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Human Pathology Mar 2024The biological mechanisms and potential clinical impact of heterotopic ossification (HO) in colorectal neoplasms are not fully understood. This study investigates the... (Review)
Review
The biological mechanisms and potential clinical impact of heterotopic ossification (HO) in colorectal neoplasms are not fully understood. This study investigates the clinicopathological characteristics of colorectal neoplasms associated with HO and examines the potential role of the bone morphogenetic protein (BMP) pathway in development of HO. An artificial intelligence (AI) based classification of colorectal cancers (CRC) exhibiting HO and their association with consensus molecular subtypes (CMS) is performed. The study included 77 cases via the Dutch nationwide Pathology databank. Immunohistochemistry for BMP2, SMAD4, and Osterix was performed. An AI algorithm assessed the tumour-stroma ratio to approximate the CMS. A literature search yielded 96 case reports, which were analysed and compared with our cases for clinicopathological parameters. HO was more frequently observed in our cohort in traditional serrated adenomas (25%), tubulovillous adenomas (25%) and juvenile polyps (25%), while in the literature it was most often seen in juvenile polyps (38.2%) and inflammatory polyps (29.4%). In both cohorts, carcinomas were mostly conventional (>60%) followed by mucinous and serrated adenocarcinomas. Higher expression of BMP2, SMAD4, and Osterix was observed in tumour and/or stromal cells directly surrounding bone, indicating activation of the BMP pathway. The tumour-stroma analysis appointed >50% of the cases to the mesenchymal subtype (CMS4) (59%). HO has a predilection for serrated and juvenile/inflammatory polyps, mucinous and serrated adenocarcinomas. BMP signalling is activated and seems to play a role in formation of HO in colorectal neoplasms. In line with TGFβ/BMP pathway activation associated with CMS4 CRC, HO seems associated with CMS4.
Topics: Humans; Colonic Polyps; Artificial Intelligence; Adenoma; Colorectal Neoplasms; Intestinal Polyps; Carcinoma; Adenocarcinoma; Ossification, Heterotopic
PubMed: 38367815
DOI: 10.1016/j.humpath.2024.02.006 -
Life Science Alliance May 2024Heterotopic ossification (HO) is a non-physiological bone formation where soft tissue progenitor cells differentiate into chondrogenic cells. In fibrodysplasia...
Heterotopic ossification (HO) is a non-physiological bone formation where soft tissue progenitor cells differentiate into chondrogenic cells. In fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated ACVR1/mTORC1 cascade induces HO in progenitors in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA-sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A-induced chondrogenesis of mesenchymal stem cells derived from FOP patient-specific induced pluripotent stem cells. Functional analyses showed a metabolic transition from glycolysis to OXPHOS during chondrogenesis, along with increased mitochondrial biogenesis. mTORC1 inhibition by rapamycin suppressed OXPHOS, whereas OXPHOS inhibitor IACS-010759 inhibited cartilage matrix formation in vitro, indicating that OXPHOS is principally involved in mTORC1-induced chondrogenesis. Furthermore, IACS-010759 inhibited the muscle injury-induced enrichment of fibro/adipogenic progenitor genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target.
Topics: Mice; Animals; Humans; Myositis Ossificans; Oxidative Phosphorylation; Ossification, Heterotopic; Signal Transduction; Mice, Transgenic; Mechanistic Target of Rapamycin Complex 1
PubMed: 38365425
DOI: 10.26508/lsa.202302219 -
European Spine Journal : Official... Mar 2024A recent study reported a 34% mid-term revision rate after M6-C™ cervical total disc replacement (CTDR) for wear-related osteolysis. Here, we aim to investigate the...
INTRODUCTION
A recent study reported a 34% mid-term revision rate after M6-C™ cervical total disc replacement (CTDR) for wear-related osteolysis. Here, we aim to investigate the prevalence, risk factors, and radiographic characteristics of periprosthetic bony changes and implant failure of the M6-C™ artificial disc.
METHODS
We retrospectively analysed radiographic (conventional X-ray, CT scan) and clinical outcomes (EQ-5D-5L, Neck Disability Index (NDI), and Visual Analog Scale (VAS) for neck and arm pain) data collected during routine follow-up of patients who underwent CTDR with the M6-C™ between 2011 and 2015.
RESULTS
In total, 85 patients underwent CTDR with the M6-C™. Follow-up data were available for 43 patients (54% female, mean age 44 years) with 50 implants and a mean follow-up of 8.1 years (6.5-11 years). Implant failure with the presence of severe osteolysis was identified in 5 (12%) patients who were all male (p = 0.016) and implanted at the C5/6 level (p = 0.11). All failed implants required revision surgery. The overall prevalence of osteolysis was 44% (22/50 implants) and 34% (17/50 implants) for significant heterotopic ossification. Patients with high-grade osteolysis showed higher VAS arm pain (p = 0.05) and lower EQ-5D-VAS health VAS (p = 0.03).
CONCLUSION
We report a lower reoperation rate for failed M6-C™ implants than previously published, but confirmed that osteolysis and heterotopic ossification are common following CTDR with the M6-C™ and may be asymptomatic. Therefore, we strongly recommend ongoing clinical and radiographic monitoring after CTDR with the M6-C™, particularly for male patients implanted at the C5/6 level.
