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Liver Volume as a Predictor of Functional Improvement Post-DAA Treatment

Di Maira, Tommaso MD1; Torregrosa, Asunción MD2; Navarro, Vicente MD2; Sánchez, Daniel MD2; Fornés, Victoria MSc3; Berenguer, Marina MD, PhD1,4

doi: 10.1097/TP.0000000000001990
Original Clinical Science—Liver

Background New direct antiviral agents (DAA) for hepatitis C virus treatment result in sustained virologic response (SVR) in most patients. However, predicting the point of no return is still an unmet need for those with advanced liver disease. The aim is to assess if baseline liver volume is a predictor of post-SVR liver function.

Methods Cirrhotic patients assessed for liver transplantation and consecutively treated with DAA between September 2014 and 2015 who achieved an SVR were included. Pretreatment liver volume (LV) and spleen volume (SV) adjusted by body surface area (BSA) were calculated from computed tomography/magnetic resonance images. Liver function was assessed by Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores, and a multivariable mixed regression model was used to identify baseline factors associated with improvement of liver function overtime.

Results We included 42 patients with a median age of 58.6 years (first quartile to third quartile, 52.7-68.8); MELD, 14 (11-17); CTP, 9 (8-10); LV, 1400.9 mL (1183.2-1601.4); SV, 782.9 mL (490.6-1118.8). MELD scores at baseline and at last control were 14 (11-17) and 10 (8-12), respectively (P < 0.001); CTP scores were 9 (8-10) and 6 (5-7), respectively (P < 0.001). In the multivariable model, higher LV/BSA was associated with an improvement of MELD and CTP over time (P = 0.03 and P = 0.044, respectively).

Conclusions LV is a noninvasive tool that can predict functional improvement in cirrhotic patients undergoing DAA therapies.

The authors present data indicating that baseline liver volume can be used to predict functional response of HCV treatment with DAA in liver transplant candidates. Supplemental digital content is available in the text.

1 Liver Transplantation and Hepatology Unit, La Fe University Hospital, Valencia, Spain.

2 Radiology, Abdominal Organs Department, La Fe University Hospital, Valencia, Spain.

3 Biostatistics Unit, Instituto de Investigación Sanitaria (IIS) La Fe, Valencia, Spain.

4 Ciberehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain.

Received 30 May 2017. Revision received 30 August 2017.

Accepted 24 September 2017.

T.D.M. was financed by Rio Hortega research grant 15/00133, supported by Instituto de Salud Carlos III. Ciberehd is partially funded by the Instituto de Salud Carlos III.

The authors declare no conflicts of interest.

Correspondence: Tommaso Di Maira, MD, Avenida Fernando Abril Martorell, 106 (Torre F5), 46026 Valencia, Spain. (dimaira@me.com).

All authors have made substantial contribution to the article. T.D.M. and M.B. designed the research study. T.D.M. collected data, performed the research, analyzed, and interpreted the data, wrote and submitted the article. M.B. wrote and reviewed the article and mentored all phases of the study. A.T., V.N., and D.S. performed CT and RM imaging volumetry, collected the data and reviewed the article. V.F. performed the statistical analysis and reviewed the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Interferon-free therapies have markedly improved outcomes for hepatitis C virus (HCV)–infected patients. Successful viral eradication in patients with decompensated cirrhosis reduces portal hypertension, decreases the risk of clinical decompensation, and improves survival, which may further facilitate, delay, or avoid liver transplantation (LT) as well as prevent HCV recurrence after LT.1,2 However, data are limited regarding the long-term recovery of liver function after HCV eradication, especially among patients with advanced liver disease. Additional concerns that temper the enthusiasm to treat decompensated cirrhotic patients in the waiting list for LT, include (i) lower response rates to antiviral treatment; (ii) occurrence of resistances, especially for NS5A, that may compromise post-LT retreatment success; (iii) highly sustained virologic response (SVR) rates when therapy is administered after LT; (iv) even with successful therapy, the risk of progressive liver disease and hepatocellular carcinoma (HCC) is not eliminated; and finally, (v) the chance of being transplanted may be delayed due to the temporary improvement in Model for End-Stage Liver Disease (MELD) score as well as the inability to use anti-HCV positive organs.3 Hence, it is essential to define predictors of long-term recovery to identify which patients with advanced cirrhosis may actually benefit from direct antiviral agents (DAA) treatment.

