The repair of large bone defects with complex geometries remains a major clinical challenge. Here, we explored the feasibility of fabricating polylactic acid-hydroxyapatite (PLA-HA) composite ...scaffolds. These scaffolds were constructed from vascularized tissue engineered bone using an in vivo bioreactor (IVB) strategy with three-dimensional printing technology. Specifically, a rabbit model was established to prefabricate vascularized tissue engineered bone in two groups. An experimental group (EG) was designed using a tibial periosteum capsule filled with 3D printed (3DP) PLA-HA composite scaffolds seeded with bone marrow stromal cells (BMSCs) and crossed with a vascular bundle. 3DP PLA-HA scaffolds were also combined with autologous BMSCs and transplanted to tibial periosteum without blood vessel as a control group (CG). After four and eight weeks, neovascularisation and bone tissues were analysed by studying related genes, micro-computed tomography (Micro-CT) and histological examinations between groups. The results showed that our method capably generated vascularized tissue engineered bone in vivo. Furthermore, we observed significant differences in neovascular and new viable bone formation in the two groups. In this study, we demonstrated the feasibility of generating large vascularized bone tissues in vivo with 3DP PLA-HA composite scaffolds.
Bone marrow transplantation (BMT) performance can be limited by a lack of ideal donors, and the role of alternative donor hematopoietic cell transplantation in thalassemia is not well established. ...Here we used a new treatment protocol (Pc 26.1) in 16 thalassemia patients to perform BMT using phenotypically HLA-identical or 1-antigen–mismatched relatives (related donors RDs). We compared these results with HLA-matched sibling (matched sibling donors MSDs) BMT in 66 patients. The entire RD group and 88% of MSD group had sustained engraftment. Rejection incidence was 0% in the RD and 12% (95% confidence interval 95% CI, 6%-21%) in MSD groups (P = .15), with respective thalassemia-free survival probabilities of 94% (95% CI, 63%-99%) and 82% (95% CI, 70%-89%) (P = .24). Transplant-related mortality was 6% (95% CI, 1%-26%) in the RD group and 8% (95% CI, 3%-16%) in the MSD group (P = .83). The intensified new protocol was not associated with increased nonhematologic toxicity. The present data show that the Pc 26.1 preparative regimen allows thalassemia patients to safely undergo BMT from RDs who are not HLA-matched siblings, with transplant outcomes similar to patients with MSD grafts.
•A novel approach to BMT for thalassemia using related phenotypically matched or 1-antigen–mismatched donors improved transplant outcomes.•BMT from phenotypically matched or 1-antigen–mismatched donors is associated with a high thalassemia-free survival rate (94%).
This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT).
GNR bacteremias occurring during 6 months post-HSCT (February 2014-May ...2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas β-lactams (noncarbapenems), carbapenems, and multidrug resistance.
Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and β-lactam/β-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on β-lactam/β-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria.
Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial.
NCT02257931.
Background: Autologous bone marrow mesenchymal cells that include stem cells (MSCs) are a clinically attractive cellular therapy option to try to treat severe spinal cord injury (SCI). Objective: To ...study the possible value of MSCs injected intrathecally to enhance rehabilitation. Methods: This case control, convenience sample included 64 patients, at a mean of 3.6 years after SCI. Forty-four subjects received monthly intrathecal autologous MSCs for 6 months and 20 subjects, who would not agree to the procedures, served as controls. All subjects received rehabilitation therapies 3 times weekly. Subjects were evaluated at entry and at 12 months after completing the 6-months intervention. By the ASIA Impairment Scale, ASIA grading of completeness of injury, Ashworth Spasticity Scale, Functional Ambulation Classification, and bladder and bowel control questionnaire. Results: No differences were found in baseline measures and descriptors between the MSC group and control group. Although a higher percentage of the MSC group increased motor scores by 1-2 points and changed from ASIA A to B, no significant between-group improvements were found in clinical measures. Adverse effects of cells included spasticity and, in 24 out of the 43 patients developed neuropathic pain. One subject with a history of post-infectious myelitis developed encephalomyelitis after her third injection. Conclusion: Autologus MSCs may have side effects and may be contraindicated in patients with a history of myelitis. Their utility in treating chronic traumatic SCI needs further study in pre-clinical models and in randomized controlled trials before they should be offered to patients.
The root cause of sickle cell anemia has been known for 7 decades, yet no curative therapies have been available other than allogeneic bone marrow transplantation, for which applicability is limited. ...Two potentially curative therapies based on gene therapy and gene editing strategies have recently received US Food and Drug Administration approval. This review surveys the nature of these therapies and the opportunities and issues raised by the prospect of definitive genetically based therapies being available in clinical practice.
Background
Patients with non‐Hodgkin lymphoma (NHL) have an increased risk of venous thromboembolism (VTE), particularly when they are receiving treatment. Blood or marrow transplantation (BMT) is ...recommended for relapsed/refractory NHL, and the risk of VTE after these patients undergo BMT is uncertain.
Methods
Patients with NHL who survived 2 years or longer after BMT were surveyed for long‐term health outcomes, including VTE. The median follow‐up was 8.1 years (interquartile range, 5.6‐12.9 years). The risk of VTE in 734 patients with NHL versus 897 siblings without a history of cancer and the risk factors associated with VTE were analyzed.