Topics: Humans; Male; Female; Adult; Total Disc Replacement; Treatment Outcome; Follow-Up Studies; Intervertebral Disc Degeneration; Retrospective Studies; Osteolysis; Cervical Vertebrae; Neck Pain; Ossification, Heterotopic
PubMed: 38363365
DOI: 10.1007/s00586-024-08129-5 -
Trauma Case Reports Apr 2024Although bone morphogenetic proteins (BMPs) are used as an adjunct to promote healing, they may have unintended effects such as heterotopic ossification (HO). The...
BACKGROUND
Although bone morphogenetic proteins (BMPs) are used as an adjunct to promote healing, they may have unintended effects such as heterotopic ossification (HO). The literature is limited regarding the effect of using off-label BMPs for femur fractures.
CASE PRESENTATION
We report two outcomes after off-label use of BMPs for the treatment of femur fractures and propose a possible explanation for the difference.
CONCLUSIONS
BMPs are critical osteoinductive factors in injured bone and muscle that facilitate bony healing. However, it may be important to recognize the potentially negative effects of adding BMP to bone graft material in certain cases to stimulate bone repair. We hope this case series helps surgeons consider the risks and benefits of using BMP for femur fractures, and therefore to decide with caution when BMP is indicated.
PubMed: 38357291
DOI: 10.1016/j.tcr.2024.100979 -
Journal of Clinical Medicine Jan 2024Heterotopic ossification (HO) after elbow trauma can be responsible for significant motion restrictions. The study's primary aim was to develop a new X-ray-based...
Heterotopic ossification (HO) after elbow trauma can be responsible for significant motion restrictions. The study's primary aim was to develop a new X-ray-based classification for HO of the elbow. This retrospective study analyzed elbow injury radiographs from 138 patients aged 6-85 years (mean 45.9 ± 18) who underwent operative treatment. The new classification was applied at 6 weeks, 12 weeks, and 6 months postoperatively. The severity of HO was graded from 0 to 4 and localization was defined as r (radial), p (posterior), u (ulnar) or a (anterior) by two observers. The patients were categorized based on injury location and use of non-steroidal anti-inflammatory drugs (NSAIDs) for HO prophylaxis. The correlations between the generated data sets were analyzed using Chi-square tests (χ) with a significance level of < 0.05. The inter- and intraobserver reliability was assessed using Cohen's Kappa. In 50.7% of the evaluated X-rays, the formation of HO could be detected after 12 weeks, and in 60% after 6 months. The analysis showed a significant correlation between the injury's location and the HO's location after 12 weeks ( = 0.003). The use of an NSAID prophylaxis did not show a significant correlation with the severity of HO. The classification showed nearly perfect inter- (κ = 0.951, < 0.001) and intrareliability (κ = 0.946, < 0.001) according to the criteria of Landis and Koch. Based on the presented classification, the dimension and localization of HO in the X-ray image can be described in more detail compared to previously established classifications and, thus, can increase the comparability of results across studies.
PubMed: 38337359
DOI: 10.3390/jcm13030667 -
BMC Musculoskeletal Disorders Feb 2024Intervertebral disc calcification (IDC) combined with calcification in children has been sporadically reported, while ossification of the posterior longitudinal ligament... (Review)
Review
BACKGROUND
Intervertebral disc calcification (IDC) combined with calcification in children has been sporadically reported, while ossification of the posterior longitudinal ligament (OPLL) in the cervical spine in pediatric patients is exceedingly rare. The aim of this study is to investigate the potential prognosis and outcomes associated with this condition.
CASE PRESENTATION
We present an unusual case involving a 10-year-old Chinese child diagnosed with calcified cervical disc herniation and ossification of the posterior longitudinal ligament. Conservative treatment measures were implemented, and at the 1-month and 6-month follow-up, the patient's pain exhibited significant improvement. Subsequent cervical MRI and CT scans revealed the complete disappearance of OPLL and substantial absorption of the calcified disc. During the three-month follow-up, CT demonstrated slight residual disc calcification, however, the patient remained asymptomatic with no discernible limitation in cervical motion.
CONCLUSIONS
We conducted a comprehensive review of several cases presenting with the same diagnosis. It is noteworthy that IDC combined with OPLL in children constitutes a rare clinical entity. Despite imaging indications of potential spinal canal occupation, the majority of such cases demonstrate complete absorption following conservative treatment, with OPLL exhibiting a faster absorption rate than calcified discs.
Topics: Humans; Child; Longitudinal Ligaments; Osteogenesis; Intervertebral Disc Degeneration; Ossification of Posterior Longitudinal Ligament; Calcinosis; Chondrocalcinosis; Cervical Vertebrae; Intervertebral Disc
PubMed: 38336663
DOI: 10.1186/s12891-024-07218-2 -
Journal of Orthopaedic Translation Jan 2024It is a common clinical phenomenon that blood infiltrates into the injured tendon caused by sports injuries, accidental injuries, and surgery. However, the role of blood...
