Abstract
Background
In 2005, the model of end-stage liver disease (MELD)-based allocation system was adopted to assess potential liver transplant (LT) recipients in Argentina. The aim of the present study was to revise the activity of the MELD Exception Experts Committee.
Methods
Between 2005 and 2009, 1623 patients were listed for LT. Regulation provides extra-MELD points for amyloidosis, hepatopulmonary syndrome (HPS) and T2 hepatocellular carcinoma (T2 HCC). Centres could also request priority for other situations. Using a prospective database, we identified patients in whom priority points were requested. Pathology reports of explanted livers were analysed for patients with T2 HCC.
Results
From 234 out of 1623 (14.4%) requests, the overall approval rate was 60.2% including: 2 amyloidosis, 6 HPS, 111 T2 HCC and 22 non-regulated situations. Of the 111 patients with T2 HCC, 6 died (5.4%), 8 had tumour progression (7.2%), 94 were transplanted (84.2%) and 3 are still waiting. An explants correlation showed that presumed diagnosis of T2HCC was incorrect in 20/94 (22%) and was correct in only 41/94 (43%) cases being T1 HCC in 9 and T3 HCC in 23.
Conclusions
MELD exceptions are frequently requested in Argentina. Unfortunately, most receiving priority points for T2 HCC benefited by medical error or imaging limitations. An intense review process is urgently needed to maintain equity and justice in the allocation system.
Keywords: transplant, hepatocellular carcinoma < liver, cirrhosis < liver, quality of life < transplant, indications < transplant
Introduction
Equitable allocation of donor organs to patients on the waiting list (WL) is crucial.1 Clearly, if an adequate number of organs was available, organ allocation would be a much less controversial issue.2 Thus, any effort to optimize organ allocation should be accompanied by similar intensive efforts to increase the number of organ donors.3 The ideal allocation system must be based on equity and justice with objective parameters and transparency.4 In this scenario, the model for end-stage liver disease (MELD) score aims to stratify recipients by disease severity according to a score estimating the 3-month probability of death on the WL. Although the implementation of the MELD-based allocation system for liver transplantation has reduced mortality on the WL in US, this has not been validated in other countries.5
In Argentina, the first liver transplant was performed in 1988. After being implemented in US, the MELD allocation system was adopted in 2005 for LT (liver transplant) candidates. In contrast to other countries, all patients in Argentina are listed in a ‘unique national’ waiting list, and thus, there is no regional or LT-centre allocation of deceased liver organs. On the national liver WL, two major categories are identified. Emergency candidates are referred to as having acute graft failure within 7 days post-transplant and receive top priority on the WL. The remaining elective candidates are ranked based as a function of their MELD score within a single national liver transplant waiting list. However, it has been recognized that not all LT candidates benefit from LT because they face a greater risk of dying from intrinsic liver disease. Thus, for patients whose disease severity is not adequately reflected by the MELD score, exceptional MELD points can be submitted to a national board. This exceptional MELD can be requested for only a few entities with very strict inclusion criteria determined under specific regulation, or for other medical conditions. These additional point requests are revised by a national group of experts.
In the present study, the activity of a national MELD Exceptions Experts Committee was analysed during a period of almost 4 years after implementing this novel allocation system using the official database from the INCUCAI (Instituto Nacional Central Unico Coordinador de Ablacion e Implante) that represents the national institute for organ allocation in Argentina. The precision of the pre-operative staging was also assessed as reported by centres seeking to receive the increased early HCC stage priority by the Experts Committee using reported histology from the explanted livers.
Materials and methods
Between July 2005 and April 2009, a total of 2182 patients were listed for LT in Argentina: 1773 (81.1%) adult and 409 (18.9%) paediatric candidates. Among the adult population, 150 patients were listed under emergency and 1623 patients under elective status and stratified according to the MELD-based allocation system. Of all elective patients listed under the MELD system, laboratory values were regularly updated depending on the patient's medical condition or the MELD score as follows: every 7 days for patients with MELD points > 20, every 30 days for MELD points 15–19, every 3 months for MELD points 11–14 and every 12 months for MELD points ≤ 10.
For patients in whom the MELD score was thought to estimate inaccurately the need for LT, each centre could request priority points to an Experts Committee that constituted a national peer review system. With the aim of analysing the activity of this MELD Exceptions Committee a prospective collected national database was reviewed to include all adult elective patients (i.e. ≥18 years) listed for LT in Argentina for whom the Experts Committee opinion was requested.