Results
BMT survivors of NHL were at increased risk for VTE in comparison with siblings (odds ratio for allogeneic BMT survivors, 4.61; P < .0001; odds ratio for autologous BMT survivors, 1.75; P = .035). The cumulative incidence of VTE was 6.3% ± 0.9% at 5 years after BMT and 8.1% ± 1.1% at 10 years after BMT. In allogeneic BMT recipients, an increased body mass index (BMI; hazard ratio HR for BMI of 25‐30 kg/m2, 3.52; 95% confidence interval CI, 1.43‐8.64; P = .006; HR for BMI > 30 kg/m2, 3.44; 95% CI, 1.15‐10.23; P = .027) and a history of chronic graft‐versus‐host disease (HR, 3.33; 95% CI, 1.59‐6.97; P = .001) were associated with an increased risk of VTE. Among autologous BMT recipients, a diagnosis of coronary artery disease (HR, 5.94; 95% CI, 1.7‐20.71; P = .005) and prior treatment with carmustine (HR, 4.91; 95% CI, 1.66‐14.51; P = .004) were associated with increased VTE risk.
Conclusions
Patients with NHL who survive BMT are at risk for developing late occurring VTE, and ongoing vigilance for this complication is required. Future studies assessing the role of thromboprophylaxis in high‐risk patients with NHL are needed.
The risk of venous thromboembolism remains high several years after blood or marrow transplantation for patients with non‐Hodgkin lymphoma. An increased body mass index and a history of chronic graft‐versus‐host disease are associated with an increased risk of venous thromboembolism in allogeneic blood or marrow transplantation recipients, whereas in autologous blood or marrow transplantation recipients, a history of coronary artery disease and prior treatment with carmustine are associated with high risk.
The interest on applying mesenchymal stromal cells (MSCs) in orthopedic disorders has risen tremendously in the last years due to scientific successes in preclinical in vitro and animal model ...studies. In a wide range of diseases and injuries of the musculoskeletal system, MSCs are currently under evaluation, but so far have found access to clinical use only in few cases. The current assignment is to translate the acquired knowledge into clinical practice. Therefore, this review aims at presenting a synopsis of the up-to-date status of the use of MSCs and MSC related cell products in musculoskeletal indications. Clinical studies were included, whereas preclinical and animal study data not have been considered. Most studies published so far investigate the final outcome applying bone marrow derived MSCs. In fewer trials the use of adipose tissue derived MSCs and allogenic MSCs was investigated in different applications. Although the reported results are equivocal in the current literature, the vast majority of the studies shows a benefit of MSC based therapies depending on the cell sources and the indication in clinical use. In summary, the clinical use of MSCs in patients in orthopedic indications has been found to be safe. Standardized protocols and clear definitions of the mechanisms of action and the mode and timing of application as well as further coordinated research efforts will be necessary for finally adding MSC based therapies in standard operating procedures and guidelines for the clinicians treating orthopedic disorders.
To understand the role of bone marrow mononuclear cells in the treatment of acute myocardial infarction, this overview offers a retrospective examination of strengths and limitations of 3 ...contemporaneous trials with attention to critical design features and provides an analysis of the combined data set and implications for future directions in cell therapy for acute myocardial infarction.
Over the coming years, accelerating progress against cancer will be associated with an increased number of patients who require life-sustaining therapies for infectious or toxic chemotherapy-related ...events. Major changes include increased number of cancer patients admitted to the ICU with full-code status or for time-limited trials, increased survival and quality of life in ICU survivors, changing prognostic factors, early ICU admission for optimal monitoring, and use of noninvasive diagnostic and therapeutic strategies. In this review, experts in the management of critically ill cancer patients highlight recent changes in the use and the results of intensive care in patients with malignancies. They seek to put forward a standard of care for the management of these patients and highlight important updates that are required to care for them. The research agenda they suggest includes important studies to be conducted in the next few years to increase our understanding of organ dysfunction in this population and to improve our ability to appropriately use life-saving therapies or select new therapeutic approaches that are likely to improve outcomes. This review aims to provide more guidance for the daily management of patients with cancer, in whom outcomes are constantly improving, as is our global ability to fight against what is becoming the leading cause of mortality in industrialized and non-industrialized countries.
Summary Background Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated ...donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate. Methods We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia. Data were available on 1525 patients transplanted between 2002 and 2006. 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n=10), or mismatched at one (n=40) or two (n=115) antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n=632 and n=332, respectively), or mismatched at one locus (n=256 and n=140, respectively). Findings Leukaemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (HR 1·62, 95% CI 1·18–2·23; p=0·003) or bone-marrow transplantation (HR 1·69, 95% CI 1·19–2·39; p=0·003). Grades 2–4 acute and chronic graft-versus-host disease (GvHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0·57, 95% 0·42–0·77; p=0·002 and HR 0·38, 0·27–0·53; p=0·003, respectively), while the incidence of chronic, but not acute GvHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0·63, 0·44–0·90; p=0·01). Interpretation These data support the use of UCB for adults with acute leukaemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently. Funding National Cancer Institute, National Heart Lung and Blood Institute, National Institute of Allergy and Infectious Disease ( U24-CA76518 ); Health Resources and Services Administration ( HHSH234200637015C ); Office of Naval Research, Department of Navy ( N00014-08-1-1207 ); Children's Leukemia Research Association; and a Scholar in Clinical Research Award from the Leukemia and Lymphoma Society.
PDF