Liver and spleen morphologic changes have been well described in cirrhotic patients; specifically, liver atrophy is associated with the degree of liver fibrosis status and, more importantly, with the clinical status classified by Child-Turcotte-Pugh (CTP) Scale.4-6 Furthermore, spleen size and its indirect measures, such as elastography, diameter, and dynamic blood flow, have been correlated with the degree of portal hypertension in different studies.7-9 Currently, liver volume obtained by computed tomography (CT) or magnetic resonance (MR) imaging is used to define the minimum reserve volume in patients undergoing liver resection for hepatic tumor (HCC or other malignancy).10-13 On the other hand, Urata et al14 and Vauthey et al15 have demonstrated a significant correlation between derived liver volume imaging and body surface area (BSA). In fact, several studies have applied BSA to obtain standard liver volume by specific equations.

Our hypothesis was that baseline liver volume (LV) is a noninvasive predictive factor of liver improvement post-HCV eradication in cirrhosis.

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MATERIALS AND METHODS

The goal of this study was to assess whether baseline liver volume obtained by CT/MR imaging is associated with CTP or MELD improvement after HCV eradication in HCV-cirrhotic patients being evaluated for potential LT, followed up for at least 1 year. The secondary endpoint was to assess if baseline liver volume is associated with an improvement of additional liver function biomarkers.

We conducted a single-center, retrospective analysis of outcomes for patients with HCV cirrhosis evaluated for LT and consecutively treated with second-generation DAA between September 2014 and September 2015 at the Liver Transplant Unit of La Fe University Hospital in Valencia, who achieved an SVR and were followed up for at least 1 year after therapy. The period of follow-up started from the first day of DAA administration until December 31, 2016.

The diagnosis of cirrhosis was performed by biopsy (fibrosis stage ≥ 4, Ishak scoring system16) or noninvasive method (elastography) or by the presence of clinical manifestations of portal hypertension (ascites, gastroesophageal varices, variceal hemorrhage, and/or hepatic encephalopathy). The diagnosis of HCC was based on noninvasive method criteria or pathology according to the European Association for the Study of Liver and European Organization for Research and Treatment of Cancer Clinical Practice Guideline.17

Exclusion criteria were younger than 18 years, out of Milan HCC18 at baseline or HCC progression during follow-up, lack of CT or MR imaging within 1 year before start of antiviral treatment, and previous organ transplant.

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End Point Measures

The primary endpoint was assessed through CTP and MELD score at different time points: 12, 24, 52 weeks, and at the end of follow-up.

Secondary endpoints measures were bilirubin, albumin, International Normalized Ratio (INR), ascites and encephalopathy at different time points: 12, 24, 52 weeks, and at the end of the follow-up.

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Definitions

  • Improvement of ascites: defined by a reduction in the need of diuretic and/or paracentesis.
  • Improvement of encephalopathy: defined by a reduction in the need of lactulose and/or rifaximine and/or the reduction in the number and in the severity of hepatic encephalopathy.
  • Survival time: follow-up period from time of first day of antiviral treatment administration to LT, death or the last follow-up visit (up to December 31, 2016).
  • Episodes of decompensated cirrhosis: any episode of ascites, encephalopathy, spontaneous bacterial peritonitis (SBP) or variceal bleeding that required hospitalization during the follow-up.
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Patients and Demographic Characteristics

Age, sex, CTP, MELD, height, weight without ascites, body mass index (BMI), BSA calculated using the equation of DuBois14 (BSA [m2] = body weight [kg]0.425 × body height [m] × 0.007184), arterial hypertension (AHT), diabetes mellitus (DM), portal vein thrombosis (PVT), obesity defined as BMI of 30 kg/m2 or greater,19 history of alcohol consumption (alcoholic steatohepatitis [ASH]), non-ASH (NASH), creatinine, bilirubin, albumin, and INR trough levels were collected. These variables as well as the outcome events were extracted from an electronic chart.