This Committee comprises of five liver transplant specialists (minimum two surgeons and two hepatologists) representing different accredited LT programmes from the country. Every year, three of them are rotated from other centres. There is no standard application form for a MELD Exception Committee request. The application should include a letter signed by the liver transplant programme director and a signed copy of the laboratory values and imaging reports. The Committee usually performs the evaluation based on the imaging reports but they can also request the original scans. Each request must be revised in a blinded fashion by a minimum of two individuals or with a third person in cases of disagreement and within 48 h a reply must be sent by the INCUCAI to the requesting LT centre. In those cases resulting in a refusal from the Committee, each centre could request a review but only when new information becames available (i.e. laboratory values or imaging).
A specific national regulation included few categories that qualify for various degrees of upgrading of their MELD score such as patients with familial amyloidotic polyneuropathy (16 points), hepatopulmonary syndrome with PO2 < 60 mmHg (20 points) and T2 hepatocellular carcinoma (HCC) defined as 1 tumour of 2–5 cm or 2 or 3 tumours of <3 cm in diameter diagnosed according to pre-operative imaging (22 points). Patients who receive additional priority for HCC must have undergone a comprehensive assessment to evaluate the number and size of the liver tumours and to rule out any extra-hepatic spread and/or macrovascular involvement. A pre-listing biopsy was not mandatory but the lesion must fulfill the following imaging criteria. The assessment of the patient should include two non-invasive criteria that documents tumour size and number including ultrasound and contrasted computed tomography or magnetic resonance imaging of the abdomen and chest CT and bone scan to rule out metastatic disease. All other patients with HCC including those with downsized tumors in whom their original presenting tumour was greater than the T2 stage must be referred to the national review board.
Centres could request priority points for other clinical conditions not included in this regulation such as refractory ascites, chronic invalidating encephalopathy, severe pruritus, symptomatic polycystic liver disease, recurrent biliary sepsis, refractory variceal bleeding or others. Each non-established category in the regulation was considered individually by the Experts Committee to determine the appropriateness of the requested increase in priority on the basis of medical evidence from the literature or experts opinion.
Official reporting of the pathology of the explanted liver is mandatory in the national regulation only for those patients with priority points as a result of T2 HCC. To assess the precision of the pre-operative diagnosis as reported by centres seeking to receive the increase HCC priority, pathological reports were collected for denied requests. Data regarding the T stage of the explants were correlated with pre-operative diagnosis at the transplant centre. Tumor stage was considered as follows: T1, solitary tumour < 2 cm in greatest dimension; T2, 1 tumour 2–5 cm or 2 or 3 tumours ≤ 3 cm in diameter; and T3, 1 tumour > 5 cm or >3 with one or more >3 cm. Patients without malignancy in the explants or in which all nodules were entirely necrotic with no pre-operative biopsy confirming HCC were counted as T0. Patients without pathological reports available were counted as TX.
Several adult candidate variables were analysed from the database including age, gender, aetiology of liver disease, MELD score (i.e. at the time of allocation, drop-out, death or the most recent), WL time and reasons for removal from the WL (death, tumour progression or transplantation).
Statistical analysis
Summary data are presented as median (range) or interquartile range (IQR). Sensitivity, specificity, positive and negative predictive values of the Expert Committee judgment on diagnosis of T2 HCC were computed on the basis of findings at pathological examination. The differences between groups were tested using the χ2- or Fisher's exact tests for categorical variables. Statistical significance was indicated by P-values of less than 0.05. Calculations were done with SPSS statistical software package (version 13.0; SPSS Inc., Chicago, IL, USA).
Results
During the study period, 1623 patients were listed for LT in the national WL with a median MELD score of 18 points (Table 1). A total of 234/1623 (14.4%) requests were presented to the MELD Exceptions Experts Committee. In five instances, the request was because of political and non-medical reasons (e.g. paediatric LT centres asking permission to perform an adult LT) and in the other 229 cases the application was related to patients having ‘exceptional diagnoses’. In other words, in 229/1623 (14.1%) of the adult elective candidates, the LT team decided that the calculated MELD score did not assess properly the requirement for LT and, therefore, priority points were requested.
