Editorial Commentary: Biologic Stimulation Using Marrow Venting for Meniscus Repair is Cost Effective and Recommended.

Current literature offers little guidance on the most cost-effective approach to intraoperative biologic stimulation in the setting of arthroscopic meniscus repair. Combining data from robust systematic reviews into a Markov Decision Making Model reveal the ideal strategy: Strong consideration should be given to biologic stimulation for all meniscal repairs, and the most cost effective technique is marrow stimulation.

Femoral Head Core Decompression and Bone Marrow Concentrate Injection in Pediatric Sickle-cell Related Avascular Necrosis.

BACKGROUND: Femoral head avascular necrosis affects 10% to 40% of patients with sickle cell disease (SCD). The purpose of this study was to evaluate the results of femoral head core decompression and bone marrow aspirate concentrate (CD-BMAC) injection in pediatric patients with SCD. METHODS: Eligible patients were enrolled in this retrospective study of patients undergoing CD-BMAC. Patients with SCD who were younger than 18 at the time of surgery and had >1 year of follow-up were included in this analysis. Hips were staged based on the Ficat system by 2 raters. The visual analog score for pain, hip outcome score, modified Harris hip score, and the University of California, Los Angeles activity score were used as patient-reported outcome measures preoperatively, at 5 to 9 months postoperatively, and final follow-up. Treatment failure was defined as total hip arthroplasty or visual analog score >3 at the final follow-up. RESULTS: Twenty-three hips in 17 patients were included, with a median age at the time of surgery of 15.8 years (interquartile range: 13.1 to 17.8 y). Patients were followed for 4.25 ± 1.7 years. Ten hips showed a 1-stage increase in the Ficat stage at the final follow-up, whereas 11 retained the same stage, and 1 hip had a 1-stage regression. All patient-reported outcome measures showed significant improvement from the preoperative visit to short-term follow-up, but the preoperative to final follow-up improvement was not significant. Six treatment failures were recorded, including 3 total hip arthroplasties and 3 painful hips at the final follow-up. In a multivariate logistic regression model, only skeletal maturity (odds ratio = 16.2, 95% CI: 1.44-183.0, P = 0.024) and femoral head collapse (odds ratio = 12.0, 95% CI: 1.1-130.5, P = 0.041) were significant predictors of treatment failure. CONCLUSIONS: In the largest study on pediatric SCD patients undergoing CD-BMAC, we found that CD-BMAC injection offers significant improvement in pain and functional outcomes in the short term, with a very low risk for complications. Skeletal maturity and femoral head collapse were significant predictors of treatment failure. Patients with a collapsed femoral head experienced functional deterioration over time after initial improvement, whereas precollapse hips maintained their functional improvement up to the latest follow-up. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Analysis of Results After Surgical Application of Bone Marrow Aspirate Stem Cell Concentrate in the Treatment of Avascular Necrosis of the Femoral Head.

Introduction: Avascular necrosis or osteonecrosis of the femoral head is defined as a pathological process that results in a critical reduction in the blood supply to the hip head with increased intraosseous pressure. Avascular necrosis is a multifactorial disease. The treatment used so far consists of transosseous decompression of the femoral head and is the most commonly used method in the early stages of osteonecrosis. Aim: The aim of this study was to evaluate the results after application of bone marrow stem cells obtained from the pelvic ridge, which was applied to the necrotic zone after previous decompression. Material and methods. The study is of prospective character and included 30 patients with first, second, and third degrees of AVN according to the Ficat classification, determined with X-ray. The range of motion in the hip was examined preoperatively by using a goniometer, a radiological evaluation of the degree of AVN was performed, according to the Ficat classification, and the VAS scale and the Harris Hip Score were examined preoperatively and postoperatively. Results: The average value for the Harris Hip Score (HHS) preoperatively was: for Ficat I -66.32±5.1, for Ficat II - 49.19±3.4 and for Ficat III - 33.71±2.1. At the 3-month postoperative follow-up, the average HHS values were: 87.92±4.3 for Ficat I, 78.64±6.6 for Ficat II and 76.48±2.6 for Ficat III. The same values for HHS were obtained in the control examinations at the 6th and 12th month postoperatively, indicating the fact that good bone regeneration was achieved and the progression of the condition was prevented. A decrease in the HHS value was observed at the control examination at 1 year after the surgical treatment, in 3 patients according to the Ficat classification of grade III, in whom a total hip replacement surgery was performed. Conclusion: The use of stem cells in the treatment of avascular necrosis of the femoral head has achieved good functional results and reduced pain in operated patients. Radiographically, good bone regeneration was achieved and the progression of necrosis to a higher degree was prevented.

