn, 2016. - Clinical guidelines for the use of unproven therapies to seriously ill patients. Collaborative projects between the Swedish Medical Society and the Royal Academy of Science. Published June 16, 2016. - Reviewing the audit. Universitetskanslersämbetet has requested the investigation of KI so once it is completed, as well as a statement from CI for the action to be taken. - Misconduct Investigations at KI and the Central Ethical Review Board. KI has re- opened the previous fraud case led by the four doctors report in 2014. In the investigation garnering KI opinion of the expert group on research misconduct at the Central Ethical Review Board (CEPN). Notification was received at CEPN the end of June 2016. For the CEPN submitted three additional cases of Macchiarinianknytning: (a) the animal experimental study of luftstrupstransplantation published by Macchiarinigruppen in Nature Communications 2014 application filed by the four doctors who reported Macchiarini 2014 (b) experimental Article of synthetic windpipe carcass published by Macchiarinigruppen in Biomaterials 2014 Anonymous notifier, (c) notification of unauthorized use of research data directed against one of the four notifying the doctors, the complaint filed by Macchiarinis German collaborator. opinions on cases (a) and (b) expected to be completed in early autumn 2016. Issue (c) has recently received to CEPN. - Legal Council at the National Board. Prosecution Office in Stockholm submitted in January 2016 an request for an opinion from the Council. In late July or August 2016 the case was still Unfinished. - KI's examination of Paolo Macchiarinis resume. The review confirms that CV includes several inaccuracies. - Preliminary investigation. Both the Agency for Health Care (IVO) which MPA has Police notified Macchiarinis clinical operations at the Karolinska University Hospital. a preliminary investigation progress of gross negligence manslaughter and grievous bodily harm on the occasion of the operations at the Karolinska University Hospital. - Local investigations. The attention surrounding Macchiarinis operations at KI and the hospital has meant that in many parts of the country begun to review its regulations on the use of untried new methods of care. 1.6 Inquiry operation 1.6.1 Method The methodology is based on the fundamental issues that are described in SKL's handbook event analysis, but because of the complexity of the case, the methodology has been modified (1). Compared conventional case analysis, the working group more thoroughly searched for different types of written documentation and conducted far more interviews. This is to illustrate different perspective on the circumstances surrounding Macchiarinis operations at the hospital. 1.6.2 Legal requirements After consulting the General Counsel at the Stockholm County Council of the Inquiry legal conditions. The members have signed confidentiality undertakings, which collected In the medical director Nina Nelson Follin, Karolinska University Hospital. During secrecy has the Working Group had access to written records and other patient-related information as well as to Patient information obtained in interviews. The working group has worked independently from the principal. The group's report has been public document if and when it is received by the client. 1.6.3 Written material A large amount of written material gathered during the investigation, including: - Three patients' medical records - Other documented considerations and decisions - Scientific publications where the patients presented - Local policy documents - Policy documents from government agencies - Relevant legislation - Professional documents, national and international - Correspondence Macchiarinifallet - Protocols and memos In email correspondence, often written in haste, sometimes occur typo. We have consistently in report chosen to quote without making any corrections. 1.6.4 Interviews Early in the investigation, made an introductory round of interviews with a small number of key people to identify the persons who should be interviewed. Interviews with the key People have been implemented as personal meetings, primarily with the entire team present, secondly with the investigator and research assistant. Interviews with other individuals have been carried out either by personal meetings or telephone conferences. In all the interviews have at least two members of the group were present. Supplementary questions were asked in phone interviews or through mail. The following individuals and entities have benefited from the interviews: directly affected Paolo Macchiarini responsible for Macchiarinis employment at the hospital participants in decisions before surgery medoperatörer responsible for the patients' post-operative care and follow-up the doctor who reported Macchiarinis operations at the hospital to KI's Vice-Chancellor and Principal Ethics Committee  operations managers at the ear, nose, neck and thorax clinics chief physician at the time of the operations and then hospital development and innovation director hospital directors at the time of the operations and then responsible for the hospital's external communications related to operations indirect concerned Local President of the Medical Association Medicines Agency National Board The study also interviewed external experts and opinion leaders. We have also had meetings with representatives of the following patient groups: - Mouth & Throat Cancer Association - Cancer Society pALeMA - Lung Association ASSISTANCE - National Association Heart-Lung The commission has a total interviewed or met with 62 individuals (Appendix 1). 1.6.5 Macchiarinis viewpoints Comments by Paolo Macchiarini have come to the investigation part through a long interview, followed by email correspondence for some clarifications. Macchiarini also have to put the investigation material in the form of particular description of events, transplantation protocol, scientific literature and its email correspondence especially with employees and managers at Karolinska University Hospital and Karolinska Institutet. 