Graft Source Research Articles

Сhanges in the donor site following bone-patellar tendon-bone graft harvesting with open or closed defects

Background. The patellar tendon is frequently used as a graft source for anterior cruciate ligament reconstruction. The search of the factors that enhance the healing process of the donor site may contribute to improved anatomical and functional outcomes. The aim of the study — to determine the features of the harvesting techniques for better donor site healing by examining postoperative changes in the patellar tendon following two different graft harvesting methods. Methods. This study examined the condition of the patellar tendon after two methods of graft harvesting under the same early mobilization protocols. Group 1 (retrospective) enrolled 30 patients who underwent follow-up MRI at different times after surgery, during which ligamentous and bony defects were not closed. Group 2 (prospective) included 30 patients who received full-layer suturing of the patellar tendon and patellar and tibial bone defects plasty. Postoperatively, all patients underwent radiography and the Insall-Salvati ratio of their patellar position was evaluated. In Group 2, MRI was performed preoperatively and 12 months post-surgery, while CT scans were taken 1 day and 6 months post-surgery. MRI was utilized to measure the size and qualitatively assess the condition of the tendon, whereas bone defects were evaluated on CT scans. Results. The Insall-Salvati ratio of patellar position was within the physiological norm and did not differ between the groups (M1 = 1.11; SD1 = 0.13 and M2 = 1.12; SD2 = 0.15; p = 0.955). In Group 2, after 12 months, the length of the tendon was 3.1% shorter (M = -1.4 mm; SD = 2.4 mm; p = 0.003). The width of the tendon in the upper third and middle third was slightly increased (M = 0.3 mm; SD = 2.4 mm; p = 0.502 and M = 0.5 mm; SD = 2.1 mm; p = 0.205), while in the lower third it was 2.7% larger (M = 0.7 mm; SD = 1.7 mm; p = 0.034). The thickness of the tendon increased by 55% (M = 2.4 mm; SD = 1.6 mm; p = 0.001). All patients in Group 1 exhibited persistent bony and ligamentous defects. In Group 2, six months after surgery, cancellous bone filled the defects and integrated with the bone bed; 12 months later, the tendon was healed, and its shape and size approximated preoperative parameters. Conclusion. Full-layer suturing of the patellar tendon, reconstruction of defects using cancellous bone autograft, and early mobilization promote the healing of bone defects and restore the integrity, shape, and size of the tendon.

The study on the preparation of mineralized recombinant humanized collagen type I composite by a two-step method and its performance for bone regeneration

Due to the limited sources of autologous and allogeneic bone grafts, recombinant humanized collagen (rhCol) has attracted wide attention owing to its high bioactivity, good water solubility, low immunogenicity, and no virus risk. Herein, we prepare the mineralized recombinant humanized collagen type I (MrhCol I) composite to alleviate the problems of low utilization rate and rapid degradation of rhCol and promote a higher ability for bone regeneration. Based on the water-soluble characteristic of rhCol, MrhCol I composite was prepared through in vitro mineralization utilizing the two-step method of precipitation-dialysis. MrhCol I composite confirmed the presence of hydroxyapatite with an element ratio of 1.67 for calcium to phosphorus, which was similar to that of natural bone. The stepwise degradation of composite was mainly caused by the release of collagen from unreacted collagen and collagen bonded with hydroxyapatite, respectively. After 4 weeks of degradation, the degradation rate of MrhCol I composite was 16.16 % compared to 4.95 % of hydroxyapatite. Meanwhile, the scanning electron microscopy images and infrared spectra showed that MrhCol I composite still contained collagen molecules. In addition, MrhCol I composite had an excellent ability to promote MC3T3-E1 cell proliferation and differentiation. After the material was implanted into the cranial defect site of rats, bone volume fraction (BV/TV) and bone mineral density (BMD) of composite were 16.90 % and 0.42 g/cc, which were higher than those in other groups. These results indicated that MrhCol I composite provided a novel bionic artificial bone material for treating clinical bone defects.

Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant haematological disorders. Peripheral blood stem cells represent the main stem cell source in malignant diseases due to faster engraftment and practicability issues compared with bone marrow stem cells. Since the early 2000s, there have been many developments in the clinical field. Allo-HSCT using haploidentical family donors (haplo-HSCT) has emerged as an alternative for people who do not have human leukocyte antigen (HLA)-matched siblings or unrelated donors. In addition, the introduction of new methods and strategies in allo-HSCT, such as the use of post-transplant cyclophosphamide (PT-Cy), better donor selection, the more frequent administration of anti-thymocyte globulins (ATGs), but also improved management of side effects such as graft-versus-host disease (GvHD) and infection, have impacted outcomes after allo-HSCT. In addition, as transplant indications and strategies continue to adapt in line with novel research findings, the effect of the stem cell source on post-transplant outcomes is unclear. For our analysis, we considered peripheral blood stem cells as the standard graft source for adults with haematological malignancies. This is an update of a review first published in 2014. To assess the effect of bone marrow transplantation versus peripheral blood stem cell transplantation in adults with haematological malignancies with regard to overall survival, disease-free survival, incidence of non-relapse or transplant-related mortality, incidence of extensive chronic graft-versus-host disease (GvHD), incidence of acute GvHD grades III to IV, incidence of overall chronic GvHD, and quality of life. For this update we searched CENTRAL, MEDLINE, Embase, and two trials registries on 2 November 2022 with no language restrictions. We included randomised controlled trials (RCTs) comparing bone marrow transplantation (BMT) with peripheral blood stem cell transplantation (PBSCT) in adults (aged ≥ 18 years) with haematological malignancies. Two review authors independently selected studies and extracted data. We evaluated risk of bias using the original Cochrane risk of bias tool (RoB 1), and we evaluated the certainty of the evidence using the GRADE approach. The updated search identified no new studies for inclusion. We found two additional reports relating to a previously included study; they provided new data on quality of life and infection rates after transplantation. As these are clinically relevant outcomes, quality of life was added to the summary of findings table (replacing acute GvHD II to IV), and rate of infection was added to our list of secondary outcomes. We included nine RCTs with a total of 1521 participants. Overall, the risk of bias in the included studies was low. Median participant age across studies ranged from 21 to 45 years, and studies took place in Canada, the USA, New Zealand, Brazil, Australia, Egypt, and across Europe. Bone marrow transplantation (BMT) compared with peripheral blood stem cell transplantation (PBSCT) likely results in little to no difference in overall survival (hazard ratio (HR) for all-cause death 1.07, 95% CI 0.91 to 1.25; 6 studies, 1330 participants; moderate-certainty evidence). There may be little to no difference between BMT and PBSCT in terms of disease-free survival (HR for disease recurrence or all-cause death 1.04, 95% CI 0.89 to 1.21; 6 studies, 1225 participants; low-certainty evidence) and non-relapse or transplant-related mortality (HR 0.98, 95% CI 0.76 to 1.28; 3 studies, 758 participants; low-certainty evidence). BMT compared with PBSCT likely results in lower rates of extensive chronic GvHD (HR 0.69, 95% CI 0.54 to 0.90; 4 studies, 765 participants; moderate-certainty evidence) and overall chronic GvHD (HR 0.72, 95% CI 0.61 to 0.85; 4 studies, 1121 participants; moderate-certainty evidence). BMT compared with PBSCT may reduce the incidence of acute GvHD grades III to IV, although the 95% CI of the HR is also compatible with no effect (HR 0.75, 95% CI 0.55 to 1.02; 3 studies, 925 participants; moderate-certainty evidence). Evidence from two trials that used different quality of life assessment instruments suggests that BMT compared with PBSCT may be associated with higher quality of life five years after transplantation. Moderate-certainty evidence suggests little to no difference in overall survival following allo-HSCT using bone marrow versus peripheral blood stem cells (the current clinical standard stem cell source). Low-certainty evidence suggests little to no difference between the stem cell sources in terms of disease-free survival and non-relapse or transplant-related survival. BMT likely reduces the risk of extensive chronic GvHD and overall chronic GvHD compared with PBSCT. Evidence from two RCTs suggests that BMT compared with PBSCT may result in higher long-term quality of life, possibly due to the lower chronic GvHD incidence. With this update, we aimed to supply the most recent data on the choice of stem cell source for allo-HSCT in adults by including new evidence published up to November 2022. We identified no new ongoing studies and no new RCTs with published results. Further research in this field is warranted.

Sociodemographic and Patient-Related Determinants of Outcomes after Allogeneic Hematopoietic Cell Transplantation in Acute Leukemia and Myelodysplastic Syndromes

Background: Allogeneic hematopoietic stem cell transplant (allo-HCT) is a curative therapy for several high-risk hematologic disorders. Sociodemographic determinants (age, gender, and ethnicity) and patient-related factors (frailty and comorbidities) significantly impact post-transplant outcomes. We aimed to investigate the impact of sociodemographic and patient-related factors on allo-HCT outcomes. Methods: A retrospective multicenter analysis was conducted, including allo-HCT patients in the publicly available Center for International Blood and Marrow Transplant (CIBMTR) registry from 2013 to 2018 using P5646 data by Ramathan et al. Cox regression was performed to compare overall survival (OS), disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD), and platelet and neutrophil engraftment. Multivariate analyses were performed for recipient age, gender, ethnicity, Karnofsky's performance status (KPS), and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and adjusted for significant variables identified in the univariate analysis. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. SPSS version 28 and R version 4.16 were used for data analysis. Statistical significance was considered at p <0.05. Results: We included 7545 allo-HCT recipients. The median age at the time of transplant was 56 years, and 58% were men. Ethnicities were Caucasian (76%), Hispanic (8%), African American (6%), Asian (5%), and others (5%). The primary disorders included acute myeloid leukemia (47.2%), myelodysplastic syndrome (34.4%), and acute lymphoblastic leukemia (18.4%). Myeloablative conditioning was used in 53% of patients. Donor types were matched unrelated (49.5%), matched related (34.1%), and cord blood (16.4%). Graft sources were peripheral blood stem cells (68%), umbilical cord blood (16%), and bone marrow (16%). GVHD prophylaxis regimens included tacrolimus or cyclosporine-based (87%), post-transplant cyclophosphamide-based (9%), CD34 selection (2%), and others (2%). The KPS was 90% or higher (57%), 80-89 (29%), and <80 (14%). The HCT-CI was 0 (20%), 1-2 (30%), 3-4 (31%), and five or higher (19%). In the multivariate analyses adjusted for all significant predictors identified in the univariate analyses, significant predictors of outcomes included - inferior OSwas predicted by older age (HR 1.01, 95% CI 1.01-1.10, p<0.001), male gender (HR 1.08, 95% CI 1.00-1.15, p=0.030), lower KPS (HR 1.33, 95% CI 1.20-1.46, p<0.001), and higher HCT-CI (HR 1.71, 95% CI 1.53-1.92, p<0.001); lower DFSwas predicted by older age (HR 1.013, 95% CI 1.010-1.016 p<0.001), lower KPS (HR 1.30,95% CI 1.12-1.50, p<0.00), and higher HCT-CI (HR 1.66, 95% CI 1.41-1.95, p<0.001); higher NRMwas predicted by older age (HR 1.01, 95% CI 1.01-1.02, p<0.001), male gender (HR 1.13, 95% CI 1.00-1.28), lower KPS (HR 1.23, 95% CI 1.04-1.46, p=0.018), and higher HCT-CI (HR 2.17, 95% CI 1.77-2.65, p<0.001); higher rate of relapsewas predicted by older age (HR 1.01, 95% CI 1.01-1.01, p<0.001), lower KPS (HR 1.23, 95% CI 1.10-1.38, p<0.001), and higher HCT-CI (HR 1.15, 95% CI 1.02-1.30, p=0.020); higher incidence of chronic GVHD was predicted by older age (p<0.001, HR 1.01, 95% CI=1.0008-1.012), male gender (HR 1.12, 95% CI 1.04-1.20, p=0.003), and lower KPS (HR 1.134, 95% CI 1.01-1.27, p=0.028); and delayed neutrophil engraftment was predicted by older age (HR 1.01, 95% CI 1.01-1.01, p<0.001). No other significant associations were observed between these factors and post-transplant outcomes. Conclusion: The analyses identified sociodemographic factors (older age, male gender), frailty, and higher comorbidities as predictors of post-transplant outcomes, including inferior overall and disease-free survival, higher risk of relapse and non-relapse mortality, and increased incidence of chronic graft-versus-host disease in patients with acute leukemia and myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplantation. Our findings highlight the relevance of developing patient-centered interventions and a tailored selection of disease- and transplant-related factors to improve post-transplant outcomes.