Table 1.
Characteristics of elective adult liver transplant candidates included in the national waiting list
| Elective adult patients (n = 1623) | |
|---|---|
| Age (years) | 53.7 (18–74) |
| Gender (M/F) | 926/697 |
| MELD score | 18 (6–49) |
| Waiting list time (days)a | 155 (40–519) |
| Transplanted with a deceased donor LT (%) | 665 (41) |
| Transplanted with a Live donor LT (%) | 15 (0.9) |
| Number of death (%) | 240 (14.8) |
| Number of drop-out from the listb (%) | 46 (2.8) |
| Improve of clinical situation (%) | 19 (1.2) |
Data expressed as median and range.
Median and interquartile range.
Drop-out from the waiting list because of infection, poor overall status, neurological disorders or tumour progression.
LT, liver transplant.
In 189/234 cases the requests were presented for patients with one of the standardized conditions included in the official regulation. However, additional points were adjudicated in only 119 cases (62%): 2 familial amyloidotic polyneuropathy, 6 hepatopulmonary syndrome and 111 presumed T2 HCC. Among the subgroup of patients with a high suspicion of T2 HCC, 6 patients died on the WL (mortality rate = 5.4%), 8 patients were removed because of tumour progression (drop-out rate = 7.2%), 3 patients are still waiting and 94 underwent deceased LT (probability to be transplant = 84.2%). As the decision to accept or refuse a MELD exception for HCC was based on pre-transplant imaging, a whole-liver explant correlation was performed to assess discrepancy with pre-operative tumor diagnosis and staging. When 94 pathology reports were reviewed, the diagnosis of HCC was incorrect in 21/94 (22%) cases and T2 HCC was confirmed in only 41/94 patients (diagnostic accuracy = 43%). Pre-operative imaging underestimated tumour extension in 23 cases (T3 stage HCC) but overestimated the tumour size in 9 patients (T1 stage HCC). In the subgroup of patients without HCC (T0 stage = 21 cases), the pathology report identified one patient with multiple neuroendocrine tumours, one with multiple adenomas, one with liver haemangioma, three with necrotic nodules after trans-arterial chemoembolization and 15 instances of regenerative nodules.
In 70/189 (37%) patients, the request was denied for those with presumed T2 HCC. From this subgroup with no priority, 12 died on the WL (mortality rate = 17.1%), 10 patients dropped-out (14.2%), 42 underwent LT (probability to transplant = 60%) and six patients remained on the WL. In comparison with the subgroup of patients with adjudicated extra-points, these patients had a similar drop-out rate (P = 0.21) but a significantly higher mortality on the WL (P < 0.02) with considerably less access to deceased donor LT (P < 0.001). Pathological reports of the explanted livers were achieved in 40/42 transplanted candidates. Interestingly, we found that 18 had no HCC; none had T1 HCC, 11 (26.1%) had T2 HCC and 11 patients had T3 HCC. In other words, the Experts Committee judgment incorrectly denied requests in 26.1% of the patients in whom the pre-operative imaging detected T2 HCC.
An explants correlation with the Experts Committee judgment was undertaken based on the pre-transplant imaging diagnosing the presence of T2 HCC in all patients where pathological reports were available (n = 134). We observed that the sensibility of the opinion from the specialists was 78.8% but the specificity was low (37.8%). The positive predictive value of all positive approvals from the Experts Committee adjudicating additional MELD points for patients with presumed T2 HCC was 43.6% with a concomitant negative predictive value of 72.5%.
Pathological reports for the explanted livers were correlated with the LT centre judgment when requesting additional points for T2 HCC. The LT centre's diagnostic accuracy rate for T2 HCC was 38.8% (52/134) such that the priority was requested incorrectly most of the time. The absence of HCC was observed in 39/134 (29.1%) and over or under staging in the other 43/134 (32%) explants of patients in whom the LT centre asked for the exceptional request.
There was a request for special consideration in 45 of the 234 patients that were not included in the standard regulation. Five cases were approved requests because of political reasons and in another 40 cases the application was related to patients having ‘exceptional diagnoses’ associated with poor clinical conditions or impaired quality of life. Additional points were adjudicated in only 17/37 (37%) cases and denied in the others (Tables 2 and 3). Recurrent cholangitis and post-transplant complications were the most frequent arguments that the Committee positively considered to administer extra-MELD points (Table 2). In this subgroup, most patients were successfully transplanted (13/17, 76.4%), one died, one improved his clinical condition, one dropped out because of infectious complications and one patient is still waiting for a liver.
