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Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone–derived cells as healthy experimental controls.

Clonal hematopoiesis (CH) is characterized by somatic mutations in blood cells of individuals without hematologic disease. While the mutational landscape of CH in peripheral blood (PB) has been well characterized, detailed analyses addressing its spatial and cellular distribution in the bone marrow (BM) compartment are sparse. We studied CH driver mutations in healthy individuals (n = 261) across different anatomical and cellular compartments. Variant allele frequencies were higher in BM than PB and positively correlated with the number of driver variants, yet remained stable during a median of 12 months of follow-up. In CH carriers undergoing simultaneous bilateral hip replacement, we detected ASXL1-mutant clones in one anatomical location but not the contralateral side, indicating intra-patient spatial heterogeneity. Analyses of lineage involvement in ASXL1-mutated CH showed enriched clonality in BM stem and myeloid progenitor cells, while lymphocytes were particularly involved in individuals carrying the c.1934dupG variant, indicating different ASXL1 mutations may have distinct lineage distribution patterns. Patients with overt myeloid malignancies showed higher mutation numbers and allele frequencies and a shifting mutation landscape, notably characterized by increasing prevalence of DNMT3A codon R882 variants. Collectively, our data provide novel insights into the genetics, evolution, and spatial and lineage-specific BM involvement of CH.

Background: Clonal hematopoiesis (CH) describes the presence of genetic alterations and expansion of clonal cell populations in the peripheral blood (PB) of individuals without clinical manifestation of a hematologic malignancy. CH is a common, age-related state. However, individuals carrying CH are at greater risk for hematologic cancer. It has been shown that presence of TP53- and other high-risk mutations, variant allele frequency (VAF) >10% or multiple mutations in CH carriers may confer a higher risk of preleukemic development and transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Nevertheless, further insights into the role of CH in clonal evolution towards leukemia and elaborating features that are predictive of leukemic progression are needed. Aims: We have recently shown that CH is common in individuals undergoing hip replacement surgery (Hecker, Hartmann et al., Blood 2021). Here, we compared mutational spectrum in these CH individuals to MDS and secondary AML (sAML) cohorts. Additionally, we analyzed spatial and lineage distribution of CH and longitudinally monitored CH and MDS clones over time. Methods: Samples from individuals without known hematologic disease undergoing hip replacement surgery (n=288 samples from 261 individuals), patients with MDS (n=92) or sAML (n=123) were screened for variants in 68 leukemia-associated genes using a targeted sequencing approach (VAF cut off, 1%). Follow-up (FU) PB samples were available for 21 individuals with CH and 16 untreated low-risk MDS patients, 6-24 months after screening. n=5 CH bone marrow (BM) samples carrying six ASXL1-mutations were sorted for seven different cell fractions. Results: At screening, variants were detected in 127/261 (49%) healthy individuals, 84/92 (91%) MDS and 117/123 (95%) sAML patients, with median VAFs of 2.7% (ranging from 1-44%), 18.8% (1.1-87%) and 37.1% (1-99%), respectively. Individuals with CH had a median number of 1 variant per individual, whereas median detected variants per patient increased with clonal evolution with 3 variants in the MDS and 4 variants per patient in the sAML cohort. CH, MDS and sAML showed entity-specific mutation profiles (Figure 1A). Most variants in CH affected epigenetic modifiers, while mutations in splicing factors, signaling pathways and transcription factors increased with clonal progression. During FU, untreated low-risk MDS patients more frequently gained additional mutations compared to CH individuals (7/16 vs 2/21, respectively; p=0.024). However, we did not observe significant changes in clone sizes over time. In 17 hip replacement individuals both femoral heads were removed simultaneously, allowing paired analysis of two different hematopoietic sites. CH prevalence in this subgroup was 70.6% (12/17). Ten individuals showed identical mutation patterns in BM obtained from the right and left femoral head, with little differences in VAFs (Table 1). In contrast, two other individuals showed significant differences in variant detection comparing one to the other side: ASXL1-mutations were only present in one hip sample, whereas all the other variants were detectable in both sides (p To further characterize ASXL1 mosaicism across hematopoietic lineages and differentiation stages, we sorted and sequenced n=5 CH BM samples carrying six ASXL1-mutations for seven different hematopoietic cell fractions. In all cases ASXL1-mutations were identified in CD34 +CD38 -CD90 + hematopoietic stem cells (HSC). VAFs of ASXL1-mutations were differentially distributed (p=0.0049, Kruskal Wallis test): detected VAFs were significantly higher in HSC and common myeloid progenitors (CMP) compared to VAFs in T-cells (p=0.045 and p=0.011, respectively; Dunn´s multiple comparison test; Figure 1B). Conclusions: CH, MDS and sAML show characteristic mutation profiles that remained stable over a 6-24-month period. Gains of additional variants and clonal expansion associated with disease progression. Cellular distribution analysis of ASXL1 CH variants revealed characteristic repartition patterns within the hematopoietic differentiation tree. Additionally, differences in variant detection between cellular BM compartments indicates spatial heterogeneity of CH clones warranting further investigation. J.S.H. and L.H. contributed equally. Figure 1 Figure 1. Disclosures Platzbecker: Geron: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Goetze: BMS/Celgene: Other: Advisory Board, Research Funding; Abbvie: Other: Advisory Board.