27 1.6.6 review We have hired two external reviewers of chapters 11 and 12, Professor Ingemar Petersson, Head of Research at Skåne University healthcare (SUS) and Professor Jack Lysholm, head of the Register Centre Norr, Umeå. Two external experts, Lars Ek, chief of pulmonary medicine at Skåne University Hospital and associate professor Jan Nyman, Chief of Oncology at Sahlgrenska Hospital in Gothenburg, have contributed their views on the two first-transplanted patients' diagnosis and forecast. Some descriptive texts, however, no patient data, has the support of the relevant authorities. Reference 1. Manual. Risk analysis and event analysis. Third revised edition: Swedish municipalities and county; 2015. 28 Report Chapter 2 2. Medical background luftstrupstransplantationer In this chapter we provide a brief description of the trachea and the diseases where luftstrupstransplantationer could be considered (2.1). In discussing the Macchiarinis transplants Karolinska University Hospital is a central issue was whether there was enough with scientific data to start with transplants of synthetic trachea of humans. We also discuss briefly the scientific literature on luftstrupstransplantationer (2.2) and provides an overview of the growth-stimulating drugs used in connection with transplants (2.3). 2.1 The trachea and its diseases 2.1.1 The trachea The trachea, the trachea, is a 10-16 cm long pipe connecting the larynx with the lungs. The diameter is in an adult about 2.5 centimeters. It is a seemingly simple hollow organs for transport of air to and from the lungs. But unlike many other agencies where transplant may be appropriate, the trachea is exposed constantly to the environment, which means a high risk of infection. The trachea is 15-20 horseshoe-shaped elastic cartilage rings (tracheal cartilages) enclosing tube and keeps it open (Figure 2.1). It is located in a vascular area behind the aortic arch and in front of the esophagus and divides into the two main bronchi (airways; primary bronchi), to a each lung. [figure 2.1 omitted] In addition to the cartilage found in luftstrupsväggen muscle cells (which contract when coughing), connective tissue, blood vessels which stands for the nutrition and nerve fibers. The inner surface is lined with a mucous membrane with epithelial cells. Some of the epithelial cells produce mucus to keep the trachea moist and protect it, other cells have cilia that transport mucus and particles from the lungs up the pharynx. 29 2.1.2 trachea diseases Clearly the most common diseases affecting the trachea are infections and inflammations. In other diseases are the trachea relatively uncommon. The trachea displaceable tumors, both benign and malignant. Cancer that starts from the trachea are rare - in 2014 fostered fewer than ten patients in Sweden with this diagnosis. After injury to the trachea, for example, in connection with traffic accidents or after radiation therapy, scarring with narrowing occur. There are rare congenital luftstrupssjukdomar, and malformation of one or more cartilage rings constricted as a result, and as pronounced weakening of the cartilage to trachea danger of collapse (tracheomalacia). 2.1.3 Treatment of luftstrupsförträngningar At strictures, whatever the cause, which is so severe that they cause difficulty breathing, it can constricted section is removed and the ends are sewn together. One condition is that the length of the part of the trachea are removed less than six centimeters. Otherwise stenting is the most common measure - a tube inserted into the trachea and hold it open. The tube may be of synthetic material (absorbable or non-absorbable) or metal. There are also opportunities to open surgery, laser surgery, other surgical techniques or radiotherapy remove at least part of a tumor or other obstruction. In rare cases, a longer part of the trachea (or all) have to be removed because of a tumor. It is these situations transplantation of the trachea has been updated. 2.2 Luftstrupstransplantationer Both in literature as in everyday language, the concept of transplantation come to used both in the trachea replacement of organs from human donors (major transplant) and when replacing the trachea with synthetic material. Although compensation with synthetic materials strictly interpreted does not involve the transplantation, we have in this report chosen to use the concept of transplant also in the trachea replaced by a synthetic body, this not complicate terminology (in English sometimes used the concept of replacement that better describes what it concerns). Transplantation of the trachea has long been discussed as a treatment option if one is forced remove the trachea due to tumor or severe injury or if the cartilage is so weakened that the trachea risk of falling apart. The two main lines of research on luftstrupstransplantation has moved (a) the trachea or other structures taken from deceased persons (nekrotrakea) and (B) the trachea of synthetic materials. Transplantation of trachea deceased can be implemented as "conventional" transplant. But you can also, like the synthetic trachea, using as a framework nekrotrakea after living cells removed. In experimental trials, the body sometimes inserted without preparation. But more common is that they tried to dress it with cells, with the aim that these should develop into normal airway cells (epithelial cells) and cartilage cells. Ideally, the body should be biocompatible, that is not cause rejection reactions. The should be non-toxic and does not contain carcinogens. It must also meet certain mechanical requirements to be of sufficient strength and not be degraded, while it shall be flexible. For a functional trachea is also required to epithelial cells grow firmly and that there is adequate vascular supply. To provide an overview of the research situation that prevailed when luftstrupstransplantationerna was conducted at the Karolinska University Hospital, we summarize here the results of a selection of in vivo studies in experimental animals (studies on whole animals) and people published until 2012, in particular the studies reported longer periods of follow-up. Although we had the ambition to provide a picture of the overall state of knowledge, we make no claim to the case of a systematic literature review. Any irregularities in Macchiarinigruppens research has previously been investigated by KI and 30 by the expert, Bengt Gerdin, KI engaged. We have stated in the text which studies will from Macchiarinigruppen but has not taken a position on whether they are correct or not, because misconduct issue is now being investigated again, this time by the expert group for the misconduct at the Central Ethics Committee. 