Clinical outcomes of autologous platelet-rich plasma and bone marrow mononuclear cells grafting combined with core decompression for Association Research Circulation Osseous II-IIIA stage non-traumatic osteonecrosis of the femoral head.

PURPOSE: This study aimed to investigate the efficacy and safety of autologous platelet-rich plasma (PRP) and bone marrow mononuclear cells (BMMCs) grafting combined with core decompression (CD) in the treatment of Association Research Circulation Osseous (ARCO) II-IIIA stage non-traumatic osteonecrosis of the femoral head (ONFH). METHODS: The clinical data of 44 patients (44 hips) with non-traumatic ONFH from December 2018 to December 2019 were retrospectively reviewed. Twenty-four patients underwent CD combined with autologous PRP and BMMCs grafting (PRP+BMMCs group), and 20 patients underwent core decompression alone (CD group). During a minimum follow-up of 36 months, radiographic outcomes were evaluated using X-ray, radiographic failure rates were compared, and Harris hip score (HHS) and visual analog scale (VAS) were selected to evaluate clinical outcomes. The percentage of patients with minimal clinically important difference (MCID) in both groups was analyzed. Clinical failure was defined as further total hip arthroplasty (THA) with Kaplan-Meier survival analysis. Surgical complications were recorded. RESULTS: All patients had well healed wounds, and no complications such as infection and thrombosis occurred. HHS and VAS scores in both the PRP+BMMCs and CD groups were better than those preoperatively (P<0.05). At the last follow-up, the HHS and VAS scores of the PRP+BMMCs group were significantly better than those of the CD group (P<0.05). In ARCO II-IIIA stage, 66.7% of the PRP+BMMCs group and 30.0% of the CD group achieved the MCID (P<0.05). The clinical and imaging failure rates in the PRP+BMMCs group were 12.5% and 20.8%, respectively, compared with 40.0% and 50.0% in the CD group (P<0.05). In ARCO II stage, the MCID, clinical and imaging failure rates of PRP+BMMCs group and CD group were 66.7% and 33.3% (P<0.05), 4.8% and 33.3% (P<0.05), 14.3% and 44.4% (P<0.05), respectively. The PRP+BMMCs group had better hip survival rate compared with CD group (P<0.05). CONCLUSION: CD combined with autologous PRP and BMMCs grafting is a safe and effective method for the treatment of ARCO II-IIIA stage non-traumatic ONFH, especially for ARCO II stage, effectively reducing the collapse rate of the femoral head and delaying or even avoiding THA.

Core decompression combined with intralesional autologous bone marrow derived cell therapies for osteonecrosis of the femoral head in adults: A systematic review and meta-analysis.

BACKGROUND: Core decompression (CD) is beneficial in the early stage of osteonecrosis of the femoral head (ONFH). Adjunctive bone marrow derived cell therapies (BMDCT) have been advocated which potentially aid the regenerative process. QUESTION/PURPOSE: This study was conducted to determine potential benefit of CD + BMDCT in ONFH, in terms of disease progression, conversion to arthroplasty (primary outcomes), and functional outcomes and complication rates (secondary outcomes). METHODS: A systematic review of literature was performed on 3 databases. Studies reporting CD + BMDCT (intralesional instillation) in ONFH, with a minimum follow up of 1 year and reporting the pre-defined outcome measures were included in the review. Meta-analysis consisted of two different arms: a comparative arm, to compare CD + BMDCT to CD alone, and a non-comparative meta-analysis arm, to determine pooled rates of disease progression, conversion to arthroplasty and complication rates. RESULTS: A total of 18 studies were included in the systematic review. CD + BMDCT had lower rates of disease progression (OR 0.19 [95% CI, 0.09, 0.40]) and conversion to arthroplasty (OR 0.20 [95% CI, 0.11, 0.40]) as compared to CD alone. Functional score (MD = -7.07 [95% CI, -12.28, -1.86]) and visual analog scale also showed better improvement with the use of CD + BMAC (MD = -10.39 [95% CI, -12.87, -7.90]). Increasing age and post-collapse stage at presentation were noted to have an adverse effect on the outcomes. CONCLUSION: CD + BMDCT was found to decrease disease progression and conversion to arthroplasty, and was noted to have better functional outcome scores as compared to CD alone.