Cytokine Release Syndrome in HSCT May Affect Dendritic Cell Recovery and Early Development of aGVHD

Background: Cytokine release syndrome (CRS), also known as cytokine storm, is a severe systemic inflammatory response triggered by the activation of immune cells and the release of large quantities of cytokines and is characterized by fever and multi-organ dysfunction. With the spread of hematopoietic stem cell transplantation therapy, CRS is no longer limited to complications after chimeric antigen receptor T therapy. Acute graft-versus-host disease (aGVHD) represents a significant contributor to early mortality following allo-HSCT, exhibiting a notable morbidity. Dendritic cells (DCs) are non-redundant in regulating immunity and tolerance. Clinical and preclinical studies suggest that impaired reconstitution of donor DCs is associated with an increased risk of severe aGVHD. However, the relation of donor DCs with CRS is unknown. Methods: Fifty patients with acute leukemias undergoing allo-HSCT at the Children's Hospital of Soochow University were eligible for this study. Peripheral blood samples were collected from the patients after allo-HSCT, and DC subsets were analyzed by flow cytometry. CRS was defined as a new fever of 38°C or higher within 5 days of HSCT based on the absence of any evidence of infection. Univariate and multivariate logistic regression analyses were utilized to investigate the association between cytokine release syndrome (CRS), pDC reconstitution levels, and the occurrence of aGVHD. Mediation analysis was performed to explore the interrelationships between CRS, pDC reconstitution levels, and aGVHD. Results: The study cohort included acute myeloid leukemia (AML) (n=16, 32%), acute lymphoblastic leukemia (ALL) (n=32, 64%), and mixed phenotype acute leukemia (MPAL) (n=2, 4%). 49 graft source were PB /BM and 1 graft source was UCB. 36 graft types were HID, 11 were MURD , 3 were MRD and 1 was UCB. In the study, CRS occurred in 29 children, 48% on the day of transplantation and 38% on the first day after transplantation, with a median fever peak of 39.0°C (38.0, 40.4°C). 22 of the 29 children who developed CRS developed aGVHD within one month. Patients developing CRS after HSCT were found to have a lower frequency and several pDCs (median frequency, 0.01%; range, 0.00~0.06%, median number, 0.13cell/μl, range, 0.03~0.29 cell/μl) than patients without CRS (median frequency, 0.10%, range, 0.04%~0.17%, P=0.003; mediate number, 0.34 cell/μl, range, 0.18~0.62cell /μl, P=0.05). Patients who developed CRS showed significantly lower frequency CD1c+DCs (median, 0.02%; range, 0.01%~0.13%) than patients without CRS (median frequency, 0.15%; range, 0.03%~0.26%, P=0.017). The occurrence of CRS (Odd ratio [OR] = 10.06 [95%CI 2.89-41.15], p < 0.001) and pDC reconstitution levels (OR = 0.23 [95%CI 0.08-0.49], p < 0.001) were found to be associated with aGVHD, which occurred during the first month after transplantation. Based on mediation analysis, with pDC reconstitution level as the mediator, we found that the total effect of CRS on aGVHD was 0.52 (0.26 ~ 0.73, p < 0.001 ), the average direct effect (ADE) of CRS on aGVHD was 0.37 (0.079 ~ 0.64, p < 0.001), and the average causal mediation effect (ACME) of pDCs was 0.14 (0.06 ~ 0.29, p < 0.001 ). These data suggest that the CRS is linked to the occurrence of aGVHD, especially during the first month after HSCT, and this may be achieved by influencing the immune reconstitution of pDCs. Conclusion: CRS was associated with the level of pDC reconstruction and the development of aGVHD within one month after HSCT. CRS promotes the occurrence of aGVHD, whereas pDC reconstruction level is a protective factor. It would be beneficial to investigate the mechanisms by which CRS affects the immune reconstitution of DCs, particularly pDCs, in the initial stages of HSCT and subsequently influences the development of aGVHD. This could potentially lead to the control of the initial trigger for aGVHD.