2.2.1 Nekrotrakea (trachea from a deceased) The three patients who luftstrupstransplanterades at Karolinska University Hospital surgery in 2011-2012 (patient 3 underwent a second transplant in 2013). We have therefore chosen to share up this summary overview of what was known at the time of transplantation (even 2012) and what is to come then. Preclinical studies until 2012. A significant number of experimental studies have been conducted at laboratories around the world with a view to developing a technology that would be adapted for transplantation of donor trachea from a deceased person, called nekrotrakea. Several of these have been published by Macchiarini and his associates. Trachea from donor animals are usually prepared by removing living cells to eliminate the risk of rejection. The results have been mixed. Macchiarinigruppen has reported that pigs transplanted with nekrotrakea prepared as before transplantation exposed to the epithelial cells on the inside and cartilage cells on the outside ( "bio-engineering"), survived in up to 60 days of observation without the emergence of any rejection reaction [3,4]. It is,probably these studies Macchiarini intended when he at information for patients and the The recent debate said that there existed own experimental studies on large animals. In these studies reported Macchiarinigruppen while that in other experimental groups (Pigs) with more limited transplantation preparatory efforts had to kill the animal prematurely because of severe complications. Although other research groups had reported before 2011 problems in experimental transplantation of nekrotrakea in pigs (for example). There was no single report that after transplantation with nekrotrakea in pigs could observe basically normal airway epithelium eight weeks after surgery. In a more complicated animal model (human nasal mucosa was transferred to the trachea in rats transplanted to mice with reduced immune function) were one outgrowth of the human airway epithelium.. Without vascular supply breaks down the cartilage tissue and a variety of methods to stimulate angiogenesis had been launched before 2011 [7-9]. While other organs and tissues in the trachea had been used in experimental luftstrupstransplantationer, for example tissue from the aorta, small intestines, peritoneum and pericardium, with very limited or no long-term success. Clinical studies until 2012. The first transplantation of the trachea in humans was performed in 1979. It moved as if a "conventional" transplantation (allo- transplantation) with a trachea from a deceased person. Allo-transplantation of the trachea involves two major problems. The first is common for allo transplants in general - to prevent rejection of the organ requires lifelong immunosuppressive therapy, but even this is no guarantee that the transplanted trachea rejection. The second problem concerns the vascular supply. They have tried different techniques, example, to wrap the transplanted trachea of a piece of it abundantly vascularized mesentery (Omentum). It was also the technology Macchiarini used to try to create vascular supply to the synthetic luftstruparna. To overcome problems of immune rejection and the need for immunosuppressive drugs (With the risk of side effects) has been working to modify the trachea from a deceased ( "Bio-engineering"). In 2004 transplanted Macchiarini and his colleagues a 1.5 x 1.5 cm large tunntarmsbit porcine, which prepared with bioengineeringteknik, to luftstrupsväggen in a patient. It reported early outgrowth of airway epithelium and good vascular supply after six weeks. 31 The first transplantation in humans with nekrotrakea prepared by bio-engineeeringteknik conducted by Macchiarini and his team in Barcelona in 2008. The patient was a 30- year-old woman with congenital weakening of the cartilage in the windpipe (trakeomalaci), something that made the trachea in danger of falling apart. The transplanted trachea had pretreated for six weeks to eliminate the living cells that could cause rejection. It had also made a seeding of cartilage cells and cells from the nasal mucosa. Macchiarini and his colleagues described the surgery as successful in the short term. It reported early growth of airway epithelium (within one month) in the transplanted trachea. In 2012, reported a research team in London transplantation as a treatment nekrotrakea severe luftstrupsförträngning of a 10 year old boy. A year after the transplant was observed ingrowth of airway epithelium, and two years after the procedure stated that the boy had been functioning airways and that he did not need any medication. Macchiarini has our investigation submitted a list of nine transplants nekrotrakea which he conducted in the years 2008-2011 due to trakeomalaci (weakening of luftstrupsbrosket) fistula, cancer or congenital severe narrowing. Five patients were at life of 37-67 months after surgery. Four had died after 1-24 months. Publications after 2012. In the literature that emerged after the transplants at the Karolinska University Hospital have problems in transplantation nekrotrakea in laboratory reported [16,17]. Macchiarini and co-workers published 2014, a 5 year follow up of the patient transplanted in Barcelona in 2008. It described the progress and her condition as satisfactory, albeit not without complications In a follow-up report four years after the transplantation of nekrotrakea of the boy in London as previously described research group reported that his condition was good - he went in school. He had had to comprehensive treatment and total treatment costs during those first four years was estimated at over half a million dollars. The Belgian ear, nose and throat surgeon Delaere and his colleagues have presented a alternative surgical techniques. Their starting point was the need to secure supply vessels to the transplanted nekrotrakean by first implanting under the skin of the forearm for about four months, this is for capillaries to grow into the implant. They have reported the technology applied in eight transplants in six patients. the research team has in the scientific literature have reported long-term survival in four of the patients [8,21,22]. Delaere told us to hold on to complete a script where long-term survival also described for the remaining 2 patients. 