All patients underwent antiviral treatment with new interferon-free regimens during 12 or 24 weeks, and all achieved an SVR.

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Liver and Spleen Volume

All images obtained from CT and MR were transferred to a workstation, and a detailed volume analysis was performed at baseline. CT studies were performed in a 256-multislice scanner with an acquisition protocol consisting on axial 3-mm slices with an interval of reconstruction of 1.5 mm. MR was performed on different 1.5 and 3 T scanners. Standard gradient echo chemical shift T1-weighted, turbo-spin echo T2-weighted, diffusion-weighted with large b values (800-1000 s/mm2) and dynamic contrast-enhanced spoiled gradient echo T1-weighted (late arterial, portal, equilibrium, and interstitial phases) sequences were performed. The dynamic study was acquired with a spatial resolution of 0.5 to 1 mm and a slice thickness of 1 to 2 mm. The portal or the equilibrium phases of the dynamic study were used for the volumetric quantification. All radiologic studies were performed using intravenous contrast. In CT studies, around 100 cc of iodinated contrast (Iomeprol, Iomeron 350; Bracco Imaging, Italy) were used at a flow rate of 3 mL/s. For MR, gadolinium-based intravenous contrast (Gadobenate dimeglumine, Multihance; Bracco Imaging) at a dose of 0.1 mmol/kg body weight was used. The spleen and liver volumetric delineation was performed twice by radiologists, and 2 different semiautomatic softwares were used depending on the type of radiological study (CT or MR), due to a different kind of images acquisition whose analysis is incompatible using the same software. Philips IntelliSpace Portal (version 6.0.3.02500, October 15, 2014; 2010 Koninklijke Philips Electronics N. V.) and Functool application of General Electric Advantage Workstation VolumeShare4 (General Electric Medical Systems LLC, General Electric Healthcare 2012) medical imaging softwares were used in CT and MR studies, respectively. A computer-assisted semiautomatic volumetric drawing of hepatic and splenic parenchyma on portal or equilibrium phase was performed for each study. Whole parenchyma, including HCC lesions, bile, and vessels structures, were included to avoid high variability of data owing to imaging limitation, ensuring a better generalization of results (Figure S1, SDC, http://links.lww.com/TP/B501).

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Statistics

Data were expressed as median and first (Q1), third (Q3) quartiles for continuous variable and with absolute or relative frequencies in categorical variables. Continuous variables were compared by Wilcoxon signed pair test for related variables. Patient survival was performed by Kaplan-Meier curve.

Multivariable mixed regression model was performed for baseline parameters (LV/BSA, SP/BSA, age, sex, human immunodeficiency virus [HIV] infection, history of alcohol consumption, DM, AHT, obesity, PVT, gastroesophageal varices, HCC, and MELD) to define which one was independently associated with MELD and CTP progression over time.

Lin’s concordance correlation coefficient for agreement by each repeated measure of LV and spleen volume (SV) was performed. SV and LV were expressed as average of both values.

LV and SV were adjusted by BSA and then represented by logarithmic transformation according to most parsimonious model.

A post hoc subanalysis was performed including only the patients with advanced cirrhosis (CTP ≥ 8 and MELD ≥ 12) without HCC. A sensitivity analysis was performed by multiple imputation (MI) analysis of missing data. A linear regression accounting for the independent variables that explain missing data was introduced in MI model to fit 100 imputations for each missing value. A mixed linear regression was finally used within MI model to analyze the estimated data set. A P value lower than 0.05 was considered statistically significant. Statistical analysis was performed using R software (version 3.3.2, released in October 31, 2016) and Ime4 package (version 1.1-12, released in April 16, 2016).

