Search

Background Context: Early fusion is crucial in interbody procedures to minimize mechanical complications resulting from delayed union, especially for patients with osteoporosis. Bone morphogenetic proteins (BMPs) are used in spinal fusion procedures; however, limited evaluation exists regarding time-to-fusion for BMP use, particularly in patients with osteoporosis., Purpose: To evaluate the difference in time-to-fusion after single-level transforaminal lumbar interbody fusion (TLIF) surgery between recombinant human bone morphogenetic protein-2 (rhBMP-2) usage and nonusage groups according to bone density., Study Design: Retrospective single-center cohort study., Patient Sample: This study enrolled 132 patients (mean age, 65.25±8.66; male patients, 40.9%) who underwent single-level TLIF for degenerative disorders between February 2012 and December 2021, with pre- and postoperative computed tomography (CT)., Outcome Measure: The interbody fusion mass and bone graft status on postoperative CT scans was obtained annually, and time-to-fusion was recorded for each patient., Methods: The patients were divided into 2 groups based on rhBMP-2 use during the interbody fusion procedure. Patients were further divided into osteoporosis, osteopenia, and normal groups based on preoperative L1 vertebral body attenuation values, using cutoffs of 90 and 120 Hounsfield units. It was strictly defined that fusion is considered complete when a trabecular bone bridge was formed, and therefore, the time-to-fusion was measured in years. Time-to-fusion was statistically compared between BMP group and non-BMP groups, followed by further comparison according to bone density., Results: The time-to-fusion differed significantly between BMP and non-BMP groups, with half of the patients achieving fusion within 2.5 years in the BMP group compared with 4 years in the non-BMP group (p<.001). The fusion rate varied based on bone density, with the maximum difference observed in the osteoporosis group, when half of the patients achieved fusion within 3 years in the BMP group compared to 5 years in the non-BMP group (p<.001). Subgroup analysis was conducted, revealing no significant associations between time-to-fusion and factors known to influence the fusion process, including age, gender, medical history, smoking and alcohol use, and medication history, except for rh-BMP2 use and bone density., Conclusions: RhBMP-2 usage significantly reduced time-to-fusion in single-level TLIF, especially in patients with osteoporosis., Level of Evidence: Level III., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is effective for promoting robust fusion for long-level cervical deformity and revision surgeries. However, only a few studies have reported its efficacy and complications in posterior cervical fusion (PCF)., Methods: Therefore we evaluated the efficacy and complications of rhBMP-2 application in PCF surgery by searching 3 electronic databases (PubMed, Cochrane Database, and EMBASE) for studies that evaluated the use of rhBMP-2 in PCF. Five studies (1 prospective and 4 retrospective) were included in the meta-analysis., Results: The quality of each study was assessed, and data on pseudarthrosis, wound infection, neurologic, and immediate medical complications were extracted and analyzed. We found that the use of rhBMP-2 in PCF showed significant benefits in terms of pseudarthrosis and no significant increases in the risk for neurologic and immediate medical complications regardless of the dose. However, high-dose (>2.1 mg/level) rhBMP-2 was a risk factor for wound infection after PCF., Conclusions: Our meta-analysis of the currently available literature suggests that patients with PCF may benefit from BMP-2 usage without increasing the risk of complications. However, dose control and containment are important to ensure a low risk of complications., (Copyright © 2023. Published by Elsevier Inc.)

&lt;b&gt;Background and Objective:&lt;/b&gt; Liver fibrosis (LF) is a most common pathological process characterized by the activation of hepatocytes leading to the accumulation of extracellular matrix (ECM). Hypoxia precondition treated in MSCs (H-MSCs) could enhance their immunomodulatory and regeneration capability, through expressing robust anti-inflammatory cytokines and growth factors, known as H-MSCs secretome (SH-MSCs) that are critical for the improvement of liver fibrosis. However, the study regarding the efficacy and mechanism of action of SH-MSCs in ameliorating liver fibrosis is still inconclusive. In this study, the therapeutic potential and underlying mechanism for SH-MSCs in the treatment of liver fibrosis were investigated. &lt;b&gt;Materials and Methods:&lt;/b&gt; A rat model with liver fibrosis induced by CCl&lt;sub&gt;4&lt;/sub&gt; was created and maintained for 8 weeks. The rats received intravenous doses of SH-MSCs and secretome derived from normoxia MSCs (SN-MSCs), filtered using a tangential flow filtration (TFF) system with different molecular weight cut-off categories, both at a dosage of 0.5 mL. The ELISA assay was employed to examine the cytokines and growth factors present in both SH-MSCs and SN-MSCs. On the ninth day, the rats were euthanized and liver tissues were collected for subsequent histological examination and analysis of mRNA expression. &lt;b&gt;Results:&lt;/b&gt; The ELISA test revealed that SH-MSCs exhibited higher levels of VEGF, PDGF, bFGF, IL-10, TGF-β and IL-6 compared to SN-MSCs. &lt;i&gt;In vivo&lt;/i&gt;, administration of SH-MSCs notably decreased mortality rates. It also demonstrated a reduction in liver fibrosis, collagen fiber areas, α-SMA positive staining and relative mRNA expression of TGF-β. Conversely, SN-MSCs also contributed to liver fibrosis improvement, although SH-MSCs demonstrated more favorable outcomes. &lt;b&gt;Conclusion:&lt;/b&gt; Current findings suggested that SH-MSCs could improve CCl&lt;sub&gt;4&lt;/sub&gt;-induced liver fibrosis and decrease α-SMA and TGF-β expression.

Background & Aims: Glycation, oxidative stress, and inflammation due to the elevation of transforming growth factor-β1 (TGF-β1) participate in diabetic nephropathy (DN). Thus, we investigated for the first time the effect of crocetin (Crt) on the renal histopathological parameters, TGF-β1 and glycation, oxidative stress, as well as inflammatory markers in the DN rat model., Methods: Forty male Wistar rats were randomly divided into 4 equal groups: normal (N), N + Crt, DN, and DN + Crt. DN was induced in rats with a combination of nephrectomy and streptozotocin. Treated groups received 100 mg/kg of Crt via intraperitoneal injection monthly for 3 months. Different glycation (glycated albumin, glycated LDL, Methylglyoxal, and pentosidine), oxidative stress (advanced oxidation protein products, malondialdehyde, glutathione, and paraoxonase-I (PON-1)), and inflammatory markers (tumor necrosis factor-α, myeloperoxidase, and TGF-β1), blood glucose, insulin, lipid profile, creatinine in the serum, and proteinuria, as well as the glyoxalase-1 (GLO-1) activity, was determined., Results: Crt decreased renal biochemical (Cre and PU) and histopathological (glomerulosclerosis) renal dysfunction parameters, diverse glycation, oxidative stress, and inflammatory markers in the DN rats. Furthermore, the treatment corrected glycemia, insulin resistance, and dyslipidemia as well as induced the activities of GLO-1 and PON-1. Over and above, the treatment decreased TGF-β1 in their serum (p > 0.001)., Conclusions: Crocetin improved DN owing to an advantageous effect on metabolic profile. Further, the treatment with a reducing effect on TGF-β1, oxidative stress, glycation, and inflammation markers along with an increase in Glo-1 activity showed multiple protective effects on kidney tissue., Competing Interests: Declaration of competing interest There is no conflict interest., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Chronic renal failure (CRF) is the result of kidney damage. Puerarin is a flavonoid with specific nephroprotective effect, but its effect on CRF needs further research. This study explored the effect of puerarin on CRF and the potential molecular mechanism., Methods: Adenine was used to establish an in vivo CRF model in rats, and rats were intragastrically administered with puerarin at a dose of 400 mg/kg body weight once a day from day 1 to day 28. Hematoxylin and eosin (HE) and Masson staining were used to observe the morphology and fibrosis of kidney tissue. Lipopolysaccharide (LPS) (400 ng/mL)/H 2 O 2 (200 µM) was applied to human kidney 2 (HK-2) cells to construct an in vitro CRF model. Enzyme-linked immunosorbent assay (ELISA) was performed to validate interleukin (IL)-1β and IL-18 levels. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to detect microRNA (miR)-342-3p levels. Transforming growth factor beta (TGF-β)1, SMAD2, SMAD3, and pyroptosis marker proteins were detected by Western blot. The interaction between miR-342-3p and TGF-β/SMAD was determined by a dual-luciferase reporter gene assay. Cell Counting Kit-8 (CCK-8) assay was utilized to determine cell viability., Results: In the CRF model, puerarin alleviated renal injury and fibrosis and reduced creatinine (Cr) and blood urea nitrogen (BUN) levels. At the same time, miR-342-3p was downregulated, while the TGF-β/SMAD axis was activated and levels of IL-1β and IL-18 were increased. After treatment of CRF rats with puerarin, the expression level of miR-342-3p was increased, the TGF-β/SMAD axis was inhibited, and the secretion of IL-1β and IL-18 was decreased. MiR-342-3p directly bound to and negatively regulated the expression of TGF-β1, SMAD2, and SMAD3. In the in vitro CRF model, miR-342-3p inhibited HK-2 cell pyroptosis by inhibiting the TGF-β/SMAD axis., Conclusion: Puerarin reduced renal injury and pyroptosis in CRF rats by targeting the miR-342-3p/TGF-β/SMAD axis., (© 2023. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Purpose: Safety concerns regarding the application of bone morphogenetic proteins (BMPs) have been highlighted in recent years. It is noted that both BMP and their receptors being identified as a trigger for cancer growth. Here, we aimed to determine the safety and efficacy of BMP for spinal fusion surgery., Methods: We conducted this systematic review on topics of spinal fusion surgery with rhBMP application from three database (PubMed, EuropePMC, and Clinicaltrials.gov) with MeSH phrases such as "rh-BMP," "rhBMP," "spine surgery," "spinal arthrodesis," and "spinal fusion" were searched (using the Boolean operators "and" and "or"). Our research includes all articles, as long as published in English language. In the face of disagreement between the two reviewers, we discussed it together until all authors reached a consensus. The primary key outcome of our study is the incidence of cancer following rhBMP implantation., Results: Our study included a total of 8 unique studies (n = 37,682). The mean follow-up varies among all studies, with the longest follow-up is 66 months. Our meta-analysis showed that exposure to rhBMP in spinal surgery did increase the risk of cancers (RR 1.85, 95%CI [1.05, 3.24], p = 0.03)., Conclusions: Our study found that rhBMP was not associated with the increased risk of cancer incidence within the rhBMP cohort. Still, we did face several limitations, in which further studies are needed to confirm the result of our meta-analysis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The role of activin B, a transforming growth factor β (TGFβ) superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl 4 )-induced liver fibrosis. Hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. Injured hepatocytes produced excessive activin B. Neutralizing activin B largely prevented, as well as improved, CCl 4 -induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B mediated the activation of c-Jun-N-terminal kinase (JNK), the induction of inducible nitric oxide synthase (iNOS) expression, and the maintenance of poly (ADP-ribose) polymerase 1 (PARP1) expression in injured livers. Moreover, activin B directly induced a profibrotic expression profile in hepatic stellate cells (HSCs) and stimulated these cells to form a septa structure. Conclusions: We demonstrate that activin B, cooperating with activin A, mediates the activation or expression of JNK, iNOS, and PARP1 and the activation of HSCs, driving the initiation and progression of liver fibrosis., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been widely used as an alternative bone graft in spine fusion surgery. However, clinical outcome such as effects and complications has not yet been revealed for transforaminal lumbar interbody fusion (TLIF). Although previous studies have reported some results, the evidence is weak. Therefore, the purpose of this trial is to evaluate the effectiveness and safety of Escherichia coli-derived rhBMP-2 combined with hydroxyapatite (HA) in TLIF., Methods: This trial is designed as a prospective, assessor-blinded, open-label, multicenter, randomized controlled study. Participants will be recruited from six tertiary teaching hospitals. All randomized participants will be undergoing one- or two-level TLIF with rhBMP-2 (77 participants) as the active experimental group or with an auto-iliac bone graft (77 participants) as the control group. The primary interbody fusion rate outcome will be evaluated using computed tomography (CT) 12 months after surgery. The secondary outcomes will be as follows: clinical outcomes (visual analog scale score, EuroQol-5-dimensions-5-level score, Oswestry Disability Index score, and some surgery-related variables) and adverse effects (radiculitis, heterotrophic ossification, endplate resorption, and osteolysis). Radiological outcomes will be evaluated using simple radiography or CT. All outcomes will be measured, collected, and evaluated before surgery and at 12, 24, and 52 weeks postoperatively., Discussion: This study will be the primary of its kind to evaluate the effectiveness and safety of E. coli-derived rhBMP-2 with HA in one- or two-level TLIF. It is designed to evaluate the equivalence of the results between rhBMP-2 with HA and auto-iliac bone graft using an appropriate sample size, assessor-blinded analyses, and prospective registration to avoid bias. This study will set up clear conclusions for using E. coli-derived rhBMP-2 with HA in TLIF., Trial Registration: This study protocol was registered at Korea Clinical Research Information Service ( https://cris.nih.go.kr ; number identifier: KCT0005610) on 19 November 2020. And protocol version is v1.1, January 2022., (© 2022. The Author(s).)