2.2.2 Synthetic trachea At the three luftstrupstransplantationerna at Karolinska University Hospital has used three various synthetic materials. In preclinical studies, a wide range of research groups around the world have studied a variety of synthetic materials. We describe here only the study of solid or porous polymers ( "plastics"), but not studies where they used other materials, such as metals and glass. Preclinical studies until 2012. There are a number of studies of transplantation of synthetic trachea in laboratory animals (rats, mice, rabbits, dogs). In most of these studies, before transplantation sown implants with cells of different types. Several reports outgrowth of airway epithelium on the synthetic grafts have been published (for example, [2,3,24-27]). mortality after transplantation of synthetic trachea of experimental animals has varied from low (eg [25-27]) to very high (eg [28-30]). At the first luftstrupstransplantationen at Karolinska University Hospital used a material (POSS-PCU polymer; POSS stands for polyoctahedral silsesquioxanes and PCU poly (carbonate-urea) urethane) as before the operation prepared with bone marrow cells (including another contains stem cells, albeit small portion) to create the outgrowth of epithelial cells on the porous 32 polymer surfaces. POSS-PCU is usually described as a nanomaterials and since the middle of 2000s investigated as biomaterials in preclinical studies. The material had been tested before 2011 in experimental animals in sterile environments [31,32]. It has created this material including synthetic heart valves, blood and lymph vessels, stents and outer ear, without the material appears to have clinical application. The development of POSS- PCU is mostly made by researchers in London [32,33], which Macchiarini collaborated with [32,33]. Macchiarini and his research team reported in 2012 the results of laboratory studies of other polymers which examined how cells grow on these materials in vitro ("test tubes"). At the time of luftstrupstransplantationerna at Karolinska University Hospital 2011- 2012, Macchiarini and / or his associates reported no results from experiments on whole animals that have used the techniques applied in luftstrupstransplantationerna of the three patients, that is, different polymers exposed to bone marrow cells and administration of growth factors. In the total of four transplants (two in patient 3) they used three different kinds polymeric material. These materials had undergone toxicity and biokompabilitetstetser at second laboratories, but they had not tested the trachea in animal models. Clinical studies until 2012. The transplant of a synthetic windpipe conducted at the Karolinska University Hospital in June 2011 was the first of its kind in the world (patient 1). The transplant brought already when it was made considerable media attention. In November 2011, published a scientific report in the prestigious journal The Lancet. In Chapter 4 we describe in more detail for this transplant. Lancet article has been cited frequently - 196 citations at the end of July 2016 according to Web of Science. In review articles, it has usually been regarded as a breakthrough study in the field of transplantation by synthetic means (e.g. ). It has, however, in the scientific literature also been critical voices as described Macchiarinigruppens methodological approach as unrealistic. The clinical course of patient 2 does not appear to have been reported in the scientific literature. Patient 3 has been mentioned cards (without the clinical course reported) in a work on cell survival 2013. At a cursory literature search, we have not been able to find that other researchers than Macchiarinigruppen published clinical results from the transplantation of synthetic trachea in patients (July 2016). Publications and other experiences after 2012. On the occasion of news interview with Macchiarini in May 2016 wrote the four doctors who notified him of research misconduct a memo in which they commented it Macchiarini said in the interview. This memorandum described the doctors to Macchiarinigruppen began animal experiments with the methodology used in the clinical transplants only after the third patient received its first synthetic windpipe. In Macchiarinigruppens first attempt should be 5-7 rats have been transplanted, half of whom died within two days and the other half survived "several weeks" with increasing luftstrupsförträngningar. These results were not published. Then began a series of transplants of synthetic trachea of 8 rats. results have been published in three articles 2013-2014 [35,38,39]. Two different synthetic materials tested, previously used in transplantation of patient 2 and 3. The synthetic luftstruparna had been sown with mesenchymal stem cells. The research team reported that after a 30-day observation period epithelium observed on the synthetic body and nascent vessel formation. There was no evidence of inflammation or necrosis. The rats were said to feel good with hefty weight gain during follow-up. Two of these articles [35.38] included in the material previously investigated for research misconduct and is now being investigated again. The Belgian ENT Professor