Research Spotlight

Huddleston, J. I., 3rd, A. De, H. Jaffri, J. W. Barrington, P. J. Duwelius and B. D. Springer (2021). “Cementless Fixation Is Associated With Increased Risk of Early and All-Time Revision After Hemiarthroplasty But Not After THA for Femoral Neck Fracture: Results From the American Joint Replacement Registry.” Clin Orthop Relat Res Aug 16. [Epub ahead of print].

Full text of this article.

BACKGROUND: Despite ample evidence supporting cemented femoral fixation for both hemiarthroplasty and THA for surgical treatment of displaced femoral neck fractures, cementless fixation is the preferred fixation method in the United States. To our knowledge, no nationally representative registry from the United States has compared revision rates by fixation for this surgical treatment. QUESTION/PURPOSE: After controlling for relevant confounding variables, is femoral fixation method (cemented or cementless) in hemiarthroplasty or THA for femoral neck fracture associated with a greater risk of (1) all-cause revision or (2) revision for periprosthetic fracture? METHODS: Patients with Medicare insurance who had femoral neck fractures treated with hemiarthroplasty or THA reported in the American Joint Replacement Registry database from 2012 to 2017 and Centers for Medicare and Medicaid Services claims data from 2012 to 2017 were analyzed in this retrospective, large-database study. Of the 37,201 hemiarthroplasties, 42% (15,748) used cemented fixation and 58% (21,453) used cementless fixation. Of the 7732 THAs, 20% (1511) used cemented stem fixation and 80% (6221) used cementless stem fixation. For both the hemiarthroplasty and THA cohorts, most patients were women and had cementless femoral fixation. Early revision was defined as a procedure that occurred less than 90 days from the index procedure. All patients submitted to the registry were included in the analysis. Patient follow-up was limited to the study period. No patients were lost to follow-up. Due to inherent limitations with the registry, we did not compare medical complications, including deaths attributed directly to cemented fixation. A logistic regression model including the index arthroplasty, age, gender, stem fixation method, hospital size, hospital teaching affiliation, and Charlson comorbidity index score was used to determine associations between the index procedure and revision rates. RESULTS: For the hemiarthroplasty cohort, risk factors for any revision were cementless stem fixation (odds ratio 1.42 [95% confidence interval 1.20 to 1.68]; p < 0.001), younger age (OR 0.96 [95% CI 0.95 to 0.97]; p < 0.001), and higher Charlson comorbidity index (OR 1.06 [95% CI 1.02 to 1.11]; p = 0.004). Risk factors for early revision were cementless stem fixation (OR 1.77 [95% CI 1.43 to 2.20]; p < 0.001), younger age (OR 0.98 [95% CI 0.97 to 0.99]; p < 0.001), and higher Charlson comorbidity index (OR 1.09 [95% CI 1.04 to 1.15]; p < 0.001). Risk factors for revision due to periprosthetic fracture were cementless fixation (OR 6.19 [95% CI 3.08 to 12.42]; p < 0.001) and higher Charlson comorbidity index (OR 1.16 [95% CI 1.06 to 1.28]; p = 0.002). Risk factors for early revision due to periprosthetic fracture were cementless fixation (OR 7.38 [95% CI 3.17 to 17.17]; p < 0.001), major teaching hospital (OR 2.10 [95% CI 1.08 to 4.10]; p = 0.03), and higher Charlson comorbidity index (OR 1.20 [95% CI 1.09 to 1.33]; p < 0.001). For the THA cohort, there were no associations. CONCLUSION: These data suggest that cemented fixation should be the preferred technique for most patients with displaced femoral neck fractures treated with hemiarthroplasty. The fact that stem fixation method did not affect revision rates for those patients with displaced femoral neck fractures treated with THA may be due to current practice patterns in the United States. LEVEL OF EVIDENCE: Level III, therapeutic study.

Kim, W. R., A. Mannalithara, J. K. Heimbach, P. S. Kamath, S. K. Asrani, S. W. Biggins, N. L. Wood, S. E. Gentry and A. J. Kwong (2021). “MELD 3.0: The Model for End-stage Liver Disease Updated for the Modern Era.” Gastroenterology Sep 2;S0016-5085(21)03469-7. [Epub ahead of print].

Full text of this article.