Objectives: To determine the anti-fibrotic effects of Wnt/β-catenin signaling inhibitors on urethral stricture., Methods: Human fibroblasts were exposed to transforming growth factor beta 1 combined with various concentrations of Wnt/β-catenin inhibitors (ICG-001, IWR-1, and PRI-724), and cell proliferation and migration were evaluated. Urethral fibrosis was induced in male Sprague-Dawley rats by urethral injection of transforming growth factor beta 1 and co-treatement with inhibitors. Urethral tissues were harvested 2 weeks after the injection. The messenger ribonucleic acid and protein expression was examined for fibrosis markers Axin-1, collagen type 1, alpha smooth muscle actin, and β-catenin. Histological analysis of fibrosis and collagen deposition was also performed., Results: Cell migration was ameliorated by ICG-001 and PRI-724. Protein and messenger ribonucleic acid expression of collagen type 1 and alpha smooth muscle actin in transforming growth factor beta 1-treated fibroblasts decreased in a concentration-dependent manner with the ICG-001 and PRI-724 treatments (P < 0.05). However, there were no significant changes with the IWR-1 treatment. Collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression were both significantly increased in the urethral tissues of rats with transforming growth factor beta 1-induced urethral fibrosis. Rats co-treated with ICG-001 or PRI-724 showed relatively mild fibrosis and significantly reduced collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression (P < 0.05)., Conclusions: ICG-001 and PRI-724 significantly ameliorated urethral fibrosis induced by transforming growth factor beta 1 in rats. These results suggest that ICG-001 and PRI-724 can be developed as therapeutics for treating urethral stricture., (© 2022 The Japanese Urological Association.)

Liver fibrosis progression in chronic liver disease leads to cirrhosis, liver failure, or hepatocellular carcinoma and often ends in liver transplantation. Even with an increased understanding of liver fibrogenesis and many attempts to generate therapeutics specifically targeting fibrosis, there is no approved treatment for liver fibrosis. To further understand and characterize the driving mechanisms of liver fibrosis, we developed a high-throughput genome-wide CRISPR/Cas9 screening platform to identify hepatic stellate cell (HSC)-derived mediators of transforming growth factor (TGF)-β-induced liver fibrosis. The functional genomics phenotypic screening platform described here revealed the novel biology of TGF-β-induced fibrogenesis and potential drug targets for liver fibrosis.

Objectives: Angiotensin II (Ang II)-induced atrial fibrosis plays a vital role in the development of atrial fibrillation (AF). Lysyl oxidase-like 2 (LOXL2) plays an essential role in matrix remodeling and fibrogenesis, indicating it may involve fibrosis-associated diseases. This study aims to elucidate the role of LOXL2 in AF, and its specific inhibitor can suppress Ang II-induced inflammatory atrial fibrosis and attenuate the enhanced vulnerability to AF., Methods: Male mice C57BL/6 were subcutaneously infused with either saline or Ang II (2 mg/kg/day) for 4 weeks. DMSO or LOXL2 inhibitor LOXL2-IN-1 hydrochloride (LOXL2-IN-1) at a dose of 100 μg/kg/day were intraperitoneally injected once daily for 4 weeks. Morphological, histological, and biochemical analyses were performed. AF was induced by transesophageal burst pacing in vivo., Results: Expression of LOXL2 was increased in serum of AF patients and Ang II-treated mice. LOXL2-IN-1 significantly attenuated Ang II-induced AF vulnerability, cardiac hypertrophy, atrial inflammation, and fibrosis. LOXL2-IN-1 suppressed Ang II-induced expression of transforming growth factor beta-1 (TGF-β1) and collagen I and phosphorylation of Smad2/3 in atrial tissue., Conclusions: LOXL2 is a target of AF, and its inhibitor prevents atrial fibrosis and attenuated enhanced vulnerability to AF potentially through the TGF-β/Smad pathway., (© 2021 S. Karger AG, Basel.)

Objective: Bone morphogenetic protein (BMP) is a growth factor that aids in osteoinduction and promotes bone fusion. There is a lack of literature regarding recombinant human BMP-2 (rhBMP-2) dosage in different spine surgeries. This study aims to investigate the trends in rhBMP-2 dosage and the associated complications in spinal arthrodesis., Methods: A retrospective study was conducted investigating spinal arthrodesis using rhBMP-2. Variables including age, procedure type, rhBMP-2 size, complications, and postoperative imaging were collected. Cases were grouped into the following surgical procedures: anterior lumbar interbody fusion/extreme lateral interbody fusion (ALIF/XLIF), posterior lumbar interbody fusion/transforaminal lumbar interbody fusion (PLIF/TLIF), posterolateral fusion (PLF), anterior cervical discectomy and fusion (ACDF), and posterior cervical fusion (PCF)., Results: A total of 1209 patients who received rhBMP-2 from 2006 to 2020 were studied. Of these, 230 were categorized as ALIF/XLIF, 336 as PLIF/TLIF, 243 as PLF, 203 as ACDF, and 197 as PCF. PCF (P < 0.001), PLIF/TLIF (P < 0.001), and PLF (P < 0.001) demonstrated a significant decrease in the rhBMP-2 dose used per level, with major transitions seen in 2018, 2011, and 2013, respectively. In our sample, 129 complications following spinal arthrodesis were noted. A significant relation between rhBMP-2 size and complication rates (χ 2 = 73.73, P = 0.0029) was noted. rhBMP-2 dosage per level was a predictor of complication following spinal arthrodesis (odds ratio = 1.302 [1.05-1.55], P < 0.001)., Conclusions: BMP is an effective compound in fusing adjacent spine segments. However, it carries some regional complications. We demonstrate a decreasing trend in the dose/vertebral level. A decrease rhBMP-2 dose per level correlated with a decrease in complication rates., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Transdifferentiation of lung fibroblasts to myofibroblasts is a crucial pathophysiological process in pulmonary fibrosis. MicroRNA‑375 (miR‑375) was initially identified as a tumor‑suppressive factor, and its expression was negatively associated with the severity of lung cancer; however, its role and potential mechanism in myofibroblast transdifferentiation and pulmonary fibrosis remain unclear. In the present study, human lung fibroblasts were stimulated with transforming growth factor‑β (TGF‑β) to induce myofibroblast transdifferentiation. A mimic and inhibitor of miR‑375, and their negative controls, were used to overexpress or suppress miR‑375 in lung fibroblasts, respectively. The mRNA expression levels of fibrotic markers, and protein expression of α‑smooth muscle actin and periostin, were subsequently detected by reverse transcription‑quantitative PCR and western blotting, to assess myofibroblast transdifferentiation. miR‑375 was markedly upregulated in human lung fibroblasts after TGF‑β stimulation. The miR‑375 mimic alleviated, whereas the miR‑375 inhibitor aggravated TGF‑β‑dependent transdifferentiation of lung fibroblasts. Mechanistically, miR‑375 prevented myofibroblast transdifferentiation and collagen synthesis by blocking the P38 mitogen‑activated protein kinases (P38) pathway, and P38 suppression abrogated the deleterious effect of the miR‑375 inhibitor on myofibroblast transdifferentiation. Furthermore, the present study revealed that mitogen‑activated protein kinase kinase 6 was involved in P38 inactivation by miR‑375. In conclusion, miR‑375 was implicated in modulating TGF‑β‑dependent transdifferentiation of lung fibroblasts, and targeting miR‑375 expression may help to develop therapeutic approaches for treating pulmonary fibrosis.