A Phase IB/IIA Study of Allogeneic, Bone Marrow-derived, Mesenchymal Stem Cells for the Treatment of Refractory Ileal-anal Anastomosis and Peripouch Fistulas in the Setting of Crohn's Disease of the Pouch.

BACKGROUND AND AIMS: Mesenchymal stem cells [MSCs] have been used for the treatment of perianal Crohn's fistulising disease by direction injection. No studies to date have included patients with an ileal pouch-anal anastomosis [IPAA] in situ. METHODS: A phase IB/IIA, randomised, control trial of bone marrow-derived, allogeneic MSCs via direct injection to treat adult patients with a peripouch fistula[s] was conducted; 75 million MSCs were administered with a 22 G needle, with repeat injection at 3 months if complete clinical and radiographic healing was not achieved. Adverse and serious adverse events at post-procedure Day 1, Week 2, Week 6, Month 3, Month 6, and Month 12 were assessed. Clinical healing, radiographic healing per pelvic magnetic resonance imaging [MRI], and patient-reported outcomes were assessed at the same time points. RESULTS: A total of 22 patients were enrolled and treated; 16 were treated and six were controls. There were no adverse or serious adverse events related to MSC therapy. At 6 months, 31% of the treatment group and 20% of the control had complete clinical and radiographic healing. When stratifying the treatment group into perianal [n = 7] and ano-vaginal [n = 8] fistulas, 6-month healing in the treatment groups was 57% and 0%, respectively. The perianal Crohn's disease activity index [PCDAI], Wexner incontinence score, and van Assche score all significantly decreased in treatment patients at 6 months; only the PCDAI decreased in the control group. CONCLUSION: Bone marrow-derived, allogeneic MSCs offer a safe and effective alternative treatment approach for peripouch fistulas in the setting of a Crohn's like phenotype of the pouch [ClinicalTrials.gov Identifier: NCT04519684.].

Influence of Autologous Bone Marrow Stem Cell Therapy on the Levels of Inflammatory Factors and Conexin43 of Patients with Moyamoya Disease.

Moyamoya disease is a medical condition that shows the typical characteristics like continuous and chronic thickening of the walls and the contraction of the internal carotid artery; as a result, the internal diameter of the artery gets narrowed. There are six phases of the disease ranging from I to VI (moyamoya vessels completely disappear, followed by the complete blockage of the arteries). Surgery is a commonly recommended treatment for the moyamoya disease. Our research study identifies the effect of autologous bone marrow stem cell therapy (ABMSCT) on the levels of inflammatory factors and Conexin43 (Cx43) protein in patients suffering from moyamoya. In our study, we have selected 52 moyamoya patients admitted to our hospital from 30 July 2019 to 10 February 2020. The control group (CG) was treated with superficial temporal artery to a middle cerebral artery (STA-MCA) bypass + encephalo-duro-myosinangiosis (EDMS). The experimental group (Exp. Grp) was treated with ABMSC. The cerebral vascular tissue of the patients was treated with hematoxylin-eosin (HE) staining. Immunohistochemical staining was used to identify the levels of Cx43 protein. The concentrations of vascular endothelial growth factor (VEGF), inflammatory factor interleukin-6 (IL6), interleukin-1ß (IL1ß), tumor necrosis factor (TNFα), and anti-inflammatory factor interleukin-1ß (IL1ß) were determined by enzyme-linked immunosorbent assay (ELISA). We have found that after treatment of the expression of Cx43 protein, the proportions of grade IV (7.7%), grade III (311.5%), and grade II (3.8%) patients in the Exp. Grp were lower than those in the CG. The proportion of grade I patients in the Exp. Grp (77%) was higher than that in the CG (38.5%). After treatment, the inflammatory factors IL6 (0.97 ± 0.82 pg/mL), IL1ß (8.33 ± 1.21 pg/mL), and TNFα (1.73 ± 0.71 pg/mL) in the Exp. Grp were lower than those in the CG. The anti-inflammatory factor IL1ß (15.09 ± 4.72 pg/mL) increased in the Exp. Grp compared with the CG (11.25 ± 3.48 pg/mL) post treatment. Intracranial infection, hydrocephalus, hemiplegia, and transient neurological dysfunction in the Exp. Grp were lower than those in the CG, with statistical differences (P < 0.05). Our study suggests that the treatment of autologous bone marrow stem cells (ABMSC) was beneficial to balance the inflammatory response of disorders, reduce the damage of vascular tissue in the brain, and regulate tissue repair by co-acting with various inflammatory factors as compared to traditional surgery. We conclude that the involvement of Cx43 in the occurrence and development of moyamoya. We also have found that the risk factors of intracranial infection after ABMSCT were less as compared to those after conventional surgery.