Pierre Delaere (which itself uses nekrotrakea, see above) have review articles 2014 and 2016 in very powerful terms renounced Macchiarinigruppens strategies [20,40]. He says that there is any scientific basis to stem cells could give rise to respiratory tissue when synthetic trachea used. 33 As ending to his last article he describes Macchiarinigruppens approach hypothetical and scientifically unfounded. The references he gives for this conclusion are limited: own previous article and an article in the scientific journal Nature about the charges against Macchiarini of research fraud. Macchiarini has submitted to the inquiry a list of the transplants with synthetic trachea he performed in addition to the Karolinska University Hospital. The case of five patients operated in the 2012-2014 period. Four of them were transplanted in Krasnodar (Russia) and a in Preoria (USA). Of the five patients had two omtransplanterats, which means a total seven transplants with synthetic trachea performed elsewhere than in Stockholm. Of the Five patients were at least still alive (July 2016); the latter had the transplant removed after seven months. For one of the patients lacked information about survival. One of the deaths were caused by car accident. In our interview with Professor Martin Birchall, London, declared him to be inspired by Macchiarinis report on patient 1, performed a transplant of synthetic trachea 2011 or 2012. The patient died shortly after the transplant. This patient has not been reported in thescientific literature. In the recent public debate, the whole idea of transplantation of synthetic trachea challenged, often ridiculed. It might then be worth recalling that synthetic materials today in fairly large scale in health care, and then you work - in sterile environments. In non- sterile environments, the problems are far greater. The trachea has been shown in experimental studies to be a body means very special mechanical and biological challenges. Macchiarini contacted in March 2013 operations manager at the Department of Thoracic Surgery of plans for a Clinical trials of synthetic trachea in collaboration with Harvard Bioscience. Since His transplants as had been questioned, was not completed this idea. But in several countries an ongoing preclinical development of synthetic trachea with a view to transplantation in humans. Projects have large research grants from countries including the EU. Clinical trials are planned but there is contradictory information about getting started or not. 2.3 Drugs In connection with transplants used three drugs in a way that challenged: NeoRecoromon (erythropoietin) NEUPOGEN (G-CSF, filgrastim, granulocyte colony stimulating factor) TGF-β3 (transforming growth factor) All three substances used in the preparation of the benmärgscellsbesådda synthetic luftstruparna facing operations. NeoRecormon and Neupogen was also given as injections into the first two transplant patients, possibly even to the third, for two weeks after the operations. According to patient records and scientific articles published Macchiarinigruppen used these substances as regenerative boosting therapy, the aim was therefore to stimulate cell formation luftstruparnas on the synthetic surface. NeoRecormon is a drug that is approved in Sweden. It stimulates the formation of red blood cells and its licensed indication the treatment of various forms of anemia [45,46]. The dose the first two transplant patients had exceeded the recommended initial dose more than 10 times. At the time of transplantation at the Karolinska University Hospital was it is well documented that drug in recommended doses increases the risk of clot formation with an average of 60-70 percent [47,48]. According to the company, the effects and side effects of very high doses of NeoRecormon is not studied. Neupogen is a drug that is approved to stimulate the formation of white blood cells in patients with a deficiency of white blood cells, such as during cancer chemotherapy. It can also mobilize peripheral stem cells in organ donors. The dose of both first transplanted patients were in line with the recommended dose. 34 The interaction (interaction) between NeoRecormon and Neupogen not studied. According to the treatment protocol used TGF-β3 only during the preparation of the synthetic luftstruparna; it was never given directly to patients. The substance is not approved for use in humans. The manufacturer, the British company Bio-Techne, has stated that the only is intended for research and not for use in humans or animals. The substance is only partly purified, so one can not rule out that it contains, for example, viral components with the contingency effects if used for human purposes. The company has stated that it used for human use as it is against their license agreements with users of the substance. The pharmaceutical company Roche, the company that manufactures NeoRecormon, and Amgen, manufacturers of Neupogen, have both stated that the use as regenerative therapy is boosting foreign for them and that they take away from this unproven use [45,50]. They do not have known to some studies where drugs used for this purpose. 2.4 Summary When Macchiarini recruited and when transplants were performed at the Karolinska University Hospital (2010-2013) was a small number of preclinical studies that showed encouraging result of transplantation of nekrotrakea. While it was apparent that several problems remain to solve before in the laboratory had fully developed a successful and safe method. MAN had also reported favorable results in the short term from two transplants with nekrotrakea in patients; Macchiarini and his associates accounted for one of these reports. Regarding the transplantation of synthetic trachea has been greatly among experts divergent opinion, if this is a viable option or not. Several reports outgrowth the airway epithelium of synthetic grafts have been published. The survival of laboratory animals varied considerably between studies. When luftstrupstransplantationerna at Karolinska University Hospital was conducted, there were no results from experiments on whole animals that have used the specific techniques applied for transplants at Karolinska University Hospital. When these luftstrupstransplantationer conducted Macchiarinigruppen had not yet started Animal studies with the transplant concepts that have been used on patients (this except for the second transplantation in patient 3). The therapy with growth-promoting drugs used as the boosting regenerative therapy was largely experimental. References 1. Socialstyrelsen. Statistikdatabas för diagnoser i sluten vård. http://www.socialstyrelsen.se/statistik/statistikdatabas/diagnoserislutenvard. 