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RESULTS

Patient and Radiologic Characteristics

Of 73 cirrhotic patients evaluated for LT, free of organ transplant, treated with DAA second-generation regimen between September 2014 and September 2015, 42 sustained viral responders were included. Reasons for exclusion were as follows: lack of CT/MR imaging (n = 25), HCC undergoing major resection (n = 1), acute leukemia with rapid progression (n = 1), HCC progression out of Milan Criteria during the follow-up (n = 4) (see Figure 1).

FIGURE 1

FIGURE 1

The main characteristics of the patient population are shown in Table 1. At baseline, 24 (57.1%) patients were men with a median age of 58.6 years (Q1, Q3, 52.7-68.8); albumin, 3.2 g/dL (3-3.5); bilirubin, 2 mg/dL (1.4-2.9); INR, 1.3 (1.2-1.7); platelets/mm3; 70 500 (53 750-94 500); MELD, 14 (11-17); CTP, 9 (8-10); LV, 1400.9 mL (1183.2-1601.4); SV, 782.9 mL (490.6-1118.8); BSA 1.8 m2 (1.7-2). Gastroesophageal varices classified as small or large were present in 18 (42.9%) and 19 (45.2%) patients, respectively. PVT was present in 4 (9.5%) patients. Etiologies associated with HCV cirrhosis were ASH and NASH in 13 (31%) and 4 (9.5%) patients, respectively. Obesity, DM and AHT were observed in 28.6%, 19% and 19%, respectively. HCC was present in 14 (33.3%); 3 (7.1%) patients were HIV positive. Twenty (47.6%) HCC-negative patients had advanced liver disease (CTP ≥ 8 and MELD ≥ 12).

TABLE 1

TABLE 1

During the follow-up, no patients had alcohol resumption, nor were there modifications in either the treatment and/or the manifestations of comorbidities (obesity, DM, and AHT). All patients with a history of alcohol had stopped any alcohol consumption at least 1 year before study inclusion. Importantly, 2 patients developed a PVT during the follow-up, although neither of them had a major outcome (death or LT) nor a significant change in MELD or CTP scores.

Lin’s concordance correlation coefficient by each repeated measure of LV and SV was higher than 0.95 (0.989; 95% confidence interval [CI], 0.98-0.99) and 0.996 (95% CI, 0.992-0.997), respectively.

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Outcome

LT-free survival was 95.2%, 85.7%, and 75.5% at 3, 6, and 12 months. Of 42 patients, 2 (4.8%) died because of decompensated liver disease, whereas 8 (19%) underwent LT (Figure S2, SDC, http://links.lww.com/TP/B501). The indication for LT was decompensated liver disease in 4 and HCC in the remainder 4 (Table 2). Decompensated cirrhosis occurred in 9 (21.4%) patients at a median time of 3.6 months (1.5-7.4). The most common reasons for decompensation were as follows: SBP (n = 5), variceal bleeding (n = 2), refractory ascites (n = 1), and encephalopathy (n = 1). Patients with poor outcomes (death, LT, or liver decompensation) had a baseline CTP score significantly higher than that of patients with favorable prognosis: 10 (9-10) versus 9 (8-9), respectively (P = 0.013); in contrast, MELD score, LV/BSA, and SV/BSA at baseline were not significantly different between the 2 groups (P = 0.204, P = 0.152, and P = 0.332, respectively).

TABLE 2

TABLE 2

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Impact of HCV Eradication on Liver Function in the Overall Population

As shown in Table 3, MELD scores at baseline 12, 24, 52 weeks and at last control were 14 (11-17), 14 (12-16), 13 (10-16), 11 (9-15), and 10 (8-12), respectively; in turn, CTP scores were 9 (8-10), 9 (8-10), 8 (7-9), 7 (5-8), and 6 (5-7), respectively. MELD and CTP scores at the end of follow-up were significantly improved compared with baseline values (P < 0.001 in both cases).

TABLE 3

TABLE 3

HCV eradication was followed by a significant improvement in most liver function biomarkers over time, including bilirubin, albumin, INR, ascites, and encephalopathy (P < 0.001) (Figure 2).