Limited evidence of adjuvant biologics with bone marrow stimulation for the treatment of osteochondral lesion of the talus: a systematic review.

PURPOSE: To evaluate the complication rates, continuous functional outcome scores, and return to play data following bone marrow stimulation (BMS) versus biologics ± BMS for the treatment of osteochondral lesion of the talus (OLT). METHODS: A systematic review was performed. The PubMed and Embase databases were searched using specific search terms and eligibility criteria according to the PRISMA guidelines. The level of evidence was assessed using published criteria by The Journal of Bone & Joint Surgery, and the quality of evidence using the Modified Coleman Methodology Score. Continuous variables were presented as mean ± standard deviation and categorical variables as frequencies (percentages). RESULTS: BMS versus BMS + hyaluronic acid (HA): no complications in either treatment arm were reported. The mean American Orthopaedic Foot and Ankle Society score was 43.5 to 67.3 points and 44.0 to 72.4 points, respectively. The mean 10 mm Visual Analogue Scale pain score was 7.7 to 3.8 points and 7.5 to 2.5 points, respectively. BMS versus BMS + concentrated bone marrow aspirate (CBMA): the pooled overall complication rate was 17/64 (26.6%) versus 11/71 (15.5%), respectively (non-significant). The pool revision rate was 15/64 (23.4%) versus 6/71 (8.5%), respectively (p = 0.016). There has been a notable poor reporting of complication rates for the use of ADSC and PRP as adjuvant biological therapies to BMS for the treatment of OLT. CONCLUSION: There was an overall limited comparative clinical evidence of adjuvant biologics with BMS versus BMS alone for the treatment of OLT. BMS + HA and BMS + CBMA can provide superior outcomes, albeit the currently limited evidence. Further studies are warranted to establish the true clinical superiority of the various biologics ± BMS versus BMS alone. These studies must also compare the various biologics against one another to determine, if any, the optimal biologic for OLT. Clinicians should counsel patients accordingly on these findings as required. LEVEL OF EVIDENCE: Level III.

Editorial Commentary: Bone Marrow Aspirate Concentrate May Accelerate Anterior Cruciate Ligament Allograft Using Bone Patellar Tendon Bone Maturation on Magnetic Resonance Imaging, but Clinical Differences Have Not Been Demonstrated.

Accelerating graft healing in anterior cruciate ligament reconstruction (ACLR) continues to be an elusive proposition. In vivo assessments of graft histology are challenging to perform, especially in human subjects. Multiple authors have reported on the utility of magnetic resonance imaging as a noninvasive modality in characterizing postoperative changes, suggestive of graft maturation. However, previous literature, by and large, has been limited by heterogenous scanning protocols and underpowered comparisons of dissimilar treatment techniques, and these issues complicate efforts to assess the benefits (if any) of adjuncts focused on improving graft healing after ACLR. Particularly in cases of allograft ACLR, where concerns persist regarding the pace and quality of tissue healing and graft integration, the use of orthobiologic adjuncts represents a promising area for ongoing investigation. Although there has been great enthusiasm for the use of bone marrow aspirate concentrate as an adjunct in a variety of applications, high level evidence substantiating its use in ACLR is lacking. Even when significant differences between groups treated with and without such adjuncts may be apparent radiographically, demonstrating a concrete, clinical benefit will continue to be a difficult proposition.

Review of K.H. Pridie (1959) on "A method of resurfacing osteoarthritic knee joints".