Aims: This study aimed to examine the anti-fibrotic role of Nuclear Factor-Erythroid derived 2 (NF-E2) in human renal tubule (HK-11) cells and in type 1 and type 2 diabetic (T1D, T2D) mouse kidneys., Main Methods: Anti-fibrotic effects of NF-E2 were examined in transforming growth factor-β (TGF-β) treated HK-11 cells by over-expressing/silencing NF-E2 expression and determining its effects on profibrotic signaling. NF-E2 proteasomal degradation was confirmed by proteasome inhibition in HK-11 cells and diabetic mice. Clinical relevance of changes in NF-E2 expression to fibrotic changes in the kidney were assessed in T1D and T2D mouse kidneys., Key Findings: NF-E2 expression was significantly decreased in TGF-β treated HK-11 cells and in kidneys of diabetic mice with concurrent increase in expression of fibrotic proteins. TGF-β treatment of HK-11 cells did not inhibit NF-E2 mRNA expression, suggesting that the post-translational changes may contribute to NF-E2 protein degradation. The down-regulation of NF-E2 expression was attributed to its proteasomal degradation, as TGF-β- and diabetes-induced NF-E2 down regulation was prevented by proteasome inhibitor treatment. In HK-11 cells TGF-β treatment decreased E-cadherin expression and induced pSer 82 Hsp27/NF-E2 association, likely to promote NF-E2 degradation, as Hsp27 can target proteins to the proteasome. A critical role for NF-E2 in regulation of renal fibrosis was demonstrated as over-expression of NF-E2 or silencing NF-E2 expression, decreased or increased profibrotic proteins in TGF-β-treated HK-11 cells, respectively., Significance: NF-E2, a novel anti-fibrotic protein, is down-regulated in diabetic kidneys. Preserving/inducing NF-E2 expression in diabetic kidneys may provide a therapeutic potential to combat DN., Competing Interests: Declaration of competing interest Authors declare they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background Context: The effects of using off-label recombinant human bone morphogenetic protein (rhBMP)-2 for interbody fusion are controversial. Although animal models of posterolateral fusion are well-established, establishing animal models to validate the safety and efficacy of interbody fusion is difficult, which may contribute to the inconsistent clinical results., Purpose: To develop a novel animal model of interbody fusion in rat coccygeal vertebrae without destroying bony endplates., Study Design: An experimental animal study., Methods: Forty-five male Sprague-Dawley rats underwent coccygeal interbody fusion without violating vertebral endplates. The animals were divided into three different groups based on the materials that were implanted into the interbody space (1) allogeneic iliac bone (IB) alone (IB group), (2) IB and 3 µg of rhBMP-2 (BMP low-dose group), or (3) IB and 10 µg of rhBMP-2 (BMP high-dose group). Fusion rates were investigated using microcomputed tomography 6 weeks after the operation. The incidence of adverse events, including soft-tissue swelling, delayed wound healing, osteolysis, and ectopic bone formation were evaluated. The total number of adverse events (using the adverse event score) in each group and the swelling ratio (calculated using the surgical site tissue volume [TV; TV on postoperative day 1/preoperative TV]) were also evaluated., Results: The fusion rates in the BMP low- and high-dose groups (33.3% and 46.7%) were not significantly different, but both were significantly higher than that in the IB group (0%) (p=.042 and .006, respectively). Significant differences in the incidence of osteolysis, adverse event scores, and swelling ratios were observed only between the BMP high-dose and IB groups (p=.043, .006 and .014, respectively)., Conclusions: We developed a novel rat model of interbody fusion in which the vertebral endplates were not violated, reflecting the normal clinical setting. rhBMP-2 use increased the fusion rate, but a higher dose of rhBMP-2 did not lead to a higher fusion rate than that for low-dose rhBMP-2; conversely, it led to an increase in the occurrence of adverse events., Clinical Significance: This novel rat model of coccygeal interbody fusion that preserved bony endplates has clinical significance for validating the effectiveness of biologics or bone graft substitutes before clinical trial., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cystic fibrosis (CF) is a lethal genetic disease characterized by progressive lung damage and airway obstruction. The majority of patients demonstrate airway hyperresponsiveness (AHR), which is associated with more rapid lung function decline. Recent studies in the neonatal CF pig demonstrated airway smooth muscle (ASM) dysfunction. These findings, combined with observed CF transmembrane conductance regulator (CFTR) expression in ASM, suggest that a fundamental defect in ASM function contributes to lung function decline in CF. One established driver of AHR and ASM dysfunction is transforming growth factor (TGF) β1, a genetic modifier of CF lung disease. Prior studies demonstrated that TGFβ exposure in CF mice drives features of CF lung disease, including goblet cell hyperplasia and abnormal lung mechanics. CF mice displayed aberrant responses to pulmonary TGFβ, with elevated PI3K signaling and greater increases in lung resistance compared with controls. Here, we show that TGFβ drives abnormalities in CF ASM structure and function through PI3K signaling that is enhanced in CFTR-deficient lungs. CF and non-CF mice were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA, empty vector, or PBS only. We assessed methacholine-induced AHR, bronchodilator response, and ASM area in control and CF mice. Notably, CF mice demonstrated enhanced AHR and bronchodilator response with greater ASM area increases compared with non-CF mice. Furthermore, therapeutic inhibition of PI3K signaling mitigated the TGFβ-induced AHR and goblet cell hyperplasia in CF mice. These results highlight a latent AHR phenotype in CFTR deficiency that is enhanced through TGFβ-induced PI3K signaling.

Background and Objective: Malnutrition is a major complication of inflammatory bowel disease (IBD). Our aim of the study was to examine the effects of Modulen IBD supplementation, which was administered to IBD patients without limiting their daily diet in addition to medical treatment, on the clinical, laboratory, anthropometric values, and disease activities of these patients. Materials and Methods: Seventy three children with IBD were evaluated retrospectively. The cases were classified as those who had Crohn disease receiving (CD-M; n = 16) or not receiving Modulen IBD (CD; n = 19) and those who had ulcerative colitis receiving (UC-M; n = 13) or not receiving Modulen IBD (UC; n = 25). Disease activities, laboratory values, remission rates, and anthropometric measurements of the groups were compared. In addition to IBD treatment, Modulen IBD in which half of the daily calorie requirement was provided was given for eight weeks. Results: In the third month of treatment, 14 (88%) patients were in remission in CD-M group and eight (42%) patients were in remission in CD group. The height and weight z scores, which were low at the time of diagnosis, improved in the first week in CD-M group. Inflammatory parameters (UC) were significantly lower in the UC-M group compared to the UC group in first and third months. In the third month, eight (62%) patients in the UC-M group and four (16%) in the UC group were remitted clinically and in terms of laboratory values. Conclusions: TGF-β-rich enteral nutrition support in children with IBD is an easy, effective, and reliable approach. It was shown that TGF-β-rich enteral nutritional supplementation enabled the disease to enter the remission earlier, and contributed to the early recovery of weight and height scores.

Cardiac fibrosis (CF), a process characterized by potentiated proliferation of cardiac fibroblasts and excessive secretion and deposition of extracellular matrix (ECM) from the cells, contributes strongly to the pathogenesis of a series of cardiovascular (CV) diseases, including AMI, heart failure and atrial fibrillation. Endothelial-mesenchymal transition (EndMT), one of the sources of transformed cardiac fibroblasts, has been reported as a key factor involved in CF. However, the molecular basis of EndMT has not been thoroughly elucidated to date. At the posttranscriptional level, of the three epigenetic regulators, writer and eraser are reported to be involved in EndMT, but the role of reader in the process is still unknown. In this study, we aimed to explore the role of Bromodomain-containing protein 4 (BRD4), an acetyl-lysine reader protein, in EndMT-induced CF and related mechanisms. We found that BRD4 was upregulated in endothelial cells (ECs) in the pressure-overload mouse heart and that its functional inhibitor JQ1 potently attenuated the TAC-induced CF and preserved cardiac function. In umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs), bothJQ1 and shRNA-mediated silencing of BRD4 blocked TGF-β-induced EC migration, EndMT and ECM synthesis and preserved the EC sprouting behavior, possibly through the downregulation of a group of transcription factors specific for EndMT (Snail, Twist and Slug), the Smads pathway and TGF-β receptor I. In the absence of TGF-β stimulation, ectopic expression of BRD4 alone could facilitate EndMT, accelerate migration and increase the synthesis of ECM. In vivo, JQ1 also attenuated TAC-induced EndMT and CF, which was consistent with JQ1's intracellular mechanisms of action. Our results showed that BRD4 plays a critical role in EndMT-induced CF and that targeting BRD4 might be a novel therapeutic option for CF., (Copyright © 2018. Published by Elsevier Ltd.)

Poly- adenosine diphosphate (ADP)-ribose (PAR) is a polymer synthesized as a posttranslational modification by some poly (ADP-ribose) polymerases (PARPs), namely PARP-1, PARP-2, tankyrase-1, and tankyrase-2 (TNKS-1/2). PARP-1 is nuclear and has also been detected in extracellular vesicles. PARP-2 and TNKS-1/2 are distributed in nuclei and cytoplasm. PARP or PAR alterations have been described in tumors, and in particular by influencing the Epithelial- Mesenchymal Transition (EMT), which influences cell migration and drug resistance in cancer cells. Pro-EMT and anti-EMT effects of PARP-1 have been reported while whether PAR changes occur specifically during EMT is currently unknown. The PARP-1/2 inhibitor Olaparib (OLA) is approved by FDA to treat certain patients harboring cancers with impaired homologous recombination. Here, we studied PAR changes and OLA effects on EMT. Total and nuclear PAR increased in EMT while PAR belts were disassembled. OLA prevented EMT, according to: (i) molecular markers evaluated by immuno-cytofluorescence/image quantification, Western blots, and RNA quantitation, (ii) morphological changes expressed as anisotropy, and (iii) migration capacity in the scratch assay. OLA also partially reversed EMT. OLA might work through unconventional mechanisms of action (different from synthetic lethality), even in non-BRCA (breast cancer 1 gene) mutated cancers.