Sociodemographic Determinants of Allogeneic Hematopoietic Stem Cell Transplant Outcomes

Background: Allogeneic hematopoietic stem cell transplant (allo-HCT) is a curative therapy for several high-risk hematologic disorders. While clinical factors significantly impact post-transplant outcomes, socio-demographic determinants such as age, gender, and ethnicity play a crucial role in the success of allo-HCT. Furthermore, performance status and comorbidities also affect the outcomes. We aimed to investigate the influence of socio-demographic determinants on allo-HCT outcomes. Methods: For this retrospective single-center study, we included all patients undergoing matched unrelated donor (MUD) and haploidentical (haplo) allo-SCT at the University of Kanas Medical Center from August 2016 to July 2021. Cox regression analysis compared overall survival (OS) and disease-free survival (DFS). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Logistic regression was performed to compare relapse, non-relapse mortality (NRM), acute and chronic graft versus host disease (GVHD), and GVHD-free Relapse-free survival (GRFS). Odds ratios (0R) with 95% CI were calculated. Linear regression was performed to compare platelet and neutrophil engraftment, and the correlation coefficient (R) was calculated. Multivariate analyses were performed for recipient age, gender, ethnicity, Karnofsky's performance status (KPS), and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). SPSS version 28 and R version 4.16 were used for data analysis. Statistical significance was considered at p<0.05. Results: A total of 452 patients were included, of which 276 had MUD allo-HCT while 176 had haplo allo-HCT. The median age of the recipients was 57 years (18-77), of which 61% were male (n=277). Ethnicity was Caucasians (n=381, 84%), Hispanics (n=28, 6%), African Americans (n=20, 5%), and others (n=23, 5%). KPS was 60-80% in 67% (n=304) patients and 90% or higher in 33% (n=148) of patients. Fifty-six percent of patients (n=251) had an HCT-CI score of 3 and above. Myeloablative and reduced-intensity conditioning were performed in 169 (37%) and 283 (63%) recipients. The graft source was bone marrow in 224 (49.6%) and 228 (50.4%) had peripheral blood stem cell grafts. The median graft cell dose was 4 million CD34 cells/kg. GVHD prophylaxis included tacrolimus/methotrexate (n=241, 53%) and post-transplant cyclophosphamide-based (n=211, 47%). Hematologic diagnoses included myeloid (n=322, 71%), lymphoid (n=101, 22%), and others (n=29, 7%). In univariate analyses for recipient age, gender, ethnicity, KPS, and HCT-CI, predictors include OS: age (years, HR 1.03, 95% CI 1.01-1.04, p<0.001), HCT-CI (≥3 vs 0-1: HR 1.40, 95% CI 1.03-1.91, p=0.030), and KPS (60-80% vs ≥90%: HR 1.61, 95% CI 1.14-2.26, p=0.006); DFS: age (years, HR 1.02, 95% CI 1.01-1.03, p<0.001) and KPS (60-80% vs ≥90%: HR 1.41, 95% CI 1.04-1.90, p=0.028); GRFS: None; Relapse: None; NRM: age (years, HR 1.02, 95% CI 1.01-1.04, p=0.001); acute GVHD: gender (male vs female, HR 0.59, 95% CI 0.40-0.87, p=0.007); chronic GVHD: KPS (60-80% vs ≥90%: HR 0.64, 95% CI 0.43-0.96, p=0.029); engraftment: None. Multivariate models were adjusted for all significant predictors identified in the univariate analyses. After adjusting for confounders, higher recipient age significantly predicted inferior OS (HR 1.10, 95% CI 1.01-1.04, p=0.0084), inferior DFS (HR 1.02, 95% CI 1.01-1.03, p=0.0012), and higher NRM (OR 1.03, 95% CI 1.01-1.04, p=0.005). Male gender significantly predicted lower risk of acute GVHD ((OR 0.59, 95% CI 0.40-0.86, p=0.007). African American ethnicity compared to Caucasians significantly predicted inferior OS (HR 1.90, 95% CI 1.01-3.58, p=0.046). KPS was a significant predictor of a higher risk of chronic GVHD (HR 0.62, 95% CI 0.40-0.95, p=0.028). HCT-CI did not predict any of the outcomes. No other significant associations were observed between these factors and post-transplant outcomes. Conclusion: In this single-center study, recipient age significantly affected OS, DFS, and NRM. The recipient's gender had a notable impact on acute GVHD, while ethnicity influenced OS. KPS was associated with chronic GVHD; interestingly, HCT-CI had no impact on post-transplant outcomes. Our findings suggest the need for larger studies to explore and mitigate the sociodemographic determinants of transplant outcomes.