This classic discusses the original publication "A method of resurfacing osteoarthritic knee joints" by Dr K.H. Pridie (1959), where this pioneer surgeon described a newly developed method for the treatment of osteoarthritic joint surfaces of the knee, which he named subchondral drilling. This short and concise 11-line publication appeared in the Proceedings of the Congress of the British Orthopaedic Association. It has generated 464 citations since 1959, becoming part of the hundred most-cited publications in knee research. Pridie introduced in clinical experimentation the entity of Marrow Stimulation Techniques to liberate mesenchymal stem cells from cancellous bone. He was aware that the results induced, in terms of quality of the regrown tissue, was limited and "only" fibrocartilage. His idea might have been raised from the work of numerous animal researchers who confirmed repeatedly since 1905 that cartilage needed an osseous perforation to heal. Although the past 60 years brought modifications from the technique described in the original article, the concept of marrow stimulation introduced by Pridie remains the most frequently used in cartilage repair surgery today.

Radiological and Clinical Outcomes after Anterior Cervical Discectomy and Fusion (ACDF) with an Innovative 3D Printed Cellular Titanium Cage Filled with Vertebral Bone Marrow.

Objectives: To assess the clinical and radiological outcomes after ACDF with 3D printed cellular titanium cages filled with bone marrow and to compare the clinical and radiological results with the current scientific literature. Methods: ACDF was performed monosegmentally under standardized conditions. X-rays were analyzed to determine the range of motion, fusion rates, and subsidence preoperatively and 3 and 12 months postoperatively. Clinical outcome measurements included neck disability index (NDI), visual analogue scale (VAS) for brachialgia and cervicalgia, and patient satisfaction. Results: 18 patients were included in the study. The mean RoM decreased from 7.7° ± 2.6 preoperatively to 1.7° ± 1.1° after 3 months and 1.8° ± 1.2° 12 months after surgery. The fusion rates were at 94.4% after 3 and 12 months. The mean subsidence was 0.9 mm ± 0.5 mm 3 months postoperatively and 1.1 mm ± 0.5 mm 12 months after surgery. The mean NDI improved significantly from preoperatively to 12 months postoperatively (34.6 ± 6.2 and 3.4 ± 4.1, respectively). The VAS-neck also showed a large improvement from 5.8 ± 2.2 before and 1.3 ± 1.4 12 months after surgery, as did the VAS-arm (6.4 ± 1.5 and 0.9 ± 1.6, respectively). Patient satisfaction was high throughout the follow-up period. Conclusion: ACDF with a 3D printed titanium cage resulted in fast fusion without pathological subsidence. In comparison to other cage materials such as PEEK, the 3D printed titanium cage was noninferior in regard to its fusion rate and clinical results.

Core Decompression and Bone Marrow Aspiration Concentrate Grafting for Osteonecrosis of the Femoral Head.

BACKGROUND: Core decompression (CD) with bone marrow aspiration concentrate (BMAC) is a technique that may improve outcomes in osteonecrosis of the femoral head (ONFH). The primary aim of this study was to evaluate the radiographic progression free survival (PFS) of CD augmented with BMAC. Secondary aims were to determine the survivorship with conversion (CFS) to total hip arthroplasty (THA) as an endpoint, determine prognostic factors, and characterize the cellular quality of the BMAC. METHODS: A retrospective cohort study of 61 femoral heads (40 patients) was performed. Patient demographics, comorbidities, BMI, smoking status, etiology, location and extent of ONFH were recorded. The primary endpoint was radiographic progression of ONFH and secondarily, conversion to THA. Additional aims were to determine predictive factors for progression and report the cellular characteristics of the BMAC. Data obtained were compared to the results of a prior randomized controlled trial comparing CD alone versus CD with polymethylmethacrylate cement (PMMA) augmentation. RESULTS: Radiographic PFS of CD with BMAC at 2 and 5 years was 78.3% and 53.3%, respectively. The risk of progression was lower in the CD with BMAC group compared to CD alone (HR0.45, p = 0.03), however this difference no longer remained statistically significant on multivariate analysis. Conversion to total hip arthroplasty free survival (CFS) of CD with BMAC at both 2 and 5 years was 72.1% and 54.6%, respectively with no differences compared to the control groups (CD alone, CD and PMMA). The predictive factors for progression were obesity (BMI ≥ 30) and the extent of the disease as quantified by either percentage involvement, necrotic index or modified necrotic index. CONCLUSIONS: No differences in PFS or CFS between CD with BMAC compared to CD alone or CD with PMMA were identified. Independent statistically significant predictors of progression-free survival or conversion to THA are BMI ≥ 30 and the extent of ONFH. Further research with an adequately powered randomized controlled trial is needed. LEVEL OF EVIDENCE: 3.