Case: We present 2 cases of postoperative seroma formation following posterior cervical fusion with the use of recombinant human bone morphogenetic protein-2 (rhBMP-2)., Conclusion: Although some who advocate for the off-label use of rhBMP-2 in patients undergoing posterior cervical spine fusion believe it to be safe, relatively little has been published regarding complication rates. We believe that rhBMP-2 carries a risk of seroma formation in patients who undergo posterior cervical fusion, which necessitates the use of a postoperative drain. Surgeons should have a low threshold for obtaining postoperative magnetic resonance imaging in a symptomatic patient.

Introduction: The restoration of acetabular bone stock during revision hip arthroplasty remains a challenge. There have been no clinical series reporting the efficacy of bone morphogenic protein-2 (rhBMP-2) in the revision hip setting., Methods: We retrospectively reviewed the radiographs and records of 15 patients who received rhBMP-2 mixed with allograft bone chips (+BMP), and 14 who received allograft bone chips alone (-BMP) for their acetabular defect during revision total hip arthroplasty with a mean two-year follow up. Radiographs were evaluated for acetabular defect size, superior cup migration, and changes in the lateral cup abduction angle. Modified Harris hip scores were used for evaluation of clinical outcomes., Results: Patients in the +BMP group compared to the -BMP group had significantly larger amounts of cancellous bone chips used (72.1 ± 35.5 cc vs. 38.6 ± 14.1 cc; p = 0.003). Mean rhBMP-2 used per case was 7.4 ± 3.1 mg in the +BMP group. Three patients in the -BMP group had cup migration which was not observed in the +BMP group. Mean Harris hip scores (HHS) improved post-operatively in both groups (40.1 ± 20.9 to 71.9 ± 19, p < .0001). No local adverse reaction was noted in the +BMP group., Conclusion: rhBMP-2 had modest clinical benefit in the setting of revision THA. Cost of this synthetic biologic versus the added clinical benefit should be carefully considered when being used in the revision hip setting.

Background Context: Recombinant human bone morphogenetic protein 2 (rhBMP-2) plays a pivotal role in complex spine surgery. Despite its limited approval, the off-label use of rhBMP-2 is prevalent, particularly in transforaminal lumbar interbody fusions (TLIFs)., Purpose: To determine the effectiveness and safety of rhBMP-2 use in TLIF procedures versus autograft., Study Design: Retrospective cohort study., Patient Sample: Patients older than 18 years undergoing spine surgery for lumbar degenerative spine disease at a single academic institution., Outcome Measures: Clinical outcome was determined according to patient records. Radiographic outcome was determined according to plain X-rays and computed tomography (CT)., Methods: A retrospective study from 1997 to 2014 was conducted on 191 adults undergoing anterior-posterior instrumented spinal fusion with TLIF at a single academic institution. Patient data were gathered from operative notes, follow-up clinic notes, and imaging studies to determine complications and fusion rates. One hundred eighty-seven patients fit the criteria, which included patients with a minimum of one TLIF, and had a minimum 2-year radiographic and clinical follow-up. Patients were further classified into a BMP group (n=83) or non-BMP group (n=104). Three logistic regression models were run using rhBMP-2 exposure as the independent variable. The respective outcome variables were TLIF-related complications (radiculitis, seroma, osteolysis, and ectopic bone), surgical complications, and all complications., Results: Bone morphogenetic protein (n=83) and non-BMP (n=104) groups had similar baseline demographics (sex, diabetes, pre-existing cancer). On average, the BMP and non-BMP groups were similarly aged (51.9 vs. 47.9 years, p>.05), but the BMP group had a shorter follow-up time (3.03 vs. 4.06 years; p<.001) and fewer smokers (8 vs. 21 patients; p<.048). The fusion rate for the BMP and non-BMP groups was 92.7% and 92.3%, respectively. The pseudoarthrosis rate was 7.5% (14 of 187 patients). Radiculitis was observed in seven patients in the BMP group (8.4%) and two patients in the non-BMP group (1.9%). Seroma was observed in two patients in the BMP group (2.4%) and none in the non-BMP group. No deep infections were observed in the BMP group, and in one patient in the non-BMP group (0.96%). Although patients exposed to BMP were at a significantlygreater risk of developing radiculitis and seroma (odds ratio [OR]=4.53, confidence interval [CI]=1.42-14.5), BMP exposure was not a significant predictor of surgical complications (OR=0.32, CI=0.10-1.00) or overall complications (OR=1.11, CI=0.53-2.34). The outcome of TLIF-related complications was too rare and the confidence interval too wide for practical significance of the first model., Conclusion: Evidence supports the hypothesis that off-label use of rhBMP-2 in TLIF procedures is relatively effective for achieving bone fusion at rates similar to patients receiving autograft. Patients exhibited similar complication rates between the two groups, with the BMP group exhibiting slightly higher rates of radiculitis and seroma., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We conducted a study to determine the common characteristics of patients who developed radiculopathy symptoms and corresponding heterotopic ossification (HO) from transforaminal lumbar interbody fusions (TLIF) using recombinant human bone morphogenetic protein 2 (rhBMP-2). HO can arise from a disk space with rhBMP-2 use in TLIF. Formation of bone around nerve roots or the thecal sac can cause a radiculopathy with a consistent pattern of symptoms. We identified 38 patients (26 males, 12 females) with a mean (SD) age of 50.8 (7.5) years who developed radiculopathy symptoms and corresponding HO from TLIF with rhBMP-2 in the disk space between 2002 and 2015. To document this complication and improve its recognition, we recorded common patterns of symptom development and radiologic findings: specifically, time from implantation of rhBMP-2 to symptom development, consistency with side of TLIF placement, and radiologic findings. Radicular pain generally developed a mean (SD) of 3.8 (1.0) months after TLIF with rhBMP-2. Development of radiculopathy symptoms corresponded to consistent "pseudo-pedicle"-like HO. In all 38 patients, HO arising from the annulotomy site showed a distinct pseudo-pedicle pattern encompassing nerve roots and the thecal sac. In addition, development of radiculopathy symptoms and corresponding HO appear to be independent of amount of rhBMP-2. HO resulting from TLIF with rhBMP-2 in the disk space is a pain generator and a recognizable complication that can be diagnosed by assessment of symptoms and computed tomography characteristics., Competing Interests: Authors’ Disclosure Statement: The authors report no actual or potential conflict of interest in relation to this article.

Background Context: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been widely adopted as a fusion adjunct in spine surgery since its approval in 2002. A number of concerns regarding adverse effects and potentially devastating complications of rhBMP-2 use led to a Food and Drug Administration (FDA) advisory issued in 2008 cautioning its use, and a separate warning about its potential complications was published by The Spine Journal in 2011., Purpose: To compare trends of rhBMP-2 use in spine surgery after the FDA advisory in 2008 and The Spine Journal warning in 2011., Study Design: Retrospective cross-sectional study using a national database., Patient Sample: All patients from 2002 to 2013 who underwent spinal fusion surgery at an institution participating in the Nationwide Inpatient Sample (NIS)., Outcome Measures: Proportion of spinal fusion surgeries using rhBMP-2., Methods: We queried the NIS from 2002 to 2013 and used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes to identify spinal fusion procedures and those that used rhBMP-2. Procedures were subdivided into primary and revision fusions, and by region of the spine. Cervical and lumbosacral fusions were further stratified into anterior and posterior approaches. The percentage of cases using BMP was plotted across time. A linear regression was fit to the data from quarter 3 of 2008 (FDA advisory) through quarter 1 of 2011, and a separate regression was fit to the data from quarter 2 of 2011 (The Spine Journal warning) onward. The slopes of these regression lines were statistically compared to determine differences in trends. No funding was received to conduct this study, and no authors had any relevant conflicts of interest., Results: A total of 4,167,079 patients in the NIS underwent spinal fusion between 2002 and 2013. We found a greater decrease in rhBMP-2 use after The Spine Journal warning compared with the FDA advisory for all fusion procedures (p=.006), primary fusions (p=.006), and revision fusions (p=.004). Lumbosacral procedures also experienced a larger decline in rhBMP-2 use after The Spine Journal article as compared with the FDA warning (p=.0008). This pattern was observed for both anterior and posterior lumbosacral fusions (p≤.0001 for both). Anterior cervical fusion was the only procedure that demonstrated a decline in rhBMP-2 use after the FDA advisory that was statistically greater than after The Spine Journal article (p=.02)., Conclusions: Warnings sanctioned through the spine literature may have a greater influence on practice of the spine surgery community as compared with advisories issued by the FDA.Comprehensive guidelines regarding safe and effective use of rhBMP-2 must be established., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Both the map3 Cellular Allogeneic Bone Graft® and recombinant human bone morphogenetic protein 2 (rhBMP-2, Infuse®) were developed to provide an alternative to iliac crest autograft, thus eliminating the morbidity associated with its harvest. The recent literature concerning adverse events associated with the use of rhBMP-2, however, highlights the need for a safe and effective alternative. The multipotent adult progenitor cells (MAPC) found in map3 allograft may provide this alternative. The purpose of this study is to report 1-year outcomes of patients treated via anterior lumbar interbody fusion (ALIF) using either map3 Cellular Allogeneic Bone Graft or rhBMP-2 for bony fusion., Methods: This was a retrospective evaluation of 41 patients treated via ALIF with either map3 or rhBMP-2 in a polyetheretherketone cage with posterior stabilization at 1, 2, or 3 consecutive levels (L3-S1). Patients were equally divided between treatment groups. The Oswestry Disability Index (ODI) and visual analog scores (VAS) for pain were documented as part of the standard of care. An independent radiologist assessed bridging of bone, disc height, and lordosis. Primary outcome measures included radiographic analysis of fusion by plain film and CTs. Secondary clinical outcomes included visual analogue scale for neck and arm pain and low back disability index scores., Results: The overall fusion rate was 91%, with no significant difference between groups. Improvements in ODI and VAS were observed among all patients (p < 0.001), with no significant difference between groups for ODI (p = 0.966) or VAS (p = 0.251). There was no significant difference in terms of changes to disc height and lordosis between groups (p < 0.05). The rhBMP-2 group had increased post-operative complications when compared to the map3 group, but the low numbers precluded statistical analysis., Conclusion: Improvements in radiographic and clinical findings were observed in both treatment groups one-year postoperatively. Map3 allograft demonstrated equivalent fusion rates to rhBMP-2. A review of surgical supply costs at the treatment facility favored map3 allograft for the treatment of patients with DDD undergoing an ALIF in 1-3 levels compared to rhBMP-2. Further studies to evaluate long-term outcomes and post-operative complications are required.