Background:Sequential bilateral total hip arthroplasty (THA) has the potential advantages of a single operative intervention with a single hospital stay, alongside reduced costs and total rehabilitation times. Its use has been limited, however, by a theoretical increase in perioperative complications.Objective:The purpose of this study was to assess functional outcomes and complications in patients undergoing sequential bilateral THA performed using anterior minimally invasive surgery (AMIS). We hypothesized that sequential bilateral THA yields favorable clinical outcome and is safe to perform.Methods:Two surgical centres conducted a retrospective observational analysis of 130 patients (77 females) with a mean age of 57 (range, 35-77) years, all of whom were treated by one surgeon and followed up for 24 months.Results:The mean length of hospital stay length was 8.4 (range, 6–18) days. The mean operative time was 162 (range, 92–185) minutes, the mean intraoperative blood loss was 499.1ml, and the mean preoperative and postoperative hemoglobin levels were 14.3 g/dl and 11.3 g/dl, respectively. No perioperative complications or deaths were recorded. The Harris Hip Score (HHS) improved from 44.5 ±13.7 preoperatively to 98.9 ± 1.0 at final follow-up. Also the High Activity Arthroplasty Score (HAAS) and the Questions on Life Satisfaction (FLZ) score improved significantly.Conclusion:This retrospective analysis suggests that, in selected patients, sequential bilateral THAviaan anterior minimally invasive approach appears to be a valid alternative to two-stage bilateral THA. Further studies are warranted.

This prospective 12 months of dual-energy X-ray absorptiometry (DEXA) study evaluated differences in periprosthetic bone mineral density in 40 patients undergoing cementless total hip arthroplasty (THA) by a minimally invasive anterior approach (AMIS), using Medacta AMIStem or Quadra stems. Both stems are straight rectangular. AMIStem shows reduced lateral flare and length in comparison to Quadra. The main goal of the study is to verify if bone mineral density is equivalent following THA with the AMIStem and Quadra femoral components. Forty patients were randomly allocated to the Quadra and AMIStem groups. Three patients were lost to follow-up because they moved to another town, and revision surgery was performed on one patient due to periprosthetic fracture after a car accident. Patients were examined clinically and underwent DEXA preoperatively and at 1 week, 6 weeks, 6 months, and 1 year after THA. Patients enrolled had no preexisting lower limb arthroplasty and no osteoporosis. Harris hip score increased significantly for Quadra stem 5.3 ± 14.1 and AMIStem 41.0 ± 13.4. The high-activity hip score increased significantly for Quadra stem 3.8 ±2.2 and AMIStem 4.1 ± 2.4. Considering 0.15 mg/cm2 as an acceptable difference, bone mineral density for AMIStem and Quadra groups was statistically equivalent. A limited remodeling process with slight bone loss in the proximal calcar region R7, as expected after implantation of uncemented components, was observed for both stems. The study demonstrates that the two stems are statistically equivalent in all zones at all time points investigated.

Introduction This prospective 12 months of dual-energy X-ray absorptiometry (DEXA) study evaluated differences in periprosthetic bone mineral density in 40 patients undergoing cementless total hip arthroplasty (THA) by a minimally invasive anterior approach (AMIS), using Medacta AMIStem or Quadra stems. Both stems are straight rectangular. AMIStem shows reduced lateral flare and length in comparison to Quadra.