Impact of Donor Age and Gender on Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplant (allo-SCT) is critical in managing hematologic disorders. Donor age and gender are essential factors for post-transplant outcomes, and younger male donors have been associated with improved outcomes. We aimed to investigate the impact of donor age and gender on outcomes in patients undergoing matched unrelated donor (MUD) and haploidentical (haplo) allo-SCT. Methods: For this retrospective single-center study, we included allo-SCT recipients who received a MUD (n=276) or haplo (n=176) SCT at the University of Kanas Medical Center from August 2016 to July 2021. Cox regression analysis compared overall survival (OS) and disease-free survival (DFS). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Logistic regression was performed to compare relapse, non-relapse mortality (NRM), acute and chronic graft versus host disease (GVHD), and GVHD-free Relapse-free survival (GRFS). Odds ratios (0R) with 95% CI were calculated. Linear regression was performed to compare platelet and neutrophil engraftment, and the correlation coefficient (R) was calculated. Multivariate analyses were performed for donor age as a continuous and categorical variable (<30 years vs 30 years and above). SPSS version 28 and R version 4.16 were used for data analysis. Statistical significance was considered at p<0.05. Results: We included 452 Allo-SCT recipients who received a MUD (n=276) or Haplo (n=176) SCT. The median recipient age was 57 (18-77) years and 277 (61%) were male. The median age of the donor was 28 (10-65) years, with 57% of donors being younger than 30 years. Seventy-one percent (n=331) of donors were male. Myeloablative and reduced-intensity conditioning were performed in 169 (37%) and 283 (63%) recipients. The graft source was bone marrow in 224 (49.6%), and 228 (50.4%) had peripheral blood stem cell grafts. The median graft cell dose was 4 million CD34 cells/kg. GVHD prophylaxis included tacrolimus/methotrexate (n=241, 53%) and post-transplant cyclophosphamide-based (n=211, 47%). Hematologic diagnoses included myeloid (n=322, 71%), lymphoid (n=101, 22%), and others (n=29, 7%). After adjusting for significant variables in the multivariate regression models, OS was not affected by the donor age (HR 1.005, 95% CI 0.991-1.021, p=0.476) and donor age <30 years (HR 0.923, 95% CI 0.681-1.252, p=0.608). Donor age had a marginal association with relapse (donor age: OR 0.974, 95% CI 0.950-0.997, p=0.032; donor age <30 years: OR 1.760, 95% CI 1.131-2.775, p=0.013) and NRM (donor age: OR 1.025, 95% CI 1.001-1.048, p=0.034; donor age <30 years: OR 0.656, 95% CI 0.417-1.031, p=0.067). The donor's age did not affect GRFS, DFS, acute and chronic GVHD, and engraftment. Allo-SCT with male donors had superior OS (HR 0.626, 95% CI 0.452-0.868, p=0.0049) compared to female donors. Faster platelet engraftment was observed using male donors (R -4.212, -7.90 to -0.517, p=0.0250). GRFS, Relapse, DFS, NRM, acute and chronic GVHD, and neutrophil engraftment were not affected by donor gender. Conclusion: The use of male donors was associated with superior overall survival and faster platelet engraftment, while donor age did not significantly impact post-transplant outcomes. Our findings suggest improved survival with the use of male donors regardless of donor age, and these findings should be validated in a larger contemporary cohort.

Impact of Systemic Antibiotics Use on Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Post-transplant complications lead to significant morbidity and mortality in the management of patients undergoing allogeneic hematopoietic stem cell transplant (allo-HCT). Broad-spectrum systemic antimicrobials and better prophylaxis strategies have reduced infection-related morbidity and mortality in allo-HCT patients. However, broad-spectrum antibiotic use disrupts the microbiome and immunome, which may result in poor post-transplant outcomes. We aimed to evaluate the impact of systemic antibiotics on allo-HCT outcomes. Methods: A retrospective multicenter analysis was conducted, including allo-HCT patients in the publicly available Center for International Blood and Marrow Transplant (CIBMTR) registry from 2013 to 2018 using P5646 data by Ramathan et al. Chi-square and t-tests were used to compare categorical and continuous baseline demographics. Multivariate Cox regression analyses were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for overall survival (OS), disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), engraftment, and infection-related mortality between the two groups. Statistical analysis was conducted using R version 4.16, with statistical significance defined as p <0.05. Results: Among 7524 allo-HCT patients, 5779 were administered broad-spectrum systemic antibiotics (SA) while 1745 were not given systemic antibiotics (NSA). The median age was 58.58 years (range: 2.03-82.67) in the SA group and 56.18 years (range: 2.00 - 77.86) in the NSA group, and 58% were men in both groups. Ethnicities were Caucasian (76%), Hispanic (8%), African American (6%), and others (10%). The primary disorders included acute myeloid leukemia (47%), myelodysplastic syndrome (35%), and acute lymphoblastic leukemia (18%). Myeloablative conditioning was used in 53% of patients. Donor types were matched unrelated (49.5%), matched related (34%), and cord blood (16%). Graft sources were bone marrow (15%), peripheral blood stem cells (68%), and cord blood (16%). GVHD prophylaxis regimens included Tacrolimus and Cyclosporine-based (77%), post-transplant Cyclophosphamide-based (9%), Ex vivo T-cell depletion or CD34 selection (3%), and others (11%). In the multivariate regression analyses, systemic antibiotics independently predicted poor OS (55% SA vs 57% NSA; HR 1.13, 95% CI 1.01-1.22, p=0.026). Higher incidence of NRM (19% SA vs 15% NSA; HR 1.32, 95% CI 1.12-1.55, p=0.001), grade 2-4 aGVHD (41% SA vs 34% NSA; HR 1.24, 95% CI 1.12-1.38, p<0.001), and cGVHD (40% SA vs 39% NSA; HR 1.12, 95% CI 1.01-1.24, p=0.040) were observed with SA use. The two groups had no significant difference in DFS, relapse, infection-related mortality, and engraftment rates. The outcomes analyses were adjusted for the significant predictors identified in the univariate analyses. Conclusion: Systemic antibiotics use in allo-HCT patients is associated with higher morbidity and mortality. Judicious use and de-escalation of systemic antibiotics when safe may help to improve post-transplant outcomes. Future research exploring microbiome restoration could result in better post-transplant outcomes.

Representativeness of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Trial Participants

Underrepresentation by race and ethnicity in oncology clinical trials, including those of hematopoietic cell transplantation (HCT), is a known challenge. This analysis studied accrual on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials conducted in 2014 to 2020 by race/ethnicity, age, and sex, comparing these characteristics with those of potentially eligible patients identified from the Surveillance, Epidemiology, and End Results (SEER) and Center for International Blood and Marrow Transplant Research (CIBMTR) databases for the disease, age, and years of interest of BMT CTN studies. Five BMT CTN trials met the inclusion criteria, including 1 autologous HCT trial and 4 allogeneic HCT trials. Two studies focused on multiple myeloma (BMT CTN 1302 and 1401), 2 studies focused on graft-versus-host disease (GVHD) treatment (BMT CTN 1301 and 1501), and 1 study focused on post-HCT maintenance therapy in FLT3+ acute myelogenous leukemia (BMT CTN 1506). A decline in the proportion of patients from minority racial and ethnic groups was seen from the SEER population to trial enrollees, with the largest drop seen between the SEER population and all patients who underwent HCT (on or off trial) at US transplant centers. Allogeneic HCT trials that allowed alternative donor graft sources had less decrease from the SEER population. No decrease in clinical trial enrollment was seen with respect to older age and female HCT recipients. This study provides insight into the underrepresentation of racial and ethnic minority patients in BMT CTN clinical trials, owing largely to lack of access to HCT in general. Pathways expanding access to donors and improving the outreach of HCT programs to underserved populations are needed to improve access to clinical trials.