Objective: Bone morphogenetic proteins (BMPs) have been commonly used as a graft substitute in spinal fusion. Although the U.S. Food and Drug Administration issued a warning on life-threatening complications of recombinant human BMPs (rhBMPs) in cervical spine fusion in 2008, their off-label use has been continued. This investigation aimed to review the evidence for the use of rhBMP-2 and rhBMP-7 in anterior cervical spine fusions., Methods: A comprehensive search was performed through Ovid (MEDLINE), PubMed, and Embase. The risk of bias assessment was according to the recommended criteria by the Cochrane Back and Neck group and MINORS (Methodological Index for Non-Randomized Studies). A wide array of radiographic and clinical outcomes including the adverse events were collated., Results: Eighteen articles (1 randomized and 17 nonrandomized) were eligible for inclusion. The fusion rate was higher with use of rhBMP in most studies and our meta-analysis of the pooled data from 4782 patients confirmed this finding (odds ratio, 5.45; P < 0.00001). Altogether, the rhBMP and control groups were comparable in patient-reported outcomes. However, most studies tended to show a significantly higher incidence of overall complication rate, dysphagia/dysphonia, cervical swelling, readmission, wound complications, neurologic complications, and ossification., Conclusions: Application of rhBMPs in cervical spine fusion yields a significantly higher fusion rate with similar patient-reported outcomes, yet increased risk of life-threatening complications. Thus, we do not recommend the use of rhBMP in anterior cervical fusions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Multiple case reports using recombinant human bone morphogenetic protein-2 (rhBMP-2) have reported complications. However, the local adverse effects of rhBMP-2 application are not well documented. In this report we show that, in addition to promoting lumbar spinal fusion through potent osteogenic effects, rhBMP-2 augmentation promotes local cyst-like osteolytic formations in sheep trabecular bones that have undergone anterior lumbar interbody fusion. Three months after operation, conventional computed tomography showed that the trabecular bones of the rhBMP-2 application groups could fuse, whereas no fusion was observed in the control group. Micro-computed tomography analysis revealed that the core implant area's bone volume fraction and bone mineral density increased proportionately with rhBMP-2 dose. Multiple cyst-like bone voids were observed in peri-implant areas when using rhBMP-2 applications, and these sites showed significant bone mineral density decreases in relation to the unaffected regions. Biomechanically, these areas decreased in strength by 32% in comparison with noncystic areas. Histologically, rhBMP-2-affected void sites had an increased amount of fatty marrow, thinner trabecular bones, and significantly more adiponectin- and cathepsin K-positive cells. Despite promoting successful fusion, rhBMP-2 use in clinical applications may result in local adverse structural alterations and compromised biomechanical changes to the bone., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Despite the wide use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in bone defect, its application in treating osteonecrosis of femoral head (ONFH) is yet to be elucidated. The heterotopic ossification (HO) after rhBMP-2 usage in some orthopedic surgeries has been reported previously; however, only a few studies describe this complication in the treatment of ONFH.The present study investigated whether the rhBMP-2 application would increase the risk of HO formation in selected ONFH patients with nonvascularized bone grafting surgery and enhance the surgical results of nonvascularized bone grafting as compared to patients who did not receive intraoperative rhBMP-2.A retrospective analysis was performed on 94 patients (141 hips) who, with Association Research Circulation Osseous (ARCO) stages IIb, IIc, and IIIa ONFH, underwent nonvascularized bone grafting surgery. The first 46 patients (66 hips) received intraoperative rhBMP-2. The postoperative radiographic results (X-ray and CT scan) and Harris hip score (HHS) were reviewed in each patient to record the incidence of HO formation and evaluate the clinical efficacy of rhBMP-2, respectively.HO formation frequently occurred in patients receiving intraoperative rhBMP-2 (8/66 hips) than those not receiving the protein (1/75 hips) (P = .02). HHS improved from preoperatively at the final follow-up (P < .01) in the BMP-positive group, with a survival rate of 83.3%. In the BMP-negative group, the HHS improved from preoperatively at the end of the follow-up (P < .01), and the survival rate was 72.0%.rhBMP-2 has osteoinductive property and might serve as an adjuvant therapy in the surgical treatment of ONFH. However, the incidence of HO formation might increase when used in high doses.

Introduction  Cervical spine pathologies are common in Down syndrome (DS) patients. Cervical pathologies may cause cord compression and neurologic deterioration if left untreated. Complication rates of 73-100% have been reported in DS patients after cervical spine surgery in historical studies. This study reports updated perioperative complications rates and long-term outcome in patients with DS undergoing cervical spine surgery. Methods  Retrospective review of patients with DS who have undergone cervical spine surgery from 1998 to 2011 (≥ 24 months of follow-up) was undertaken. Series of 17 adults with preoperative diagnoses that included atlantoaxial instability, stenosis, spondylosis, or cervical spondylolisthesis were evaluated. Nine patients received recombinant human bone morphogenetic protein-2 (rhBMP-2). Neurologic and ambulatory status was evaluated at regular intervals included pre- and postoperative imaging, range of motion evaluation, strength/neurologic testing, ambulation observation, and patient and caretaker pain reporting. Results  A total of 20 surgical procedures were performed in 17 patients. Average follow-up was 78.7 months (range: 25-156 months). Overall, 37 complications were observed including pneumonia, respiratory distress, reintubation, dysphagia, deep venous thrombosis, sepsis, wound infection, dehiscence, neurologic complications, loss of reduction (LOR), pseudarthrosis, and hardware failure. Postoperative pneumonia was most common (23.5%). Three patients developed pseudarthrosis (all in the rhBMP-2 group); three demonstrated LOR. Neurologic complications ( N  = 3) included spasticity, loss of ambulation, and postoperative weakness with myelomalacia. Two were transient. Respiratory complications in the rhBMP-2 group were the most common ( N  = 3). The anterior approach resulted in a higher likelihood of complications than the posterior ( p  = 0.032). Conclusions  Current techniques may improve pseudarthrosis ( p  = 0.009), LOR ( p  = 0.043), and first attempt ( p  = 0.038) and overall fusion rates ( p  = 0.018) compared with historical studies. Complications continue to challenge most patients (82.4%). A total of 16 of 17 patients (94.1%) demonstrated stabilization or improvement in neurologic status. Apparent successful outcome in the majority appears to warrant the high complication risk associated with cervical spine surgery in DS patients. The anterior approach resulted in a higher risk of complications than posterior ( p  = 0.032). We report a higher than expected incidence of pseudarthrosis in DS patients receiving rhBMP-2, putting its benefit in DS patients into question., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: It is uncertain whether the replication of systematic reviews, particularly those with the same objectives and resources, would employ similar methods and/or arrive at identical findings. We compared the results and conclusions of two concurrent systematic reviews undertaken by two independent research teams provided with the same objectives, resources, and individual participant-level data., Methods: Two centers in the USA and UK were each provided with participant-level data on 17 multi-site clinical trials of recombinant human bone morphogenetic protein-2 (rhBMP-2). The teams were blinded to each other's methods and findings until after publication. We conducted a retrospective structured comparison of the results of the two systematic reviews. The main outcome measures included (1) trial inclusion criteria; (2) statistical methods; (3) summary efficacy and risk estimates; and (4) conclusions., Results: The two research teams' meta-analyses inclusion criteria were broadly similar but differed slightly in trial inclusion and research methodology. They obtained similar results in summary estimates of most clinical outcomes and adverse events. Center A incorporated all trials into summary estimates of efficacy and harms, while Center B concentrated on analyses stratified by surgical approach. Center A found a statistically significant, but small, benefit whereas Center B reported no advantage. In the analysis of harms, neither showed an increased cancer risk at 48 months, although Center B reported a significant increase at 24 months. Conclusions reflected these differences in summary estimates of benefit balanced with small but potentially important risk of harm., Conclusions: Two independent groups given the same research objectives, data, resources, funding, and time produced broad general agreement but differed in several areas. These differences, the importance of which is debatable, indicate the value of the availability of data to allow for more than a single approach and a single interpretation of the data., Systematic Review Registration: PROSPERO CRD42012002040 and CRD42012001907 .

Ovarian cancer is characterized by being highly metastatic, a feature that represents the main cause of failure of the treatment. This study investigated the effects of γ-secretase inhibition on the TGF-β-induced epithelial-mesenchymal transition (EMT) process in ovarian cancer cell lines. SKOV3 cells incubated in the presence of TGF-β showed morphological and biochemical changes related to EMT, which were blocked by co-stimulation with TGF-β and the γ-secretase inhibitor DAPT. In SKOV3 and IGROV1 cells, the co-stimulation blocked the cadherin switch and the increase in the transcription factors Snail, Slug, Twist and Zeb1 induced by TGF-β. DAPT impaired the translocation of phospho-β-catenin to the inner cell compartment observed in TGF-β-treated cells, but was not able to block the induction at protein level induced by TGF-β. Moreover, the inhibitor blocked the increased cell migration and invasiveness ability of both cell lines induced by TGF-β. Notch target genes (Hes1 and Hey1) were induced by TGF-β, decreased by DAPT treatment and remained low in the presence of both stimuli. However, DAPT alone caused no effects on most of the parameters analyzed. These results demonstrate that the γ-secretase inhibitor used in this study exerted a blockade on TGF-β-induced EMT in ovarian cancer cells., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: For the past few years, anterior exposure for surgery of the lumbar spine has gained popularity for the treatment of disk disease or spondylosis. Cancellous bone remains the gold standard for fusion. Iliac crest bone harvesting is safe but there are donor site complications. Bone substitutes exist, like recombinant human bone morphogenic protein-2 rhBMP-2. This alternative offers a high rate of fusion but with local and general complications. The aim of our study is to show the feasibility of an endopelvic approach for iliac bone crest harvesting to avoid donor site complication., Method: Twenty anterior retroperitoneal lumbar spine approaches have been realized in the anatomy department of the University of Bordeaux. The volumes of cancellous bone have been measured and procedure complications have been reported., Results: The mean volume of cancellous bone was 5.9 cc, the maximum volume was 8.2 cc and the minimum volume was 4.5 cc. No complications have been reported during the approach or the bone harvesting., Conclusions: Anterior retroperitoneal approach for iliac bone crest harvesting is a safe way to obtain sufficient volume of cancellous bone for a single lumbar spinal fusion. This exposure avoids the risks of an iliac crest donor site complications or rhBMP-2 complications.