FIGURE 2

FIGURE 2

Most parsimonious models were applied in the multivariable mixed regression to assess the effect of baseline factors on liver function changes. Gastroesophagic varices, PVT, DM, AHT, HCC, and obesity at baseline had no significant impact in MELD and CTP evolution over time.

Only higher LV adjusted by BSA was associated with an improvement both of MELD and CTP scores over time (95% CI, −12.76 to −0.52; P = 0.03; 95% CI, −3.58 to −0.05; P = 0.044, respectively). In turn, a strong association was also found between changes of CTP score over time and MELD score at baseline (95% CI, 0.12-0.31; P < 0.001) (Table 4).

TABLE 4

TABLE 4

Considering Q1 and Q3 thresholds of LV adjusted by BSA as high and low LV/BSA, we found that among patients with CTP C status at baseline, those with lower LV/BSA (Q3) had approximately one-half probability to improve their CTP status, compared with those with a higher LV/BSA (Q1) (Figure 3). Furthermore, the improvement of liver function biomarkers, such as bilirubin, albumin, and ascites over time, were also significantly associated with higher LV/BSA at baseline (P = 0.006, P = 0.018, P = 0.025, respectively) (Figure 4). In contrast, there was no association between LV/BSA and changes in INR or encephalopathy (P = 0.067, P = 0.25, respectively). Finally, only 2 additional variables were associated whit outcome events. Specifically, the absence of HIV coinfection was associated with improvement of albumin levels over time (95% CI, −0.41 to −0.028; P = 0.032), whereas young age was associated with improvement of encephalopathy (95% CI, 0.793-0.986; P = 0.026).

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

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Impact of HCV Eradication on Liver Function in Patients With Advanced Cirrhosis (CTP ≥ 8 and MELD ≥ 12) and No HCC

As shown in Table S1 (SDC, http://links.lww.com/TP/B501), MELD scores at baseline, 12, 24, 52 weeks, and at last control were 17 (14-19), 16 (14-19), 16 (14-19), 15 (11-17), and 12 (10-16), respectively; in turn, CTP scores were 10 (9-11), 9 (9-10), 9 (8-10), 8 (6-9), and 6.5 (5-9), respectively. Improvements in MELD and CTP scores were significant (P < 0.001 for both).

In the multivariable mixed regression model, no variables were associated with an improvement of MELD score over time, whereas there was a trend between higher LV/BSA and female sex with changes of CTP score over time (P = 0.06 in both cases, Table S2 (SDC, http://links.lww.com/TP/B501).

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Sensitivity Analysis

We considered dropouts patients who either died or alternatively underwent LT during the study period. Outcome measures after these events were estimated. A total of 22 missing values were imputed across 188 observations distributed in 5 time points, yielding a missing data rate of 11.7%. The estimate results were consistent with the main results: higher LV/BSA and lower SV/BSA were independently associated with MELD improvement over time (P = 0.011 and P = 0.045, respectively); furthermore, higher LV/BSA and low MELD score at baseline were independently associated with CTP improvement over time (P = 0.011 and P < 0.001, respectively). See Table S3 (SDC, http://links.lww.com/TP/B501).