Table 2.
List of ‘exceptional diagnoses’ upgraded with extra-MELD points by the MELD Exceptions Committee (n = 17)
| 4 | Post-transplant delayed hepatic artery thrombosis |
| 4 | Recurrent cholangitis |
| 3 | Post-transplant recurrent cholangitis |
| 2 | Polycystic liver disease |
| 1 | Intractable gastrointestinal bleeding + encephalopathy |
| 1 | Hepatorenal syndrome with ascites and aedema |
| 1 | Intractable pruritus |
| 1 | Liver metastases of neuroendocrine tumour of the pancreas |
Table 3.
List of ‘exceptional diagnoses’ denied by the MELD Exceptions Committee (n = 23)
| 8 | HRSAE |
| 4 | Hepatic encephalopathy |
| 2 | Severe malnutrition |
| 2 | Intractable gastrointestinal bleeding (IGB) + encephalopathy |
| 1 | Post-transplant recurrent HCC |
| 1 | Severe hyponatremia |
| 1 | IGB + Encephalopathy + HRSAE |
| 1 | Recurrent bacterial cholangitis |
| 1 | Refractory ascites |
| 1 | Porto-pulmonary Hypertension |
| 1 | Recurrent hemangioendotelioma post-transplant |
HRSAE, hepatorenal syndrome with ascites and oedema; IGB, intractable gastrointestinal bleeding; HCC, hepatocellular carcinoma.
Inversely, the most frequent outvoted entities by the Experts Committee among the 23 denied requests not included in the standard regulation were the presence of hepatorenal syndrome with ascites and oedema, severe malnutrition and hepatic encephalopathy alone or associated with intractable gastrointestinal bleeding (Table 3). In the declined group only 12/23 patients received a LT (52.1%), four died (17.3%), two dropped out and five remained on the WL.
Discussion
The recently adopted MELD allocation system in Argentina is not perfect. It is unlikely that a mathematical scoring system would serve all patients on a LT WL equally well, and for this reason, MELD allocation policy included a mechanism by which centres could request increased priority for any patient for whom the MELD score was thought to inaccurately estimate their need for LT. We demonstrated that this mechanism has been used in almost 15% of the adult candidates listed for LT in Argentina. The consolidation of a national Experts Committee is a strategy that would permit proper evaluation of each request individually to provide equity and justice in liver allocation. Interestingly, many requests were denied and most of them for patients with a presumed diagnosis of T2 HCC. After almost 4 years of implementation, this is the first study that reports the activity of the national Experts Committee but demonstrates disappointing results. This board of experts had a very low positive predictive value in their medical decisions with an unacceptable diagnostic accuracy rate for the evaluation of patients in whom pre-operative imaging documented the presence of T2 HCC. Unfortunately, based on pathology reports of the explanted liver, most patients that were prioritized by the Experts Committee benefited erroneously. Moreover, most of the LT centre requests for patients with HCC were for patients that did not have T2 stage HCC. With this scenario of incorrect requests from LT centres and incorrect upgraded patients by the Experts Committee, an intense and continuous revision process is urgently needed to maintain equity and justice of access to the limited pool of cadaveric liver organs.
The adoption of the MELD-based allocation policy dramatically improved organ allocation in Argentina. However, the absence of Experts Committee activity control and feedback jeopardizes the principles of equity and justice in this mathematical system. To our knowledge, this is the first study that comprehensively reviewed the activity and accuracy of a national MELD exception Committee. We consider that with transparency in the medical decision-making process of this medical expert's board, an open interdisciplinary discussion will lead to continual improvement in organ allocation. There are some shortcomings in our study that need to be carefully addressed. First, the data referred for pathological examination was only based on pathology reports. We are aware that inter-observer variability could influence the final diagnosis and staging of these patients. After this study demonstrating poor explants correlation with pre-transplant HCC diagnosis, we recommend a centralized revision of each specimen by a board of experienced pathologists in a blind fashion to provide equal assessment with uniform analysis. Second, the use of a new national database has inherent limitations that may affect data quality including problems in the recording system; changes in personnel related to data entry and erroneously recorded data.6 Third, we could not analyse the utility of LT in our cohort of patients as post-operative outcome has been not recorded in the database. Therefore, the survival benefit of the MELD-base allocation policy and the MELD exception Committee opinion are unpredictable in Argentina.