2014. 2. Fishman JM, Wiles K, Lowdell MW, De Coppi P, Elliott MJ, Atala A, et al. Airway tissue engineering: an update. Expert Opin Biol Ther 2014;14:1477-91. 3. Go T, Jungebluth P, Baiguero S, Asnaghi A, Martorell J, Ostertag H, et al. Both epithelial cells and mesenchymal stem cell-derived chondrocytes contribute to the survival of tissue-engineered airway transplants in pigs. J Thorac Cardiovasc Surg 2010;139:437-43. 4. Jungebluth P, Go T, Asnaghi A, Bellini S, Martorell J, Calore C, et al. Structural and morphologic evaluation of a novel detergent-enzymatic tissue-engineered tracheal tubular matrix. J Thorac Cardiovasc Surg 2009;138:586-93; discussion 592-3. 5. Remlinger NT, Czajka CA, Juhas ME, Vorp DA, Stolz DB, Badylak SF, et al. Hydrated xenogeneic decellularized tracheal matrix as a scaffold for tracheal reconstruction. Biomaterials 2010;31:3520-6. 6. Dupuit F, Gaillard D, Hinnrasky J, Mongodin E, de Bentzmann S, Copreni E, et al. Differentiated and functional human airway epithelium regeneration in tracheal xenografts. Am J Physiol Lung Cell Mol Physiol 2000;278:L165-76. 7. Chue WL, Campbell GR, Caplice N, Muhammed A, Berry CL, Thomas AC, et al. Dog peritoneal and pleural cavities as bioreactors to grow autologous vascular grafts. J Vasc Surg 2004;39:859-67. 35 8. Delaere P, Vranckx J, Verleden G, De Leyn P, Van Raemdonck D, Leuven Tracheal Transplant G. Tracheal allotransplantation after withdrawal of immunosuppressive therapy. N Engl J Med 2010;362:138-45. 9. Walles T, Giere B, Hofmann M, Schanz J, Hofmann F, Mertsching H, et al. Experimental generation of a tissue-engineered functional and vascularized trachea. J Thorac Cardiovasc Surg 2004;128:900-6. 10. Rose KG, Sesterhenn K, Wustrow F. Tracheal allotransplantation in man. Lancet 1979;1:433. 11. Klepetko W, Marta GM, Wisser W, Melis E, Kocher A, Seebacher G, et al. Heterotopic tracheal transplantation with omentum wrapping in the abdominal position preserves functional and structural integrity of a human tracheal allograft. J Thorac Cardiovasc Surg 2004;127:862-7. 12. Macchiarini P, Walles T, Biancosino C, Mertsching H. First human transplantation of a bioengineered airway tissue. J Thorac Cardiovasc Surg 2004;128:638-41. 13. Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA, et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008;372:2023-30. 14. Elliott MJ, De Coppi P, Speggiorin S, Roebuck D, Butler CR, Samuel E, et al. Stem- cellbased, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 2012;380:994-1000. 15. Macchiarini P. Outcomes of surgeries with biological tracheal scaffolds 2008-2011. Material inlämnat till utredningen. 16. Hung SH, Su CH, Lin SE, Tseng H. Preliminary experiences in trachea scaffold tissue engineering with segmental organ decellularization. Laryngoscope 2016 doi: 10.1002/lary.25932. [Epub ahead of print]. 17. Wurtz A, Hysi I, Kipnis E, Copin MC. Recent Advances in Circumferential Tracheal Replacement and Transplantation. Am J Transplant 2016;16:1334-5. 18. Gonfiotti A, Jaus MO, Barale D, Baiguera S, Comin C, Lavorini F, et al. The first tissue-engineered airway transplantation: 5-year follow-up results. Lancet 2014;383:238 44. 19. Hamilton NJ, Kanani M, Roebuck DJ, Hewitt RJ, Cetto R, Culme-Seymour EJ, et al. Tissue- Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study. Am J Transplant 2015;15:2750-7. 20. Delaere P, Van Raemdonck D. Tracheal replacement. J Thorac Dis 2016;8:S186-96. 21. Delaere PR, Vranckx JJ, Den Hondt M, Leuven Tracheal Transplant G. Tracheal allograft after withdrawal of immunosuppressive therapy. N Engl J Med 2014;370:1568- 70. 22. Delaere PR, Vranckx JJ, Meulemans J, Vander Poorten V, Segers K, Van Raemdonck D, et al. Learning curve in tracheal allotransplantation. Am J Transplant 2012;12:2538 45. 23. Mejl från professor Pierre Delaere till utredningen 2016-06-14. 24. Chopra DP, Kern RC, Mathieu PA, Jacobs JR. Successful in vitro growth of human respiratory epithelium on a tracheal prosthesis. Laryngoscope 1992;102:528-31. 25. Nakamura T, Sato T, Araki M, Ichihara S, Nakada A, Yoshitani M, et al. In situ tissue engineering for tracheal reconstruction using a luminar remodeling type of artificial trachea. J Thorac Cardiovasc Surg 2009;138:811-9. 26. Nomoto Y, Suzuki T, Tada Y, Kobayashi K, Miyake M, Hazama A, et al. Tissue engineering for regeneration of the tracheal epithelium. Ann Otol Rhinol Laryngol 2006;115:501-6. 27. Yamashita M, Kanemaru S, Hirano S, Magrufov A, Tamaki H, Tamura Y, et al. Tracheal regeneration after partial resection: a tissue engineering approach. Laryngoscope 2007;117:497-502. 28. Grimmer JF, Gunnlaugsson CB, Alsberg E, Murphy HS, Kong HJ, Mooney DJ, et al. Tracheal reconstruction using tissue-engineered cartilage. Arch Otolaryngol Head Neck Surg 2004;130:1191-6. 36 29. Kojima K, Bonassar LJ, Roy AK, Vacanti CA, Cortiella J. Autologous tissue- engineered trachea with sheep nasal chondrocytes. J Thorac Cardiovasc Surg 2002;123:1177-84. 30. Sekine T, Nakamura T, Ueda H, Matsumoto K, Yamamoto Y, Takimoto Y, et al. Replacement of the tracheobronchial bifurcation by a newly developed Y-shaped artificial trachea. ASAIO J 1999;45:131-4. 31. Kannan RY, Salacinski HJ, Ghanavi JE, Narula A, Odlyha M, Peirovi H, et al. Silsesquioxane nanocomposites as tissue implants. Plast Reconstr Surg 2007;119:1653-62. 32. Seifalian AM, Salacinski HJ, Tiwari A, Edwards A, Bowald S, Hamilton G. In vivo biostability of a poly(carbonate-urea)urethane graft. Biomaterials 2003;24:2549-57. 