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DISCUSSION

The new era of second-generation DAA has changed the natural history of HCV liver disease. An SVR can now be achieved in more than 90% of patients with cirrhosis.20-24 Viral eradication may benefit individual LT candidates by removing them from the waiting list; in addition, this may result in a positive impact on the national waiting list and organ availability. However, data on hepatic function more than 6 months after treatment are limited, especially in patients with advanced liver disease (CTP > 12 or MELD score >20).3 During a short follow-up course after a successful treatment, a small proportion of patients with decompensated cirrhosis have no improvement or even show worsening of liver function with increase of their MELD score, indicating that there may be a point of no return for recovery in hepatic function.25-28 Unfortunately, to date, there have been no reliable baseline predictors of “liver function response” after antiviral therapy in patient with decompensated cirrhosis. Thus, we aimed to find simple noninvasive baseline predictors of functional change that could be used in patients with advanced cirrhosis. The main results from this study can be summarized as follows. First, SVR had a positive impact in liver function tests in the overall population with an improvement of the MELD score from baseline to last control averaging 6 points and a median CTP change of around 3. The change in liver function scores was greater in patients with advanced cirrhosis without HCC, finding which is likely related to their higher baseline MELD score (Supplementary tables, SDC, http://links.lww.com/TP/B501) and similar to changes described in clinical trials. Although changes in MELD and CTP scores were observed during the entire follow-up period, they did not reach a point of significance until week 24 after therapy. Interestingly, the improvement both in MELD and CTP scores overtime was independently associated with baseline LV/BSA (P = 0.03 and P = 0.044, respectively). Moreover, CTP improvement was also strongly associated with MELD score at baseline (P < 0.001), confirming its importance as shown in recent data from literature.25 In fact, several studies have shown that a MELD score over 20 points is possibly a point of no return in patients with advanced HCV cirrhosis.25-28 Interestingly, although in our study, we found a direct association between MELD score at baseline and CTP score improvement over time, patients with higher MELD scores at baseline were those who had the greatest probability to obtain a wider improvement in CTP score over time, possibly reflecting the relatively preserved liver function of our study population where only 2 patients had a MELD score over 20. Similar results were found when the individual biomarkers (bilirubin, albumin, INR, encephalopathy, and ascites) were analyzed, highlighting that LV/BSA plays an important role in predicting functional improvement towards complete recovery.

Furthermore, the sensitivity analysis, where outcome measures (MELD and CTP) were estimated up to last time point in patients who had either died or undergone LT, was consistent with the main results in the overall population.

Thus, liver volume, as assessed by LV/BSA, was predictive of functional improvement both in the overall cirrhotic population as well as in the subgroup of patients with decompensated advanced liver disease (CTP ≥ 8 and MELD ≥ 12) without HCC and in the sensitivity analysis.

CT volumetry plays an important role in the LT field, particularly in the setting of live donor LT to determine the weight of the graft.29-31 Furthermore, imaging liver volumetry is also a crucial tool to plan liver resection surgery, where a minimal residual volume should be guaranteed to allow a satisfactory parenchymal reconstitution.11 In fact, when the findings from the volumetry predict that the residual parenchyma will be lower than 40% of the initial volume, a preemptive embolization of a hepatic portal vein branch is performed to obtain a compensatory liver hypertrophy that reduces the probability of liver failure.32-34

Similarly, we analyzed baseline liver volume as a functional reservoir, hypothesizing that if it were too small, liver improvement would probably be less frequent despite successful HCV eradication. We acknowledge that other factors may also be relevant in the disease course after antiviral therapy, such as alcohol consumption or metabolic disorders, although in our cohort of patients, none of these known factors were associated with changes in MELD or CTP scores. This may be explained by the small sample size and/or the low rate of these conditions in our study population. We are also aware that controlling for multiple cofactors may have resulted in an overfitted model, even though the introduction of all variables was drawn by strong clinical motivations.

In this study, we did not find an association between baseline liver volume and hard endpoint measures, such as death, LT, and further decompensation. Several factors may account for the lack of association including the small sample size, the relatively short follow up where significant improvement in MELD score was only documented after week 24 of follow-up since the start of therapy, and/or the relatively preserved liver function of our study population.

In conclusion, this is the first study where a strong association is shown between LV and the measures commonly used to asses liver function in cirrhotic patients, such as MELD and CTP scores, after HCV eradication with the new DAA therapies. Moreover, MELD score at baseline was also found to be a strong predictor of CTP improvement over time, as previously described in other studies. Despite the small sample size of the population evaluated, our findings suggest that LV adjusted by BSA at baseline is a suitable noninvasive tool that can be helpful to predict improvement in MELD and CTP scores. These results need confirmation, particularly in patients with significantly higher baseline MELD scores given that only 2 of the patients included in the current series had a MELD score greater than 20.

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