Understanding Risk Factors for Cytomegalovirus Infection in Pediatric Hematopoietic Stem Cell Transplantation: Insights From a 10-Year Study Comparing Conditioning Regimens.

Hematopoietic stem cell transplantation is a curative therapy for pediatric patients with malignancies and blood or immune system disorders. However, recipients are at risk of opportunistic infections, including cytomegalovirus infection, due to immunosuppression from conditioning regimens. This retrospective study analyzed 439 pediatric hematopoietic stem cell transplantation patients to identify risk factors for cytomegalovirus infection and assess the impact of conditioning regimens. Significant factors included graft source, graft versus host disease, and pre-transplant clinically significant cytomegalovirus infection. Myeloablative conditioning regimens and the use of anti-thymocyte globulin increased the risk of clinically significant cytomegalovirus infection. Additionally, the risk of cytomegalovirus infection in patients was found to be statistically significant in the myeloablative subgroup analyses who received anti-thymocyte globulin alone and those who received both anti-thymocyte globulin and total body irradiation. In our study, total body irradiation did not significantly affect the risk of clinically significant cytomegalovirus infection. This study covers a 10-year period and a large pediatric patient population from a single center. Our findings highlight the importance of understanding risk factors for clinically significant cytomegalovirus infection to guide preventive strategies in pediatric HSCT recipients.

Early bone graft donor site morbidities; anterior superior iliac crest versus proximal tibia.

Autogenous bone grafting is a widely used technique in orthopaedic and reconstructive surgeries. The anterior superior iliac crest (AIC) and proximal tibia (PT) are common sources for bone grafts. While, AIC is the gold standard, PT is popular for lower extremity procedures due to its proximity. The research investigates early complications associated with these donor sites in a tertiary orthopaedic centre in Nigeria. This randomized controlled study was conducted from July 2020 to December 2021. It includes 66 patients randomized into AIC and PT groups. Pain score analysis and the incidence of surgical site infections were compared between both groups. There was no statistical difference in the incidence of surgical site infections (SSI) in both groups. The study also reveals that patients in the AIC group experienced more significant pain in the immediate postoperative period and up to two weeks after surgery, with the severity particularly pronounced on the first postoperative day. (p < 0.001). The PT had less pain severity than the AIC bone graft donor sites. The authors recommend that surgeons consider PT if bone grafting is required.

Bone Graft and Fixation Options in the Surgical Management of Scaphoid Nonunion.

Scaphoid nonunions are a complex challenge that are frequently encountered by hand surgeons. Because of the tenuous blood supply of the scaphoid and secondary deformities that occur as a result of delayed or unsuccessful treatment, the treatment of scaphoid nonunions frequently requires the use of internal fixation and supplemental bone graft. There are multiple bone graft sources and techniques that can be employed based on the patient, the viability of the proximal pole fragment, and the presence of a deformity. Without osteonecrosis or disruption of the scaphoid blood supply, nonvascularized autologous grafts can be used from the distal radius, proximal ulna, or iliac crest. In cases where there is concern for an insufficient blood supply, vascularized bone graft sources can be employed, including pedicled local grafts and free flap grafts. When there is a nonviable and fragmented proximal pole, using osteochondral autografts has become increasingly used to reconstruct the scaphoid. Bone graft substitutes can additionally be used to supplement the fixation construct. This review focuses on the indications and role of bone grafts in scaphoid nonunions to help augment internal fixation, promote healing, and restore carpal alignment.

Infection-Related Mortality in Children Undergoing Hematopoietic Stem Cell Transplants at a Referral Center in Mexico

Abstract Background Infections constitute a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, infection-associated mortality rate ranging from 7% to 17% has been reported, depending on the type of HSCT, being lower in autologous transplants and higher in cases involving unrelated donors. Other factors related to HSCT that influence the clinical outcomes of these patients include the intensity of the conditioning regimen, the development of graft-versus-host disease (GVHD), cytotoxic and immunosuppressive effects of the medications used, the presence of disease activity prior to HSCT, length of hospital stay, and the use of intravascular devices, among many others. Methods All pediatric patients (under 16 years old) undergoing HSCT at the ‘Dr. José Eleuterio González’ University Hospital over a 55-month period (March 2019 – October 2023) were included. Clinical and epidemiological characteristics of the patients, mortality rate, and risk factors related to transplantation and infectious events (IEs) in these patients were recorded. Results A total of 75 patients who received HSCT were included, among them, 52 patients (69%) presented IEs. The mortality associated with IEs among these patients was 6% at day 30 and 12% at day 100, compared to 0% and 1.3% respectively in the non-IEs related deaths. The epidemiological characteristics, baseline diagnosis, donors and graft source are described in table 1. The average number of IEs in the associated mortality cases was 2.8 compared to 1.6 in the survival group. Among the mortality group (8 cases), 67% presented multiple infections and 33% single infections, with a 75% of them caused by viral infections. Regarding HSCT characteristics, in the group with IE-associated mortality, a higher proportion of haploidentical transplants, myeloablative conditioning regimens, lower use of total body irradiation, and a higher proportion of patients with detectable disease by flow cytometry prior to HSCT were observed compared to the survival group. Among non-infectious complications related to HSCT a lower frequency of acute GVHD grade I-II, a higher frequency of acute GVHD grade III-IV in the IE-associated mortality group was identified. Among the risk factors associated with hospital care, the IE-associated mortality group showed a higher use of central venous catheters, mucositis, systemic steroids, and pediatric intensive care unit stay compared to the survival group. Conclusion Pediatric patients undergoing HSCT present multiple risk factors that increase the incidence of infectious events and contribute to higher mortality rates. It is crucial to identify those factors related to adverse events and death to implement strategies that reduce exposure to these factors and improve the clinical outcomes.