Background Context: Recombinant human bone morphogenetic protein-2 (rhBMP-2) remains the primary synthetic osteoinductive material used in spinal fusion surgery today. The early inflammation reaction to rhBMP-2 manifesting with radicular symptoms has been previously reported in patients undergoing transforaminal lumbar interbody fusion (TLIF). There is a disagreement with regard to the factors affecting its occurrence and whether such symptoms are dose dependent., Purpose: The purpose of this analysis was to determine the incidence of rhBMP-2-induced radiculitis and its relationship to dose., Study Design/setting: A retrospective cohort analysis was performed of the prospectively collected data., Patient Sample: All consecutive patients (n=204) who underwent one- or two-level TLIF and instrumented posterolateral fusion with an off-label rhBMP-2 use were included in this analysis., Outcome Measures: The patients who developed new radicular symptoms after initial improvement postoperatively and had sterile fluid collections indicative of inflammatory process, or in the absence of any structural abnormalities that would explain these symptoms on imaging studies, were deemed to have rhBMP-2-induced radiculitis., Methods: Magnetic resonance imaging (MRI) scans were obtained for all patients who developed postoperative radicular symptoms. Correlations between the total rhBMP-2 dose, dose per spinal level, and incidence of radiculitis were evaluated while controlling for age, sex, number of TLIF levels, and surgeon., Results: The incidence of postoperative radiculitis was 11.3% (23 out of 204). The average total rhBMP-2 dose was 4.9 mg (range=2.1-12) and the average dose per spinal level was 3.8 mg (range=1.05-12). Logistic regression analysis did not identify any significant correlations between the rhBMP-2 doses and the incidence of radiculitis (p=.6)., Conclusion: The incidence of rhBMP-2-induced radiculitis in patients undergoing TLIF is quite high, but there were no dose-related correlations found. The study, however, cannot rule out a possibility that a larger variation in bone morphogenetic protein (BMP) doses could still be a factor in the development of rhBMP-2-associated radiculitis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Study Design: Retrospective cohort study using the Washington State Comprehensive Hospital Abstract Reporting System, the Washington State Cancer Registry, and Washington State death certificates., Objective: To study the possible association between recombinant human bone morphogenetic protein (rhBMP) and cancer risk., Summary of Background Data: The use of rhBMP in spine fusion surgery remains controversial with respect to its possible role in tumorigenesis., Methods: We compared adults who underwent spine fusion for degenerative disease with and without rhBMP between 2002 and 2010. Patients were matched on the basis of age, sex, and year of treatment. We excluded patients with a diagnosis of cancer before or at the index procedure. The primary outcome was the first diagnosis of cancer as identified in the records of the cancer registry., Results: We included 16,914 patients who had spine fusion, of whom 4246 received rhBMP. During the study period, 449 patients received a diagnosis of cancer: 117 (2.76% of 4246) in the rhBMP group and 332 (2.62% of 12 668) in the no rhBMP group. The incidence rate was similar between the rhBMP and no rhBMP 9.5 and 9.0 per 1000 person years, respectively (hazard ratio, 1.06; 95% confidence interval, 0.86-1.30). There were no differences in the rate of cancer between the two groups in subgroups defined on the basis of site of fusion or surgical method., Conclusion: There was no increase in overall cancer incidence among those receiving rhBMP. An important limitation of this and other studies of rhBMP and cancer that have been conducted to date is their relatively limited duration of follow-up. The examination of cancer incidence following rhBMP administration must continue beyond just the first several years to adequately assess the potential of rhBMP to influence the occurrence of one or more types of malignancy., Level of Evidence: 3.

OBJECTIVE It has been hypothesized that the recombinant human bone morphogenetic protein-2 (rhBMP-2) amplification of the host inflammatory response interacts with nerves in the spine and contributes to the occurrence of new, postoperative complaints of radiculitis. This in vivo rat study was conducted to assess the capacity for rhBMP-2/ACS (rhBMP-2 applied to absorbable collagen sponge [ACS]) to stimulate pain-associated behaviors in the rat chronic constriction injury (CCI) model. METHODS Rats were randomly assigned to one of 14 treatment groups. Half of the animals underwent a sham procedure in which the left sciatic nerve was exposed and manipulated but no ligature was placed (Sham cohort), while the remaining animals had chromic gut sutures tied around the sciatic nerve to induce CCI (CCI cohort). The following test articles were applied to the sciatic nerve in each cohort: saline alone, saline applied to ACS, 0.1 mg/ml rhBMP-2 applied to ACS, or 1.0 mg/ml rhBMP-2 applied to ACS. The ACS was either wrapped around the sciatic nerve or implanted adjacent to the nerve. Thermal withdrawal latency was assessed on Days 7, 14, 21, and 28 postoperatively. Isolated nerves from selected rats in each group were examined and assessed for histopathological changes on Days 3, 7, 14, and 28. RESULTS CCI produced a significant pain behavioral response for all treatment groups at all time points. In the Sham cohort, 0.1 mg/ml rhBMP-2/ACS wrapped around the nerve (WRP) decreased thermal withdrawal on Day 28, and 1.0 mg/ml rhBMP-2/ACS placed adjacent to the nerve (ADJ) decreased thermal withdrawal on Days 21 and 28. Conversely, in the CCI cohort, 0.1 mg/ml rhBMP-2/ACS ADJ increased thermal withdrawal latencies on Day 7; 1.0 mg/ml rhBMP-2/ACS ADJ increased thermal withdrawal latencies on Day 7; and 1.0 mg/ml rhBMP-2/ACS WRP increased thermal withdrawal on Days 7 and 14. Histologically, the effect of rhBMP-2 on nerve inflammation was unclear, as inflammatory cell infiltration was similar in the rhBMP-2/ACS and saline/ACS groups. rhBMP-2 was variably associated with bone formation within the epineurium at 14 days, and more prevalently at 28 days, with no clear relationship between dose or ACS positioning. CONCLUSIONS In this study, rhBMP-2/ACS did not appear to induce pain independent of grossly visible ectopic bone formation. At the earliest time points, rhBMP-2 appeared to have a neuroprotective effect as evidenced by decreased pain exhibited by the rhBMP-2-treated animals in the CCI cohort, but this effect diminished over time, and by Day 28, the pain behavioral responses in the rhBMP-2-treated group were comparable to those in the group in which saline was applied to the nerve. In the Sham cohort, there was a dose-independent induction of pain at later time points, presumably due to new bone formation mechanically irritating the nerve. Histological examination revealed nerve lesions that appeared to be caused by mechanical trauma associated with surgical manipulation of the nerve during placement of the ACS and/or CCI sutures.

Purpose: Because of significant complications related to the use of autologous bone grafts in spinal fusion surgery, bone substitutes and growth factors such as bone morphogenetic protein (BMP) have been developed. One of them, recombinant human (rh) BMP-2, has been approved by the Food and Drug Administration (FDA) for use under precise conditions. However, rhBMP-2-related side effects have been reported, used in FDA-approved procedures, but also in off-label use.A systematic review of clinical data was conducted to analyse the rhBMP-2-related adverse events (AEs), in order to assess their prevalence and the associated surgery practices., Methods: Medline search with keywords "bone morphogenetic protein 2", "lumbar spine", "anterolateral interbody fusion" (ALIF) and the filter "clinical trial". FDA published reports were also included. Study assessment was made by authors (experienced spine surgeons), based on quality of study designs and level of evidence., Results: Extensive review of randomised controlled trials (RCTs) and controlled series published up to the present point, reveal no evidence of a significant increase of AEs related to rhBMP-2 use during ALIF surgeries, provided that it is used following FDA guidelines. Two additional RCTs performed with rhBMP-2 in combination with allogenic bone dowels reported increased bone remodelling in BMP-treated patients. This AE was transient and had no consequence on the clinical outcome of the patients. No other BMP-related AEs were reported in these studies., Conclusions: This literature review confirms that the use of rhBMP-2 following FDA-approved recommendations (i.e. one-level ALIF surgery with an LT-cage) is safe. The rate of complications is low and the AEs had been identified by the FDA during the pre-marketing clinical trials. The clinical efficiency of rhBMP-2 is equal or superior to that of allogenic or autologous bone graft in respect to fusion rate, low back pain disability, patient satisfaction and rate of re-operations. For all other off-label use, the safety and effectiveness of rhBMP-2 have not been established, and further RCTs with high level of evidence are required.