BACKGROUND: The model for end-stage liver disease (MELD) has been established as a reliable indicator of short-term survival in patients with end-stage liver disease. The current version (MELDNa), consisting of INR and serum bilirubin, creatinine, and sodium, has been used to determine organ allocation priorities for liver transplantation in the United States (US). The objective was to optimize MELD further by taking into account additional variables and updating coefficients with contemporary data. METHODS: All candidates registered on the liver transplant waitlist in the US national registry from Jan 2016 – Dec 2018 were included. Uni- and multivariable Cox models were developed to predict survival up to 90 days after waitlist registration. Model fit was tested using the concordance statistic and reclassification, and the liver simulated allocation model (LSAM) was used to estimate the impact of replacing MELDNa with the new model. RESULTS: The final multivariable model was characterized by (1) additional variables of female sex and serum albumin, (2) interactions between bilirubin and sodium and between albumin and creatinine, and (3) an upper bound for creatinine at 3.0mg/dL. The final model (MELD 3.0, henceforth), had better discrimination than MELDNa (concordance statistic 0.869 versus 0.862, p<0.01). Importantly, MELD 3.0 correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplant, particularly in women. In the LSAM analysis, MELD 3.0 resulted in fewer waitlist deaths compared to MELDNa (7,788 versus 7,850, p=0.02). CONCLUSION: MELD 3.0 affords more accurate mortality prediction in general than MELDNa and addresses determinants of waitlist outcomes including the sex disparity.

Karnam, R. S., S. Chen, W. Xu, C. Chen, P. Elangainesan, A. Ghanekar, I. McGilvray, T. Reichman, B. Sayed, M. Selzner, G. Sapisochin, Z. Galvin, G. Hirschfield, S. K. Asrani, N. Selzner, M. Cattral, L. Lilly and M. Bhat (2021). “Sex Disparity in Liver Transplant and Access to Living Donation.” JAMA Surg Aug 18;e213586. [Epub ahead of print].

Full text of this article.

IMPORTANCE: The Model for End-stage Liver Disease (MELD)-based organ allocation system has significantly decreased mortality on the transplant waiting list for patients with end-stage liver disease. However, women have remained at a disadvantage with respect to access to deceased donor liver transplant (DDLT) even after introduction of the MELD score for organ allocation. OBJECTIVE: To determine whether availability of living donation in a transplant program can offset inequity in liver transplant (LT) allocation for women. DESIGN, SETTING, AND PARTICIPANTS: This cohort study retrospectively analyzed adult patients listed for LT at the University Health Network in Toronto, Ontario, Canada. Patients included had a potential living donor (pLD) at the moment of listing. This study was performed from November 13, 2012, to May 31, 2019. A total of 1289 listed patients (830 men; 459 women) were analyzed during the study period. MAIN OUTCOMES AND MEASURES: This study performed survival analysis and competing-risk analysis to delineate how access to livers from living donors was associated with events in women vs men on the transplant waiting list (LT, death, or dropout). RESULTS: Of 1289 included patients, 459 (35.6%) were women, and the mean (SD) age was 56.1 (10.0) years at assessment and listing. A total of 783 of 1289 listed patients underwent LT. Among those with no pLD at assessment, there was a higher median (range) Model for End-stage Liver Disease incorporating sodium levels (MELD-Na) score at listing (22 [6-50] vs 19 [6-50]; P < .001) and at LT (27 [6-49] vs 20 [6-52]; P < .001) in women receiving DDLT. Women were at a significant disadvantage without a pLD (hazard ratio [HR], 1.29; 95% CI, 1.04-1.60; P = .01); there was no difference in access to LT with availability of a pLD (HR, 0.93; 95% CI, 0.76,-1.14; P = .44). The instantaneous rate of receiving a transplant in men with a pLD was 1.39 times higher than men who did not have a pLD (HR, 1.39; 95% CI; P < .001) and the instantaneous rate of receiving a transplant in women with a pLD was 1.92 times higher than in women who did not (HR, 1.92; 95% CI, 1.51-2.44; P < .001). The HR was 1.38 times higher in women compared with men across the MELD-Na score strata (HR, 1.38; 95% CI, 1.03-1.84; P = .03) and 2.04 times higher when the MELD-Na score was less than 20 (HR, 2.04; 95% CI, 1.31-3.14; P = .001). CONCLUSIONS AND RELEVANCE: These study findings suggest that women can overcome the complex problem of allocation inequity with access to livers from living donors. Women with access only to DDLT were much more unwell than men independent of liver disease at the time of listing, dropout, or LT. Therefore, the wider availability of living donation liver transplant would be helpful in addressing the sex disparity in access to LT in the current MELD-Na era.