Bone Marrow Aspirate Concentrate Augmentation May Accelerate Allograft Ligamentization in Anterior Cruciate Ligament Reconstruction: A Double-Blinded Randomized Controlled Trial.

PURPOSE: To assess the effect of bone marrow aspiration concentrate (BMAC) augmentation on clinical outcomes and magnetic resonance imaging (MRI) findings in anterior cruciate ligament (ACL) reconstruction (ACLR) with bone-patellar tendon-bone (BTB) allografts. METHODS: A double-blinded, randomized controlled trial was conducted on 80 patients undergoing ACL reconstruction using BTB allografts. Patients were randomized to 2 groups: (1) bone marrow aspirate was collected from the iliac crest, concentrated, and approximately 2.5 mL was injected into the BTB allograft, or (2) a small sham incision was made at the iliac crest (control). MRI was performed at 3 months and 9 months postoperatively to determine the signal intensity ratio of the ACL graft. RESULTS: Seventy-three patients were available for follow-up at 1-year postoperatively (36 BMAC, 37 control). International Knee Documentation Committee (IKDC) scores were significantly greater in the BMAC group versus the control at the 9-month postoperative period (81.6 ± 10.5 vs 74.6 ± 14.2, P = .048). There was no significant difference in the proportion of patients who met the minimal clinically important difference for IKDC between the BMAC and control groups at 9 months (89% vs 85%; P = .7). Three months postoperatively, signal intensity ratio of the inferior third of the ACL graft was significantly greater in the BMAC group versus the control group (3.2 ± 2.2 vs 2.1 ± 1.5; P = .02). CONCLUSIONS: Patients who received BMAC augmentation of the BTB allograft during ACL reconstruction demonstrated greater signal intensity scores on MRI at 3 months, suggesting increased metabolic activity and remodeling, and potentially accelerated ligamentization. Additionally, patients in the BMAC group had greater patient-reported outcomes (IKDC) at 9 months postoperatively when compared with those who underwent a standard surgical procedure. There was no significant difference in the proportion of patients who met the minimal clinically important difference for IKDC between the BMAC and control groups at 9 months, suggesting limited clinical significance at this time point. LEVEL OF EVIDENCE: I, randomized control trial.

Improved access to the bone marrow space by multiple perforations of the alveolar bundle bone after tooth extraction-A case report.

OBJECTIVES: The dental alveolus is lined by a thin cortical layer ("bundle bone", "alveolar bone proper", "cribriform plate", "lamina dura"), that can impede access to the bone marrow and its vasculature. During unassisted socket healing, the alveolar bundle bone is gradually resorbed allowing tissue resources from the bone marrow to enter into the socket space. An optimized wound healing process, either during unassisted socket healing or during ridge preservation procedures, with autogenous bone and/or any bone/collagen substitute material, depends at least partly on an adequate vascularization of the socket space. This ensures sufficient recruitment of osteoblast and osteoclast precursor cells and facilitates fast bone regeneration and/or uneventful integration of the augmentation material. METHODS: The present technical note describes an easy treatment step after tooth extraction aiming to improve socket healing with or without any ridge preservation procedure, by facilitating an increased blood inflow into the dental alveolus. Specifically, after tooth extraction the alveolar bundle bone is perforated several times - mainly in a palatally/lingually - by a small round bur (diameter < 1 mm) extending into the trabecular bone. RESULTS AND CONCLUSIONS: By means of this relatively simple treatment step, an increased blood inflow into the alveolus is achieved after tooth extraction, which might enhance socket healing and corticalization of the entrance, and in turn result in a lower complication rate (e.g., dry socket), in an enhanced graft incorporation, and/or in a reduced loss of alveolar ridge volume.

Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis.

Bone marrow is a preferred metastatic site for multiple solid tumours and is associated with poor prognosis and significant morbidity. Accumulating evidence indicates that cancer cells colonise specialised niches within the bone marrow to support their long-term propagation, but the precise location and mechanisms that mediate niche interactions are unknown. Using breast cancer as a model of solid tumour metastasis to the bone marrow, we applied large-scale quantitative three-dimensional imaging to characterise temporal changes in the bone marrow microenvironment during disease progression. We show that mouse mammary tumour cells preferentially home to a pre-existing metaphyseal domain enriched for type H vessels. Metastatic lesion outgrowth rapidly remodelled the local vasculature through extensive sprouting to establish a tumour-supportive microenvironment. The evolution of this tumour microenvironment reflects direct remodelling of the vascular endothelium through tumour-derived granulocyte-colony stimulating factor (G-CSF) in a hematopoietic cell-independent manner. Therapeutic targeting of the metastatic niche by blocking G-CSF receptor inhibited pathological blood vessel remodelling and reduced bone metastasis burden. These findings elucidate a mechanism of 'host' microenvironment hijacking by mammary tumour cells to subvert the local microvasculature to form a specialised, pro-tumorigenic niche.