Purpose: In an effort to improve fracture healing and decrease the need for autologous bone graft, products such as recombinant human bone morphogenetic protein (rhBMP-2) have been developed and used in both spine and nonspine surgery. There is a paucity of literature regarding the use of rhBMP-2 in scaphoid nonunion surgery with very little reporting on the complications associated with its use. The objective of this study was to retrospectively review the complications documented for a case series of patients treated with revision fixation, bone graft, and rhBMP-2 in revision scaphoid nonunion surgery., Methods: We retrospectively reviewed 6 cases of scaphoid nonunion revision surgery comprising open reduction and internal fixation (ORIF). All cases were performed for persistent nonunion after a previous scaphoid ORIF. All patients were treated with revision screw fixation, bone graft, and rhBMP-2. Union was determined by computed tomography in all cases. Complications of nonunion, heterotopic bone formation, delayed wound healing, functional loss of motion, and need for revision surgery are reported., Results: Between 2011 and 2014, 6 cases in which rhBMP-2 was used in revision scaphoid nonunion surgery were identified. All patients had failed an initial attempt at ORIF after delayed union or nonunion. The time from injury to index ORIF ranged from 3 months to 4 years (mean, 24 months). Revision surgery with rhBMP-2 was performed at an average of 6 months from the index ORIF. Of the 6 cases, 2 had resultant persistent nonunion. Both underwent scaphoid excision and midcarpal arthrodesis. Four cases developed notable heterotopic ossification (one of which required revision surgery). One patient had a loss of functional motion after the revision surgery. There were no cases of delayed wound healing. Only one of the 6 patients healed without complications., Conclusions: In this case series, the use of rhBMP-2 in scaphoid nonunions was associated with a higher complication rate than reported in previous studies. Surgeons performing off-label use of rhBMP-2 should be aware of the potential for complications including heterotopic ossification., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Recombinant human bone morphogenetic protein-2 (rhBMP-2) was recently licensed for local administration during posterior lumbar fusion. In this indication, considerable uncertainty remains about the nature and mechanisms of the many adverse effects of rhBMP-2, such as ectopic bone formation. We report a case of ectopic bone formation with impingement on a facet joint and incapacitating low back pain after minimally invasive transforaminal L5-S1 interbody fusion with local application of rhBMP-2 (InductOs(®)). Revision surgery was eventually performed to alleviate the symptoms by removing the ectopic bone. Caution is in order regarding the use of rhBMP-2 during posterior lumbar fusion. Every effort should be made to minimise the risk of complications., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Study Design: Literature review., Objective: To evaluate the association between recombinant human bone morphogenetic protein-2 (rhBMP-2) and malignancy., Summary of Background Data: The use of rhBMP-2 in spine surgery has been the topic of much debate as studies assessing the association between rhBMP-2 and malignancy have come to conflicting conclusions., Methods: A systematic review of the literature was performed using the PubMed-National Library of Medicine/National Institute of Health databases. Only non-clinical studies directly addressing BMP-2 and cancer were included. Articles were categorized by study type (animal, in vitro cell line/human/animal), primary malignancy, cancer attributes, and whether BMP-2 was pro-malignancy or not., Results: A total of 4,131 articles were reviewed. Of those, 515 articles made reference to both BMP-2 and cancer, 99 of which were found to directly examine the role of BMP-2 in cancer. Seventy-five studies were in vitro and 24 were animal studies. Forty-three studies concluded that BMP-2 enhanced cancer function, whereas 18 studies found that BMP-2 suppressed malignancy. Thirty-six studies did not examine whether BMP-2 enhanced or suppressed cancer function. Fifteen studies demonstrated BMP-2 dose dependence (9 enhancement, 6 suppression) and one study demonstrated no dose dependence. Nine studies demonstrated BMP-2 time dependence (6 enhancement, 3 suppression). However, no study demonstrated that BMP-2 caused cancer de novo., Conclusion: Currently, conflicting data exist with regard to the effect of exogenous BMP-2 on cancer. The majority of studies addressed the role of BMP-2 in prostate (17%), breast (17%), and lung (15%) cancers. Most were in vitro studies (75%) and examined cancer invasiveness and metastatic potential (37%). Of 99 studies, there was no demonstration of BMP-2 causing cancer de novo. However, 43% of studies suggested that BMP-2 enhances tumor function, motivating more definitive research on the topic that also includes clinically meaningful dose- and time-dependence., Level of Evidence: 2.

Study Design: A retrospective cohort study., Objective: The aim of this study was to determine the fusion rate using recombinant human bone morphogenetic protein (rhBMP) in spinal surgery and to estimate the risk of cancer subsequent to their use., Summary of Background Data: rhBMP may obviate the need for iliac crest bone graft harvest and provides similar or higher fusion rates than autologous bone graft. Recently, there are concerns that rhBMPs may either cause cancer or accelerate progression., Methods: Patients were treated by 2 spine surgeons between 2002 and 2012. Inclusion criteria were patients who resided in the state of Victoria, Australia, undergoing lumbar fusion (anterior, lateral, posterior, and posterolateral) with rhBMP [either rhBMP-2 (Infuse) or rhBMP-7 (OP-1)]. Exclusion criteria were patients who reported having an invasive cancer diagnosis before the spinal fusion procedure. The occurrence of incident cancers was obtained from record linkage to the Victorian Cancer Registry., Results: A total of 527 patients were included in the cohort, with a mean follow-up of 4.4 years (1.8-11.5). Patients received Infuse in 77% of cases and OP-1 in 23%. The mean Infuse does was 10.2  mg (2.5-48.0) and 3.3  mg (1.7-6.6) for OP-1. There was no significant difference in fusion rates between Infuse (90.1%) and OP-1 (91.9%) (P = 0.42). The overall success of interbody fusion with rhBMP was 93.5% at 12 months. Twenty-seven patients were diagnosed with an invasive cancer since treatment (20 Infuse and 7 OP-1 patients). Comparing the observed numbers in our study cohort with those expected on the basis of the Victorian population's age and sex-specific rates, we observed that the study cohort was not at a significantly increased risk of cancer. The standardized incidence ratio for cancer overall (of any type) was 0.84 [95% confidence interval (95% CI) 0.56-1.21]., Conclusion: Off-label use of rhBMP provided high fusion rates with no evidence of a significantly increased risk of cancer., Level of Evidence: 4.

Study Design: Prospective in vivo rodent model of bone morphogenetic protein (BMP)-induced inflammation., Objective: To evaluate the effects of the coadministration of the nonsteroidal anti-inflammatory drug, diclofenac, on BMP-induced inflammation using our rodent model., Summary of Background Data: The use of BMP-2 is associated with inflammation in the neck and back. We have previously reported on a rodent model of BMP-2-induced inflammation., Methods: Seven treatment groups were: Surgery alone; absorbable collagen sponges (ACS) alone; 20 μg rhBMP-2 on ACS with no diclofenac; 20 μg rhBMP-2 on ACS+50 mg diclofenac injections; 20 μg rhBMP-2 on ACS+75 mg diclofenac; 20 μg rhBMP-2 on ACS+100 mg diclofenac; and 20 μg rhBMP-2 on ACS+125 mg diclofenac. Using magnetic resonance imaging, inflammation (soft tissue edema volume) was assessed at 3 hours and at 2, 7, and 14 days after implantation. Western blot analysis, histology, and immunohistochemical staining were performed to compare the inflammatory response between groups. The mass size and tissue density of bone formation were compared between groups using plain radiography., Results: Soft-tissue edema volumes in all diclofenac-treated groups were significantly lower than those observed in the rhBMP-2 alone. There was no significant difference in soft tissue edema volumes between 4 diclofenac-treated groups. The expression of NF-κB signaling pathway related proteins (p65 and p-p65) were increased in the rhBMP-2+ACS group and decreased in diclofenac treatment groups. Histological findings and immunohistochemical staining were consistent with the Western blot results. There was no significant difference between the rhBMP-2+ACS group and diclofenac treatment groups in terms of the mass size and tissue density of bone formation., Conclusion: Coadministration of diclofenac sodium can reduce the inflammatory response to BMP-2 without impairing heterotopic bone formation in our rodent model of BMP-2-induced inflammation., Level of Evidence: N/A.

OBJECT The aim of this study was to determine the safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) use in posterior instrumented fusions in the pediatric population, focusing on cancer risk. In a previous study, the authors reported the short-term (mean follow-up of 11 months) safety and efficacy of rhBMP-2 in the pediatric age group. The present study reports their results with a minimum of 24 months' follow-up. METHODS The authors retrospectively reviewed 57 consecutive cases involving pediatric patients who underwent posterior occiptocervical, cervical, thoracic, lumbar, or lumbosacral spine fusion from October 1, 2007, to June 30, 2011, at Texas Children's Hospital. Seven cases were excluded from further analysis because of loss to follow-up. Three patients died during the follow-up period and were placed in a separate cohort. RESULTS The patients' average age at the time of surgery was 11 years, 4 months (range 9 months to 20 years). The mean duration of follow-up was 48.4 months (range 24-70 months). Cancer status was determined at the most recent encounter with the patient and/or caretaker(s) in person, or in telephone follow-up. Twenty-four or more months after administration of rhBMP-2, there were no cases of new malignancy, degeneration, or metastasis of existing tumors. The cause of death of the patients who died during the study period was not related to BMP or to the development, degeneration, or metastasis of cancer. CONCLUSIONS Despite the large number of adult studies reporting increased cancer risk associated with BMP use, the authors' outcomes with rhBMP-2 in the pediatric population suggest that it is a safe adjunct to posterior spine fusions of the occipitocervical, cervical, thoracic, lumbar, and lumbosacral spine. There were no new cases of cancer, or degeneration or metastasis of existing malignancies in this series.

This study evaluated the safety of 3-level anterior cervical diskectomy and fusion (ACDF) with ultra-low-dose recombinant bone morphogenetic protein-2 (rhBMP-2). Thirty-seven consecutive patients with cervical spondylotic myelopathy who were treated with 3-level ACDF and rhBMP-2 were evaluated. Complications such as airway or cervical swelling or hematoma were not observed. The rate of dysphagia was no different at 1, 2, and 6 months postoperatively compared with reports in the literature without rhBMP-2. There were significant improvements in VAS neck/arm pain, Oswestry Neck Disability Index, and cervical lordosis. The use of ultra-low-dose rhBMP-2 for 3-level ACDF may be efficacious for surgically addressing 3-level spondylotic myelopathy., (Copyright 2015, SLACK Incorporated.)

Background: Research has indicated that adverse effects terms are increasingly prevalent in the title, abstract or indexing terms of articles that contain adverse drug effects data in MEDLINE and Embase. However, it is unknown whether adverse effects terms are present in the database records of articles that contain adverse effects data of medical devices, and thus, to what extent the development of an adverse effects search filter for medical devices may be feasible., Methods: A case study systematic review of a medical device was selected. The included studies from a systematic review of the safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion were used in the analysis. For each included study, the corresponding database record on MEDLINE and Embase was assessed to measure the presence or absence of adverse effects terms in the title, abstract or indexing. The performance of each potential adverse effects search term was also measured and compared., Results: There were 82 publications (49 studies) included in the systematic review with 51 of these indexed on MEDLINE and 55 on Embase. Ninety-four percent (48/51) of the records on MEDLINE and 95% (52/55) of the records on Embase contained at least one adverse effects related search term. The wide variety of adverse effects terms included in the title, abstract or indexing of bibliographic records, and the lack of any individual high-performing search terms suggests that a combination of terms in different fields is required to identify adverse effects of medical devices. In addition, the most successful search terms differed from the most successful terms for identifying adverse drug effects., Conclusions: The search filters currently available for adverse drug effects are not necessarily useful for searching adverse effects data of medical devices. The presence of adverse effects terms in the bibliographic records of articles on medical devices, however, indicates that combinations of adverse effects search terms may be useful in search strategies in MEDLINE and Embase. The results, therefore, suggest that not only a search filter for the adverse effects of medical devices is feasible, but also that it should be a research priority.