33. Kannan RY, Salacinski HJ, Butler PE, Seifalian AM. Polyhedral oligomeric silsesquioxane nanocomposites: the next generation material for biomedical applications. Acc Chem Res 2005;38:879-84. 34. Gustafsson Y, Haag J, Jungebluth P, Lundin V, Lim ML, Baiguera S, et al. Viability and proliferation of rat MSCs on adhesion protein-modified PET and PU scaffolds. Biomaterials 2012;33:8094-103. 35. 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;34:4057-67. 36. SVT Nyheter. Macchiarini fortsätter hävda sin oskuld. 2016-05-04. http://www.svt.se/nyheter/inrikes/macchiarini-fortsatter-havda-sin-oskuld. 37. PM Referenser och kommentarer till “Transcription of the Interview with Paolo Macchiarini (unbold text) in the Swedish News Program Aktuellt (bold text) on May 4, 2016.”. 38. 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;35:5307-15. 39. Jungebluth P, Haag JC, Sjoqvist S, Gustafsson Y, Beltran Rodriguez A, Del Gaudio C, et al. Tracheal tissue engineering in rats. Nat Protoc 2014;9:2164-79. 40. Delaere PR, Van Raemdonck D. The trachea: the first tissue-engineered organ? J Thorac Cardiovasc Surg 2014;147:1128-32. 41. Cyranoski D. Investigations launched into artificial tracheas. Nature 2014;516:16-7. 42. Mejlsvar från Macchiarini till utredningen 2016-08-01. 43. Mejl från Macchiarini till verksamhetschefen på thoraxkliniken, Karolinska Universitetssjukhuset. 2013-03-17. 44. European Commission CORDIS. TETRA. Autologous Stem Cell Seeded Tissue Engineered Trachea. http://cordis.europa.eu/project/rcn/198788_en.html. 45. Mejl från Monica Bergius, Roche, 2014-09-19 till anonym mottagare, Karolinska Institutet. 46. FASS. NeoRecormon. http://www.fass.se/LIF/product?9&userType=0&nplId=19980402000045&docType=6 47. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008;299:914-24. 48. Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98:708-14. 49. FASS. Neupogen. http://www.fass.se/LIF/product?13&userType=0&nplId=19910315000023&docType=6 50. Mejl från Ali Ashraf 2014-09-10 och Gaston Friedmann 2014-09-25 (båda vid Bio- Techne) till anonym mottagare, Karolinska Institutet. 37 Report Chapter 3 3. The recruitment of Macchiarini and his operations at the hospital 3.1 Strategic considerations Of the written material we had available and of our interviews shows that the employment of Macchiarini at Karolinska Institutet and at the hospital in 2010 corresponded more need of a strategic nature. Translational and clinical research. KI already had strong pre-clinical research in the field regenerative medicine. The bridge over the clinical applications was fragile and needed to be strengthened. National Medical Care. National Medical Care Committee decides which sites should be the National Medical Care. Such care may take the maximum of two hospitals in the country. In 2005, Karolinska University Hospital submitted an application to perform heart transplants National Medical Care, but the Board had decided to give the mandate to the University Hospital in Lund (later Skåne University) and Sahlgrenska University Hospital. Karolinska University Hospital received in February 2010, no to reapply for heart transplants. National Medical Care Board demanded among other things that one could do combined heart and lung transplant; lung surgery was not sufficiently developed at the hospital. Hospital was ordered by the National Board of Health to phase out its heart transplantation [2,3]. Many of KI and the council perceived to National Medical Care Board's decision was contrary to ambitions that the hospital would be leading the country in highly specialized care. Hälsooch Medical Care at the Stockholm County Council deposed because 60 million to support efforts to get more National Medical Care is located at Karolinska University Hospital. Within Stockholm County Council was formed in 2011, a steering committee for the National Medical Care. An investment in advanced airway surgery would be well in line with these efforts. High-profile operations in ENT. KI Department CLINTEC (Department of Clinical Science, Intervention and Technology) encompasses a range of clinical entities, including ear, nose and neck sick diseases (ENT). ENT unit at KI, as well as management of the ENT clinic at the hospital, strove to create a more high-profile business by establishing a clinical and translational center for luftstrupssjukdomar with strong international position. Research policy trends. When Macchiarini recruited (and later) were strong research policy signals to recruit internationally prominent - "excellent" - researchers. Moreover, there was the 2008 research bill five billion earmarked for investment in strategic research areas. Within the framework of this venture was awarded the KI 30 million per year for five years (2010-2014) for stem cell research, some of which was used to recruit Macchiarini. In it last year's public debate, including Nobel laureate Arvid Carlsson and Professor Agnes Wold highlighted the research policy initiatives as an underlying cause To Macchiarinifallet developed as it did. 3.2 Recruitment of Macchiarini The initial contacts. The hiring process KI described in detail in Rock Heckschers investigation of KI's management Macchiarinifallet. KI tied the first contacts with Paolo Macchiarini, while the hospital came in slightly later in the hiring process. KI's principal was present at an EU symposium in Gothenburg, where Macchiarini was one of the invited speakers. Macchiarini followed up the contact which was established with an interest request by mail to the rector's scientific secretary. The first contact with the hospital appears to have been taken in December 2009, when the hospital RD & E director at the initiative of KI's headmaster invited to a meeting on Macchiarinirekryteringen. By e-mail correspondence shows that RD & E director was hesitant. He found that Macchiarini 38 gave a scattered and roving impressions with activities in many places at the same time. Macchiarini also met in March 2010, operations manager at the Gastro Centre (then a possible clinical