MELD allocation policy prioritizes patients based on a defined endpoint: the risk of death on the WL.6,7 Mortality risk is currently the most convenient but not necessarily the only endpoint possible. Only a few entities such as T2 stage HCC, amyloidosis and hepatopulmonary syndrome have been standardized to receive additional MELD points under an official regulation. Patients with T2 stage HCC are prioritized based on the risk of tumour progression but not by mortality risk on the WL. Unfortunately, for all other excellent candidates for LT in whom the MELD score does not estimate the need of LT, allocation rules remain unclear.4,8–10 In Argentina the most frequent clinical conditions that triggered a LT centre request were the presence of hepatorenal syndrome with ascites and aedema, intractable gastrointestinal bleeding, post-transplant complications and hepatic encephalopathy. Ideally, a medical decision of the magnitude of organ allocation would be made with the highest quality clinical evidence available in the literature. However, strong evidence is usually not available and many of these conditions occur so infrequently that the development of clinical relevant studies will never be possible. In this context, prioritization policy in Argentina only relies on the subjective opinion of a minimum of two experts. Thus, it is unlikely to ensure equity in the decision-making process among all independent reviewers of the national Committee. The question about why additional points for patients with intractable gastrointestinal bleeding or debilitating encephalopathy were sometimes given and others denied remains open and should be clarified. Other well-defined endpoints that are measured by objective variables should be developed for such conditions that were not included in the regulation. Prospective validation of new mathematical models using objective variables should be performed before implementing any change in the current liver allocation policy. International open and constant re-examination of models and developments are essential for continuous improvement of organ allocation worldwide.
Our data showed that LT centre opinion considered that the MELD underestimated the need of LT in nearly 15% of listed candidates. However, in this critical and competitive scenario for a scarce available liver pool, the final decision about who will receive the liver first is based on expert subjective opinions. In Argentina, 39.7% (93/234) of the requests were denied challenging the initial expert opinion from the LT centre. Hopefully, this should not end in a byzantine discussion with continuous discrepancies between transplant specialists about who is more expert or more objective at the time of organ allocation. A systematic and mandatory revision of the activity and accuracy of the Experts Committee that contrasts with an objective allocation system will provide confidence and transparency to the whole transplant community.
We investigated the capacity of liver transplant centres and also of the Experts Committee to properly assess using non-invasive modalities the existence and extent of HCC prior to transplantation in the subset of patients with presumed T2 stage HCC that had available pathological reports. This information is critical to ensure that patients enlisted for LT really present with such a cancer, but at the same time, it is relevant to properly establish whether the patient fits into the accepted criteria for LT with optimal results, or if the limits are exceeded and the patient should be denied any priority according to the current policy, or even excluded from transplantation.11–14 When all requests for additional points for HCC were correlated with the explanted liver pathology, we observed very disappointing results. First, the LT centre diagnostic accuracy rate for T2 HCC was extremely low and thus, we can confirm that the priority for these patients was most of the time incorrectly requested. Second, the positive predictive value of the Experts Committee dictate about the presence T2 HCC was unacceptably low. Third, among LT centre requests and Expert Committee approval, there were many cases without HCC (29.1% and 22%, respectively). Perhaps, the absence of a tumour may mean that the patient was transplanted without the need and/or given a priority that was not deserved. Fourth, many patients were under or over-staged in this cohort, and this fact disables the potential fairness of any priority policy based on staging. While this false-positive diagnosis should become a major concern, the data about staging are also provoking. Fifth, in 26.1% of the patients with a negative dictate from the Experts Committee this judgment was incorrect and, therefore, these patients were erroneously penalized with a higher mortality rate and lower probability to be transplanted. Finally, we can assume that with the current methodology for diagnosis and staging of HCC, the patients evaluated for LT are not properly managed.