Outcomes of Bone Marrow Stimulation for Secondary Osteochondral Lesions of the Talus Equal Outcomes for Primary Lesions.

OBJECTIVE: To compare clinical, sports, work, and radiological outcomes between primary and secondary osteochondral lesions of the talus (OLTs; <15 mm) treated with arthroscopic bone marrow stimulation (BMS). DESIGN: Secondary OLTs were matched to primary OLTs in a 1:2 ratio to assess the primary outcome measure-the Numeric Rating Scale (NRS) during activities. Secondary outcomes included the pre- and 1-year postoperative NRS at rest, American Orthopaedic Foot and Ankle Society score, Foot and Ankle Outcome Score subscales, and the EQ-5D general health questionnaire. The rates and time to return to work and sports were collected. Radiological examinations were performed preoperatively and at final follow-up using computed tomography (CT). RESULTS: After matching, 22 and 12 patients with small (<15 mm) OLTs were included in the primary and secondary groups, respectively. The NRS during activities was not different between primary cases (median: 2, interquartile range [IQR]: 1-4.5) and secondary cases (median: 3, IQR: 1-4), P = 0.5. Both groups showed a significant difference between all pre- and postoperative clinical outcome scores, but no significant difference between BMS groups postoperatively. The return to sport rate was 90% for primary cases and 83% for secondary cases (P = 0.6). All patients returned to work. Lesion filling on CT was complete (67% to 100%) in 59% of primary cases and 67% of secondary cases (P = 0.6). CONCLUSION: No differences in outcomes were observed between arthroscopic bone marrow stimulation in primary and secondary OLTs at 1-year follow-up. Repeat BMS may therefore be a viable treatment option for failed OLTs in the short term.

Sagittal Split Ramus Osteotomy in the Shortest Buccal Bone Marrow Distances of the Mandible on the Coronal Plane.

PURPOSE: This study investigated the relationship between the shortest buccal bone marrow of the ramus and skeletal patterns. MATERIALS AND METHODS: Using cone-beam computed tomography data (specifically, the A point-nasion-B point (ANB) angle), we divided patients into three groups as follows: skeletal class I (0° < ANB < 4°), class II (ANB: ≥4°), and class III (ANB: ≤0°). Sixteen vertical sections in the coronal plane were taken starting from slice 0 (original intact mandibular canal) anteriorly at 2 mm intervals to slice 15 (30 mm). The thickness of the mandible (M) and shortest buccal bone marrow (SBM) were measured. The data of SBM were divided into two groups (SBM ≥ 1 mm and SBM < 1 mm). For each skeletal pattern, an SBM value < 1 mm was considered to indicate a high possibility of postoperative nerve paresthesia and bad split. RESULTS: The three skeletal pattern groups also did not significantly differ in their M values for all sections. The mean SBM values of class III (0.91-2.11 mm) at 6-16 mm anterior to the mandibular foramen were significantly smaller than those of class II (1.53-3.17 mm). Comparing the occurrence ratio of SBM < 1 mm, the highest and lowest probabilities in class III (55% and 21.7%, respectively) were significantly larger at 6-20 mm anterior to the mandibular foramen than those in class II (28.3% and 5%, respectively). CONCLUSION: Class III had a significantly shorter SBM distance and higher SBM occurrence probability than class II at the mandibular ramus region, implying that class III participants are more likely than class II participants to have nerve paresthesia and bad split after sagittal split ramus osteotomy.

Evidence-based Treatment of Failed Primary Osteochondral Lesions of the Talus: A Systematic Review on Clinical Outcomes of Bone Marrow Stimulation.