placement for Macchiarini). For the virtues Macchiarini was judged to have heard that he had a large international network. During the recruitment process, he launched the idea of a virtual European Airway Institute, led by him and with one of the nodes in Stockholm. This Centre of Excellence described in section 3.4. KI was contacted by a physician at the ENT clinic via email. It posed the question of the there was interest in hiring Macchiarini at the clinic and be referenced to Macchiarini performed the first transplant in the world that used a stem cell-based technology trachea from a deceased person. Macchiarini understood at this time, generally as a rising international star. The article published in the Lancet in 2008, where he and his colleagues described the first transplant of stem cell prepared trachea from a deceased person, had attracted much attention. His international reputation is illustrated by him (after he was hired in Stockholm) on an American website was listed as one of the world's 20 most innovative living Surgeons. Time Magazine placed 2012 Macchiarinis luftstrupstransplantationer on his top-10 list of current medical breakthrough. Macchiarini is a thoracic surgeon. After a request from an Italian newspaper (Corriere della Sera) made subject representative in thoracic surgery a survey among key people in the hospital and KI. None of them knew Macchiarini. In June 2010, a letter was sent by 14 signatories to KI's recruitment committee. Initiator was the head of CLINTEC. Most of the signatories came from the academic side but among the signatories was also the former operations chief and the incoming operations manager at the ENT clinic. Although Macchiarini was a thoracic surgeon was no thoracic surgeon among the signatories. The letter motivated to why Macchiarini should be employed at KI and the hospital. The strategic importance of this recruitment was highlighted. Macchiarini was highlighted as a "world leader" and "the absolute leading researcher in regenerative airway transplant." According to the letter was expected to be up and running with a working business for regenerative airway transplants within three months after the Macchiarini employed at the hospital. They also foresaw that the regenerative research could spread to other nearby areas transplant, as a lung transplant. KI's recruitment committee felt it was not needed any peer review before they took the decision to hire Macchiarini part-time. Of our interviews shows that the enthusiasm for hiring Macchiarini was clearly greater in KI than on the hospital side. The former hospital director said in our interview with him His strategy to develop the hospital did not include solicitations of solitary international "Stars". The hospital's Research & Education Director was thoughtful because of Macchiarinis split operations at many locations. Long before the new operations manager was appointed at the ENT Clinic In September 2010, he was subjected to great pressure to accept Macchiarini could be employed as physician at the clinic. At the same time it should be said that both the outgoing to the incoming operations manager saw great development opportunities for the clinic in Macchiarinis clinical operations. Neither the outgoing or the incoming business manager undertook any job interview, something that Macchiarini verified in conversation with us. Macchiarini himself claims to have been surprised that it did not require a Certificate of Good Standing in Sweden, as he was used to from other countries. References. Macchiarini had collaborated with Martin Birchall, professor of ear, nose and throat diseases in Bristol and London, on the development of luftstrupstransplantationer. At a personal visit to Birchall in London 2010, the then operations manager at ENT Clinic and one of his colleagues at the clinic credentials on Macchiarini; he was not employee in London but had an unpaid honorary position at the University College of London. As Birchall told us he stressed Macchiarini’s technical skill 39 as a surgeon. At the same time, he considered Macchiarini be a difficult person to work with, but it should be possible to handle him. The head of the ENT clinic traveled in 2010, along with the head of CLINTEC and Head of Unit at KI's ENT unit, to Florence to investigate whether there was a basis for to establish a European Airway Centre as proposed Macchiarini presented. they state that they not reached by any negative signals about Macchiarini. In 2010 visited Macchiarini Stockholm and established contact with a number of researchers in regenerative medicine and clinical colleagues at the hospital. He performed “guest surgery" at the ENT Clinic and gave the impression to be a technically dazzling surgeon. There was however torque Stockholm surgeons queried the Macchiarini had, for example for surgery orderly until an aortic arch from a deceased person; This preparation was needed, however, never used. Investigation has been the Manager of the Centre for Allergy Research, professor at KI received a compilation of e-mail correspondence and comments. In August 2010, was contacted he was president of the pulmonary researchers European organization (European Respiratory Society), an Italian. This expressed severe criticism including Macchiarinis research and his clinical review. KI professor gathered since information from three places where Macchiarini earlier worked: Florence, Barcelona (two referents) and Hanover. All agreed that Macchiarini was a technically dazzling surgeon. There was also strongly critical views on major cooperation difficulties, inability to accept common decisions and too wide and risky indication standings before surgery. Addition, there were negative reviews his personal qualities. From Italian hold stressed that he did not care about ethical state. In Italy, his CV challenged by a review committee of the University of Florence in connection with he sought a chair (which he was not deemed to be qualified). His employment in Italy and Spain had been completed on the employers' initiative. Negative signals al