Hong, S., L. Rybicki, A. Zhang, D. Thomas, C. M. Kerr, J. Durrani, M. A. Rainey, A. Mian, T. R. Behera, H. E. Carraway, A. Nazha, S. Mukherjee, A. S. Advani, B. Patel, M. Kalaycio, B. J. Bolwell, R. Hanna, A. T. Gerds, B. Pohlman, B. K. Hamilton, M. A. Sekeres, N. S. Majhail, J. P. Maciejewski, M. Askar and R. Sobecks (2021). “Influence of Killer Immunoglobulin-Like Receptors and Somatic Mutations on Transplant Outcomes in Acute Myeloid Leukemia.” Transplant Cell Ther Aug 8;S2666-6367(21)01110-6. [Epub ahead of print].

Full text of this article.

Natural killer (NK) cells are regulated by killer immunoglobulin-like receptor (KIR) interactions with human leukocyte antigen class I ligands. Various models of NK cell alloreactivity have been associated with outcomes after allogeneic hematopoietic cell transplant (alloHCT), but results have varied widely. We hypothesized that somatic mutations in acute myeloid leukemia (AML) in the context of KIR profiles may further refine their association with transplant outcomes. In this single-center, retrospective, observational study, 81 AML patients who underwent matched-related donor alloHCT were included. Post-HCT outcomes were assessed based on mutational status and KIR profiles with the Kaplan-Meier method and log-rank test. On multivariable analysis those with any somatic mutations and C1/C2 heterozygosity had less acute graft-versus-host disease (GvHD) (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14-0.75; P = .009), more relapse (HR, 3.02; 95% CI, 1.30-7.01; P = .010), inferior relapse-free survival (RFS; (HR, 2.22; 95% CI, 1.17-4.20; P = .014), and overall survival (OS; HR, 2.21; 95% CI, 1.17-4.20; P = .015), whereas those with a missing KIR ligand had superior RFS (HR, 0.53; 95% CI, 0.30-0.94; P = .031). The presence of a somatic mutation and donor haplotype A was also associated with less acute GvHD (HR, 0.38; 95% CI, 0.16-0.92; P = .032), more relapse (HR, 2.72; 95% CI, 1.13-6.52; P = .025), inferior RFS (HR, 2.11; 95% CI, 1.07-4.14; P = .030), and OS (HR, 2.20; 95% CI, 1.11-4.38; P = .024). Enhanced NK cell alloreactivity from more KIR activating signals (donor B haplotype) and fewer inhibitory signals (recipient missing KIR ligand or C1 or C2 homozygosity) may help mitigate the adverse prognosis associated with some AML somatic mutations. These results may have implications for improving patient risk stratification prior to transplant and optimizing donor selection.

Blouin, A. G., F. Ye, J. Williams and M. Askar (2021). “A practical guide to chimerism analysis: Review of the literature and testing practices worldwide.” Hum Immunol Aug 14;S0198-8859(21)00187-7. [Epub ahead of print].

Full text of this article.

BACKGROUND AND PURPOSE: Currently there are no widely accepted guidelines for chimerism analysis testing in hematopoietic cell transplantation (HCT) patients. The objective of this review is to provide a practical guide to address key aspects of performing and utilizing chimerism testing results. In developing this guide, we conducted a survey of testing practices among laboratories that are accredited for performing engraftment monitoring/chimerism analysis by either the American Society for Histocompatibility & Immunogenetics (ASHI) and/or the European Federation of Immunogenetics (EFI). We interpreted the survey results in the light of pertinent literature as well as the experience in the laboratories of the authors. RECENT DEVELOPMENTS: In recent years there has been significant advances in high throughput molecular methods such as next generation sequencing (NGS) as well as growing access to these technologies in histocompatibility and immunogenetics laboratories. These methods have the potential to improve the performance of chimerism testing in terms of sensitivity, availability of informative genetic markers that distinguish donors from recipients as well as cost. SUMMARY: The results of the survey revealed a great deal of heterogeneity in chimerism testing practices among participating laboratories. The most consistent response indicated monitoring of engraftment within the first 30 days. These responses are reflective of published literature. Additional clinical indications included early detection of impending relapse as well as identification of cases of HLA-loss relapse.