An important finding was that patients with additional MELD points by presumed T2 HCC benefited with a higher access to LT and lower mortality rate. Unfortunately, many errors evidenced by the pathology reports of the explanted liver put at risk the principle of equity and justice that should rule liver allocation. A considerable amount of patients upgraded by the Experts Committee had finally no cancer or were over or under staged when correlated with explanted livers. On one hand, we are aware that diagnosis and staging of HCC could be improved in Argentina and therefore, many strategies could be recommended. First, medical decision of the Experts Committee should be made based on original copies of the imaging and not on written reports from the LT center. Second, the non-invasive diagnosis of HCC might be performed exclusively in centers with state-of-the-art resources with qualified radiologists.15 Third, the widely accepted non-invasive criteria used for diagnosing HCC are not included in the official regulation.16 HCC diagnosis using imaging techniques should only be made if the dynamic pattern of a nodule detected within a cirrhotic liver presents intense arterial uptake with contrast washout in the venous/ delayed phase.15 Fourth, the creation of an Experts Radiologist Committee could help to improve the low diagnostic accuracy for T2 HCC. Both the lack of common methodology for liver imaging together with the absence of well-established imaging criteria are the strongest drawbacks that translated into a high rate of misdiagnosis. As demonstrated, the benefit of giving priority with a high accessibility to LT contrasts with a higher mortality on patients where priority was denied. In this setting, the best notice for a patient listed for LT is to have a nodule that fulfills the non-invasive criteria for diagnosis of a T2 stage HCC. These data raise the question whether the priority points of patient with T2 stage HCC should be reduced to provide more justice.4 Further multidisciplinary discussion is needed to reach consensus regarding how to allocate fairly cadaveric livers to patients with T2 stage HCC.
Donor organ resource is more constrained that most other heath care resources. Scarce resources can be allocated using three guiding ethical principles: justice, equity and utility. The MELD allocation system quantified individual justice based on their mortality risk.17 However, some authors indicated that the MELD score predicts accurately which cirrhotic patients will live and which will die at a given score in only 80–85% of occasions.18 Unfortunately, the justice for these ‘MELD unprotected candidates’ relies only on the arms of few experts using subjective parameters with a questionable effectiveness. Equity in the MELD allocation system refers to the quality of being fair or impartial in the distribution of deceased donor livers. The Experts Committee evaluates each request individually in a blinded fashion to determinate mortality risk on the WL or sometimes subjective variables concerning quality of life. But, do hepatologists ask equally MELD exception requests for all patients in whom the MELD does not accurately predicts mortality on the WL? Do all patients have equal access to modern imaging modalities for the screening of early HCC? Some LT groups may have the necessary expertise and adequate modern imaging modalities, whereas others need to improve or modify their clinical management. Currently in Argentina, the quality of the imaging employed for each centre is not monitored and the inaccuracy in the judgment of the Experts Committee represents a major concern. Major efforts should be made to implement homogenous methods and definitions, as it is the only way to ensure optimal health care delivery and avoid unfair enlistment and management of patients considered for LT.19 Furthermore, as tumour staging plays a critical role in the points for allocation, it is the key to ensuring that all patients will be managed according to the same measurements using the same tools with the same criteria according to a modern technology. Thus, while the allocation to HCC patients according to stage may appear to offer a balanced distribution of organs, the wide inter-center variability in our country jeopardizes equity in organ distribution. It is the role of the national Ministry of Health and the INCUCAI to ensure that all patients are staged according to the same methodology to avoid inequity on the national liver WL.15,19 Finally, utility means that a liver organ would be allocated based on the overall likelihood of success with much less attention to individual characteristics of need.1 In a utilitarian system, less ill candidates might receive more priority because they are not more likely to have a good outcome. In an appropriate allocation system, it is clear that equity must be guaranteed to all patients included on the WL but there should be some balance between justice and utility in the liver allocation system.
Conclusions
MELD exceptions are frequently requested because of the fact that a MELD score does not always accurately determinate the need for LT. Unfortunately, most receiving priority points for T2 HCC were benefited just by medical mistake or imaging limitations. Further improvement in imaging modalities and the implementation of better diagnostic criteria are urgently required to improve diagnosis and staging of HCC. The activity of the Experts Committee and the accuracy of the decision-making process needs continuous overseeing to provide feedback to the transplant community and to guarantee high standards of excellence for liver allocation in our country. Periodical internal and external revisions of the MELD exceptions Committee activity are needed to unsure equity and justice in organ allocation.
Conflicts of interest
None declared.
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