OBJECTIVE
It is a common clinical phenomenon that blood infiltrates into the injured tendon caused by sports injuries, accidental injuries, and surgery. However, the role of blood infiltration into the injured tendon has not been investigated.
METHODS
A blood-induced rat model was established and the impact of blood infiltration on inflammation and HO of the injured tendon was assessed. Cell adhesion, viability, apoptosis, and gene expression were measured to evaluate the effect of blood treatment on tendon stem/progenitor cells (TSPCs). Then RNA-seq was used to assess transcriptomic changes in tendons in a blood infiltration environment. At last, the small molecule drug PI3K inhibitor LY294002 was used for and HO treatment.
RESULTS
Blood caused acute inflammation in the short term and more severe HO in the long term. Then we found that blood treatment increased cell apoptosis and decreased cell adhesion and tenonic gene expression of TSPCs. Furthermore, blood treatment promoted osteochondrogenic differentiation of TSPCs. Next, we used RNA-seq to find that the PI3K/AKT signaling pathway was activated in blood-treated tendon tissues. By inhibiting PI3K with a small molecule drug LY294002, the expression of osteochondrogenic genes was markedly downregulated while the expression of tenonic genes was significantly upregulated. At last, we also found that LY294002 treatment significantly reduced the tendon HO in the rat blood-induced model.
CONCLUSION
Our findings indicate that the upregulated PI3K/AKT signaling pathway is implicated in the aggravation of tendon HO. Therefore, inhibitors targeting the PI3K/AKT pathway would be a promising approach to treat blood-induced tendon HO.
PubMed: 38328343
DOI: 10.1016/j.jot.2023.11.003 -
Journal of the American Academy of... Feb 2024Heterotopic ossification (HO) in the knee after tibial intramedullary nailing (IMN) has yet to be thoroughly investigated. Our aim was to assess frequency and associated...
INTRODUCTION
Heterotopic ossification (HO) in the knee after tibial intramedullary nailing (IMN) has yet to be thoroughly investigated. Our aim was to assess frequency and associated factors for HO in the knee after tibial IMN.
METHODS
This is a retrospective review at a single level 1 urban trauma center of 213 patients who underwent reamed tibial IMN. Plain radiographs were reviewed postoperatively and on final follow-up (≥6 weeks). Chart review was performed for surgical approach (suprapatellar versus infrapatellar), demographics, injury characteristics, and clinical follow-up. The primary outcome was frequency of HO.
RESULTS
HO on final follow-up (mean: 41.43 weeks) was recorded in 15% cases. Postsurgical retroinfrapatellar reaming debris (odds ratio [OR], 4.73), Injury Severity Score (OR, 1.05), intensive care unit admission (OR, 2.89), chest injury (OR, 3.4), and ipsilateral retrograde femoral IMN (OR, 5.08) showed a notable association with HO development. No association was observed in HO formation between surgical approach, knee pain, or range-of-motion deficits.
DISCUSSION
Radiographic evidence of HO in the knee after reamed tibial IMN is not uncommon and is associated with retained reaming debris, Injury Severity Score, chest injury, intensive care unit admission, and ipsilateral retrograde femoral nailing. No differences were noted in HO formation between approaches. HO was not associated with knee pain or range-of-motion deficits.
Topics: Humans; Fracture Fixation, Intramedullary; Incidence; Tibial Fractures; Risk Factors; Pain; Ossification, Heterotopic; Thoracic Injuries
PubMed: 38324456
DOI: 10.5435/JAAOSGlobal-D-23-00258 -
JSES Reviews, Reports, and Techniques Feb 2024
PubMed: 38323215
DOI: 10.1016/j.xrrt.2023.09.011 -
American Journal of Translational... 2024Heterotopic ossification (HO), whether hereditary or traumatic, refers to the abnormal formation of bone in extraskeletal sites, often triggered by inflammation or...
OBJECTIVES
Heterotopic ossification (HO), whether hereditary or traumatic, refers to the abnormal formation of bone in extraskeletal sites, often triggered by inflammation or flare-ups. Unfortunately, there are currently no effective treatments for HO. Metformin is well-known for its anti-diabetic, anti-inflammatory, anti-aging, and anti-cancer effects. However, its potential role in treating HO remains uncertain.
METHODS
Metformin was dissolved into water and given to mice. All the mice in this study were examined by microCT and myeloid cell quantification using flow cytometry. Complex activity kit was used to examine the activity of mitochondrial complexes of myeloid cells.
RESULTS
In this study, we discovered that metformin effectively inhibits genetic and traumatic HO formation and progression. Additionally, we observed a significant increase in myeloid cells in the genetic and traumatic HO mouse model compared to uninjured mice. Notably, metformin specifically reduced the infiltration of myeloid cells into the injured sites of the genetic and traumatic HO model mice. Further investigations revealed that metformin targets mitochondrial complex I and suppresses mitochondrial metabolism in myeloid cells.
CONCLUSION
These findings suggest that metformin suppresses HO development by potentially downregulating the mitochondrial metabolism of myeloid cells, offering a promising therapeutic option for HO treatment.
PubMed: 38322576
DOI: 10.62347/AAPM9027