Total Marrow and Lymphoid Irradiation (TMLI) Is Associated with Good Early Outcomes in Patients Undergoing Matched Sibling Donor and Haplo-identical Transplants for Acute Lymphoblastic Leukemia

Total marrow and lymphoid irradiation [TMLI] can deliver higher doses of irradiation without increased toxicity. This study evaluated TMLI and Cyclophosphamide in patients undergoing stem cell transplantation for acute lymphoblastic leukemia [ALL] . Fifty-eight patients underwent matched related, unrelated or haplo-identical donor transplant using TMLI. The graft source was PBSC in all while GVHD prophylaxis consisted of cyclosporine with methotrexate or post-transplant cyclophosphamide. The median age was 20 years [range: 5 - 49] and included 20 children. Engraftment occurred in 56 [96.5%] at median of 15 days [range: 12 - 23] with 2 early deaths. Sinusoidal obstruction syndrome [SOS] was seen in 10 patients while hemorrhagic cystitis and cardiac dysfunction occurred in 2 patients each. Cumulative incidence of grade II - IV acute GVHD was 23.6% while grade III - IV was 10.9%. Chronic GVHD was seen in 46.9% while relapse was seen in 10 patients [17.2%]. The 2-year overall survival [OS] was 65.9 ± 6.8% and 2-year disease free survival [DFS] was 59 ± 6.7%. Outcomes were compared with 52 patients who received either Cy/TBI or Flu/Bu4 for conditioning during the same period. Engraftment rates and time to engraftment were similar. Acute GVHD [p = 0.002], regimen related toxicity [p = 0.043] and Day 100 non-relapse mortality [p = 0.020] were significantly lower with TMLI. TMLI was associated with better OS [p = 0.004] and DFS [p = 0.005] for haplo-identical transplants. Better DFS was seen with TMLI in patients with high-risk disease [p = 0.007] and disease status > CR1 [p = 0.041]. The use of TMLI and cyclophosphamide is associated with good outcomes in patients undergoing HSCT for ALL especially with haploidentical stem cell transplants.

A simplified and robust risk stratification model for stem cell transplantation in pediatric acute myeloid leukemia

The efficacy of stem cell transplantation (SCT) in pediatric acute myeloid leukemia (pAML) remains unsatisfactory due to the limitations of existing prognostic models in predicting efficacy and selecting suitable candidates. This study aims to develop a cytomolecular risk stratification-independent prognostic model for SCT in pAML patients at CR1 stage. The pAML SCT model, based on age, KMT2A rearrangement (KMT2A-r), and minimal residual disease at end of course 1 (MRD1), effectively classifies patients into low-, intermediate-, and high-risk groups. We validate the effectiveness in an internal validation cohort and in four external validation cohorts, consisting of different graft sources and donors. Moreover, by incorporating the FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) allelic ratio, the pAML SCT model is refined, enhancing its ability to effectively select suitable candidates. We develop a simple and robust risk stratification model for pAML patients undergoing SCT, to aid in risk stratification and inform pretransplant decision-making at CR1 stage.

Fresh Femoral Head Allograft in Distal Femur Cartilage Lesions. A Case Series

Abstract Background Fresh osteochondral allograft transplantation is a good treatment option of cartilage defects. However, this treatment option is not available in all countries due to limited graft availability and tissue banks limitations. The purpose of this study is to assess the short term functional and imaging outcomes of fresh osteochondral allograft transplantation in the knee using the femoral head of living donors. Hypothesis Fresh osteochondral allografts from the femoral heads of living donors is a valid graft source for management of distal Femur cartilage defects. This technique can improve functional knee scores with good radiological outcomes. Study Design Prospective case series. Methods Ten patients with full thickness cartilage defects of the distal femur underwent osteochondral allograft transplantation from the femoral heads of living donors. Grafts were transplanted by both shell and multiple dowels techniques. The average follow up duration was 9.4 months (range, 6-13 months). Patients were evaluated by Lysholm and International Knee Documentation Committee (IKDC) scores, radiography and MR imaging using Osteochondral Allograft MRI Scoring System (OCAMRISS). Results There was a statistically significant improvement (P &amp;lt; 0.001) in both Lysholm (52 to 83) and IKDC (40 to 80) average scores at 6 months postoperative. Postoperative MRI was done at an average 6.8 months (range, 5-11 months) postoperative. The mean total OCAMRISS score was 3.4 (range, 1-7). A second look arthroscopy was done in three patients and showed intact articular cartilage in all three patients. Conclusion Femoral head of living donors is a valid new source for fresh osteochondral allograft transplantation of knee osteochondral lesions. Short term results showed improvement in clinical assessment scores. Follow up imaging showed graft incorporation and good MRI scores.

Placenta as a source of autologous graft in postnatal correction of myelomeningocele.