Background: The U.S. Food and Drug Administration reported a higher incidence of cancer in patients who had spinal arthrodesis and were exposed to a high dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) compared with the control group in a randomized controlled trial. The purpose of this study was to determine the risk of cancer after spinal arthrodesis with BMP., Methods: We retrospectively analyzed the incidence of cancer in 467,916 Medicare patients undergoing spinal arthrodesis from 2005 to 2010. Patients with a preexisting diagnosis of cancer were excluded. The average follow-up duration was 2.85 years for the BMP group and 2.94 years for the control group. The main outcome measure was the relative risk of developing new malignant lesions after spinal arthrodesis with or without exposure to BMP., Results: The relative risk of developing cancer after BMP exposure was 0.938 (95% confidence interval [95% CI]: 0.913 to 0.964), which was significant. In the BMP group, 5.9% of the patients developed an invasive cancer compared with 6.5% of the patients in the control group. The relative risk of developing cancer after BMP exposure was 0.98 in males (95% CI: 0.94 to 1.02) and 0.93 (95% CI: 0.90 to 0.97) in females. The control group showed a higher incidence of each type of cancer except pancreatic cancer., Conclusions: Recent clinical use of BMP was not associated with a detectable increase in the risk of cancer within a mean 2.9-year time window., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., (Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.)

Background Context: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is commonly used to augment posterior and interbody spinal fusion techniques and has many reported side effects. Neuroforaminal heterotopic ossification (HO) is a known cause of postoperative leg pain, but the pathohistologic composition of this material is not well understood., Purpose: The purpose of this article was to report the histologic composition of a case of HO and lumbar radiculopathy after transforaminal lumbar interbody fusion with rhBMP-2., Study Design/setting: This is a case report., Patient Sample: This is a single patient case report., Outcome Measures: The outcomes considered were physician-recorded clinical, physiological, and functional measures., Methods: A retrospective review of a single patient was performed. Clinical, radiographic, and pathologic specimens were reviewed and are reported., Results: A 69-year-old woman presented with low back pain and right leg radicular pain associated with L4-L5 stenosis and a recurrent facet cyst. After attempted nonsurgical care, she underwent an L4-L5 revision decompression with interbody and posterolateral fusions including off-label rhBMP-2. Postoperatively, her symptoms resolved for approximately 7 months but then returned in association with right L4-L5 foraminal HO. The ectopic tissue was notably larger than suggested by preoperative computed tomographic scan. It was decompressed, which then improved her symptoms. Histologic examination of the specimen revealed three discrete tissue types: a nonspecific fibrovascular stroma; immature osteoid and woven bone; and chondrocyte metaplasia with chondrocyte clustering., Conclusions: Neuroforaminal HO formation is a reported side effect associated with the off-label use of rhBMP-2 for posterior lumbar interbody fusion. The mechanism of formation and the composition of this material are not well understood but may involve a chondrocyte differentiation pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background Context: Recombinant human bone morphogenetic protein 2 (rhBMP-2) is a very potent osteogenic growth factor that has been used successfully in various spine fusions, obviating the need for autologous iliac crest bone graft harvest and therefore avoiding the associated morbidities., Purpose: In the past few years, a tremendous increase in rhBMP-2 usage was noted, and concerns regarding costs, benefits, and safety issues were raised by many. The goal of this work was to provide a comprehensive review of the adverse events and complications associated with use of rhBMP-2., Study Design: Literature review., Methods: This is a review of the current literature on the reported adverse events, complications, and concerns associated with rhBMP-2 use., Results: This article discusses the wide spectrum of adverse outcomes related to rhBMP-2 use in the lumbar and the cervical spine; retrograde ejaculation, antibodies formation, postoperative radiculitis, postoperative nerve root injury, ectopic bone formation, vertebral osteolysis/edema, dysphagia and neck swelling, hematoma formation, interbody graft lucency, and wound healing complications are reviewed. Cost-related concerns, dosage considerations, carrier types, and theoretical carcinogenesis concerns were also presented., Conclusions: Despite the excellent spinal fusion rates promoted by this powerful molecule, the increasingly reported adverse outcomes associated with bone morphogenetic protein usage have created real concerns. This article will provide the reader with a good understanding of the reported complications associated with rhBMP-2 use and ultimately help recognize its safety spectrum and limits for better clinical application., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background Context: Despite common use of intraoperative electrophysiologic neuromonitoring, injuries to the lumbar plexus during lateral lumbar interbody fusion (LLIF) have been reported. Emerging data suggest that recombinant human bone morphogenetic protein-2 (rhBMP-2) use during an anterior or transforaminal lumbar interbody fusion may be associated with an increased risk of neurological deficit. Clinical data on the sequelae of rhBMP-2 implantation in close proximity to the lumbosacral plexus during LLIF remains to be understood., Purpose: The purpose of this study was to compare the incidence of neurologic deficits and pain in patients undergoing LLIF with and without rhBMP-2., Study Design/setting: Retrospective outcome analysis in controlled cohorts undergoing the lateral exposure technique for LLIF with and without rhBMP-2., Methods: The electronic medical records of patients undergoing LLIF with and without supplemental posterior fusion for degenerative spinal conditions were retrospectively reviewed over a 6-year period. Patients with previous lumbar spine surgery or follow-up of less than 6 months were excluded. Patients were divided into 2 groups, Group 1 (rhBMP-2 use; n=72) and Group 2 (autograft/allograft use; n=72), and were matched according to the age at the time of surgery, gender, weight, body mass index, side of approach, total number of treated spinal segments, use of supplemental posterior fusion, and length of follow-up., Results: Immediately after surgery, a sensory deficit was recorded in 33 patients in Group 1 and 35 patients in Group 2 (odds ratio [OR] 0.895; 90% confidence interval [CI] 0.516-1.550; p=.739). At last follow-up, a persistent sensory deficit was identified in 29 patients whose LLIF procedure was supplemented by rhBMP-2 and 20 patients in whom autograft/allograft was used (OR 1.754; 90% CI 0.976-3.151; p=.115). A motor deficit was recorded in 37 patients immediately after the rhBMP-2 procedure and 28 patients treated with autograft/allograft (OR 1.661; 90% CI 0.953-2.895; p=.133). A persistent motor deficit was recorded in 35 and 17 patients in Groups 1 and 2, respectively, at last follow-up (OR 3.060; 90% CI 1.681-5.571; p=.002). During the first postoperative examination, 37 patients in Group 1 and 25 patients in Group 2 complained of anterior thigh or groin pain (OR 1.987; 90% CI 1.133-3.488; p=.045). At last follow-up, there was a significantly higher number of patients in Group 1 who complained of persistent anterior thigh or groin pain than Group 2 (8 vs. 0 patients) (OR 16.470; 90% CI 1.477-183.700; p=.006)., Conclusions: Our results provide evidence of an increased rate of postoperative neurologic deficit and anterior thigh/groin pain after LLIF using rhBMP-2, when compared with matched controls without rhBMP-2 exposure. This study suggests a potential direct deleterious effect of rhBMP-2 on the lumbosacral plexus., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Study Design: Multicenter, prospective analysis of consecutive patients with adult spinal deformity (ASD)., Objective: Evaluate complications associated with recombinant human bone morphogenetic protein-2 (rhBMP-2) use in ASD., Summary of Background Data: Off-label rhBMP-2 use is common; however, underreporting of rhBMP-2 associated complications has been recently scrutinized., Methods: Patients with ASD consecutively enrolled into a prospective, multicenter database were evaluated for type and timing of acute perioperative complications., Inclusion Criteria: age 18 years and older, ASD, spinal arthrodesis of more than 4 levels, and 3 or more months of follow-up. Patients were divided into those receiving rhBMP-2 (BMP) or no rhBMP-2 (NOBMP). BMP divided into location of use: posterior (PBMP), interbody (IBMP), and interbody + posterior spine (I + PBMP). Correlations between acute perioperative complications and rhBMP-2 use including total dose, dose/level, and location of use were evaluated., Results: A total of 279 patients (mean age: 57 yr; mean spinal levels fused: 12.0; and mean follow-up: 28.8 mo) met inclusion criteria. BMP (n = 172; average posterior dose = 2.5 mg/level, average interbody dose = 5 mg/level) had similar age, smoking history, previous spine surgery, total spinal levels fused, estimated blood loss, and duration of hospital stay as NOBMP (n = 107; P > 0.05). BMP had greater Charlson Comorbidity Index (1.9 vs. 1.2), greater scoliosis (43° vs. 38°), longer operative time (488.2 vs. 414.6 min), more osteotomies per patient (4.0 vs. 1.6), and greater percentage of anteroposterior fusion (APSF; 20.9% vs. 8.4%) than NOBMP, respectively (P < 0.05). BMP had more total complications per patient (1.4 vs. 0.6) and more minor complications per patient (0.9 vs. 0.2) than NOBMP, respectively (P < 0.05). NOBMP had more complications requiring surgery per patient than BMP (0.3 vs. 0.2; P < 0.05). Major, neurological, wound, and infectious complications were similar for NOBMP, BMP, PBMP, IBMP, and I + PBMP (P > 0.05). Multivariate analysis demonstrated small to nonexistent correlations between rhBMP-2 use and complications., Conclusion: RhBMP-2 use and location of rhBMP-2 use in ASD surgery, at reported doses, do not increase acute major, neurological, or wound complications. Research is needed for higher rhBMP-2 dosing and long-term follow-up., Level of Evidence: 2.