OBJECTIVE: The purpose of this study is to systematically review the literature and to evaluate the outcomes following bone marrow stimulation (BMS) for nonprimary osteochondral lesions of the talus (OLT). DESIGN: A literature search was performed to identify studies published using PubMed (MEDLINE), EMBASE, CDSR, DARE, and CENTRAL. The review was performed according to the PRISMA guidelines. Two authors separately and independently screened the search results and conducted the quality assessment using the Methodological Index for Non-Randomized Studies (MINORS). Studies were pooled on clinical, sports, work, and imaging outcomes, as well as revision rates and complications. The primary outcome was clinical success rate. RESULTS: Five studies with 70 patients were included in whom nonprimary OLTs were treated with secondary BMS. The pooled clinical success rate was 61% (95% confidence interval [CI], 50-72). The rate of return to any level of sport was 83% (95% CI, 70-91), while the return to pre-injury level of sport was 55% (95% CI, 34-74). The rate of return to work was 92% (95% CI, 78-97), and the complication rate was assessed to be 10% (95% CI, 4-22). Imaging outcomes were heterogeneous in outcome assessment, though a depressed subchondral bone plate was observed in 91% of the patients. The revision rate was 27% (95% CI, 18-40). CONCLUSIONS: The overall success rate of arthroscopic BMS for nonprimary osteochondral lesions of the talus was 61%, including a revision rate of 27%. Return to sports, work, and complication outcomes yielded fair to good results.

Incidence of thyroid dysfunction in children after HSCT with reduced intensity conditioning (RIC) or myeloablative conditioning (MAC).

We have previously demonstrated a 11% incidence of post-transplant de novo thyroid disease, even with a radiation-free RIC regimen. Following the enactment of a universal late effects screening program at our institution, we compared the outcomes of 108 pediatric hematopoietic stem cell transplant recipients after a RIC regimen (n = 33) to those after a MAC regimen (n = 75) during the same time period. Overall, 10% of subjects developed thyroid dysfunction after HSCT, with a median follow-up of 669 days. Seven subjects had primary hypothyroidism prior to HSCT. Of the thirty-one subjects who received RIC, one (3.2%) developed a new thyroid disorder, compared to the nine of sixty-nine (13.0%) subjects who received MAC (p = .167). No significant associations were seen with donor type, graft-vs.-host disease, or total body irradiation. Nine of the 10 subjects who developed thyroid disease after transplant were asymptomatic. Continued follow-up of this contemporary cohort will further delineate risk factors for post-transplant-associated thyroid dysfunction and better inform discussions of transplant-associated sequelae.

Next-Generation Marrow Stimulation Technology for Cartilage Repair: Basic Science to Clinical Application.

¼: Given the relatively high prevalence of full-thickness articular cartilage lesions, including in patients who are <40 years of age, and an inability to detect some of these lesions until the time of arthroscopy, there is value in performing a single-stage cartilage procedure such as marrow stimulation (MS). ¼: While the positive outcomes of first-generation MS (namely microfracture) have been observed to drop off after 24 months in several studies, improvements have been seen when compared with preoperative conditions for lesions that are 2 to 3 cm2 in size, and MS is considered to be a procedure with technical simplicity, fairly short surgical times, and relatively low morbidity. A recent study showed that autologous chondrocyte implantation (ACI) and osteochondral allograft (OCA) transplantation remain viable treatment options for chondral defects of the knee in the setting of failed MS. ¼: Basic science principles that have been elucidated in recent years include (1) the creation of vertical walls during defect preparation, (2) an increased depth of subchondral penetration, (3) a smaller awl diameter, and (4) an increased number of subchondral perforations, which are all thought to help resolve issues of access to the mesenchymal stromal cells (MSCs) and the subchondral bone structure/overgrowth issues. ¼: Pioneering and evolving basic science and clinical studies have led to next-generation clinical applications, such as a hyaluronic acid-based scaffold (ongoing randomized controlled trial [RCT]), an atelocollagen-based gel (as described in a recently published RCT), a micronized allogeneic cartilage scaffold (as described in a recently completed prospective cohort study), and a biosynthetic hydrogel that is composed of polyethylene glycol (PEG) diacrylate and denatured fibrinogen (as described in an ongoing prospective study). ¼: This review summarizes important points for defect preparation and the recent advances in MS techniques and identifies specific scaffolding augmentation strategies (e.g., mesenchymal augmentation and scaffold stimulation [MASS]) that have the capacity to advance cartilage regeneration in light of recent laboratory and clinical studies.