This integrative literature review aims to discuss the benefits and limitations of postnatal surgery to correct myelomeningocele using the placenta as an autologous graft used on the lesion; in addition, it seeks to highlight the placental properties and the benefits and indications of surgery. For this production, the PRISMA criteria were used. PubMed was used as a database on October 19, 2023, and three searches were made, all using the words "myelomeningocele" and "surgery" varying only between "amnion," "placenta," and "chorion" as the third word. A total of 91 articles were found, and after analysis of duplicates and inclusion and exclusion criteria, only 11 articles were used in this systematic review. Properties of the amniotic membrane were observed, such as anti-inflammatory, stimulation of native tissue growth, regenerating action by the secretion of neutrophil factors, promotion of epithelialization, inhibition of fibrosis and healing, and antibacterial effect. It is observed that there are benefits in using the placenta as an autograft and there are contradictions between the periods of surgery. Due to its properties that accelerate healing, the absence of the possibility of rejection, and its easy access make this choice more frequently adopted. We are confident in saying that the effectiveness of the amniotic membrane is widely reliable.

Hematopoietic stem cell transplantation activity in China 2022-2023. The proportions of peripheral blood for stem cell source continue to grow: a report from the Chinese Blood and Marrow Transplantation Registry Group.

Over past two years, a total of 39,918 hematopoietic stem cell transplantation (HSCT) cases were reported, with 18,194 and 21,714 transplants performed in 2022 and 2023, respectively. Autologous HSCT accounted for 6562 cases (31%) in 2022, while allogeneic HSCT comprised 12,632 cases (69%). In 2023, the number of allogeneic HSCTs exceeded 15,000, maintaining a 69% share. Participation in the 2022 and 2023 surveys included 193 and 212 transplantation teams, respectively, from 27 provinces, municipalities, or autonomous regions. The leading indication of HSCT was acute leukemia, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed phenotype acute leukemia, with a total of 17,421 cases. AML was the most common disease (10,339, 38%) for allogeneic HSCT, which was followed by ALL (5925 cases, 21%). Peripheral blood emerged as the primary source of stem cell grafts, utilized in 54% of matched sibling donor transplants and 77% of haploidentical donor transplants. The BuCy-based conditioning regimen was the most prevalent, used in 53% of allogeneic HSCT cases in the past two years. This survey offers a comprehensive overview of the current HSCT landscape and serves as a valuable resource for clinical practice.

Peroneus Longus vs Hamstring Tendon Autografts in ACL Reconstruction: A Comparative Study of 106 Patients' Outcomes.

BACKGROUND Anterior cruciate ligament (ACL) reconstruction commonly uses a hamstring tendon autograft, but the peroneus longus tendon can also be used. This study aimed to compare outcomes of anterior cruciate ligament reconstruction in 106 patients using peroneus longus tendon and hamstring tendon autografts. MATERIAL AND METHODS ACL repair was performed on 54 patients using a hamstring tendon autograft and 52 patients with a peroneus longus tendon autograft. Knee function was assessed using the International Knee Documentation Committee (IKDC) and Lysholm scores, while the ankle was evaluated using the American Orthopedic Foot and Ankle Score (AOFAS) and the Foot &amp; Ankle Disability Index (FADI) scores. Donor-site morbidity and graft characteristics were compared. RESULTS There was no difference between the 2 groups in terms of knee IKDC and Lysholm scores (p=0.49, p=0.68, respectively). The diameter of the peroneus longus tendon graft (8.56±0.93) was significantly larger than the hamstring tendon (7.44±0.6) (p<0.001). The peroneus graft harvesting time was significantly shorter (p<0.001). Thigh hypotrophy and donor-site morbidity were significantly higher in the hamstring group (p<0.001 and p=0.006). The donor ankle AOFAS score was 93.46±3.8, and the FADI score was 93.48±4.6. No morbidity associated with the peroneus longus graft was observed. CONCLUSIONS Patients who underwent ACL reconstruction using the peroneus longus tendon experienced faster knee rehabilitation and less donor-site morbidity, such as thigh hypotrophy and knee pain. The peroneus longus tendon, with its larger diameter, fewer graft-related complications, and similar knee scores compared to the hamstring group, is considered a suitable alternative graft source.

Evaluating Gait with Force Sensing Insoles 6 Months after Anterior Cruciate Ligament Reconstruction: An Autograft Comparison.

Aberrant knee mechanics during gait 6 months after anterior cruciate ligament reconstruction (ACLR) are associated with markers of knee cartilage degeneration. The purpose of this study was to compare loading during walking gait in quadriceps tendon, bone-patellar tendon-bone (BPTB), and hamstring tendon autograft patients 6 months post-ACLR using loadsol single sensor insoles, and to evaluate associations between loading and patient-reported outcomes. Seventy-two patients (13 to 40 yr) who underwent unilateral, primary ACLR with BPTB, quadriceps tendon, or hamstring tendon autograft completed treadmill gait assessment, the International Knee Documentation Committee (IKDC) survey, and the ACL-Return to Sport after Injury (ACL-RSI) survey 6 ± 1 months post-ACLR. Ground reaction forces were collected using loadsols. Limb symmetry indices (LSI) for peak impact force (PIF), loading response instantaneous loading rate (ILR), and loading response average loading rate (ALR) were compared between groups using separate analyses of covariance. Survey scores were compared between groups using one-way ANOVAs. The relationships between IKDC, ACL-RSI, and LSI were compared using Pearson's product moment correlation coefficients. There were no significant differences between graft sources for LSI in PIF, ILR, ALR, or impulse. Patient-reported knee function was significantly different between graft source groups with the BPTB group reporting the highest IKDC scores; however, there was no significant difference between groups for ACL-RSI score. There were no significant associations between IKDC score, ACL-RSI score, and biomechanical symmetry among any of the graft source groups. Autograft type does not influence PIF, ILR, ALR, or impulse during walking 6 months post-ACLR. Limb symmetry during gait is not strongly associated with patient-reported outcomes regardless of graft source. Loadsols appear to be a suitable tool for use in the clinical rehabilitation setting.