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Modulating the inflammatory microenvironment to reconstruct the fibrocartilaginous layer while promoting tendon repair is crucial for enhancing tendon-to-bone healing in rotator cuff repair (RCR), a persistent challenge in orthopedics. Small extracellular vesicles (sEVs) hold significant potential to modulate inflammation, yet the efficient production of highly bioactive sEVs remains a substantial barrier to their clinical application. Moreover, achieving minimally invasive local delivery of sEVs to the tendon-to-bone interface presents significant technical difficulties. Herein, the circadian rhythm of adipose-derived stem cells is modulated to increase the yield and enhance the inflammatory regulatory capacity of sEVs. Circadian rhythm-regulated sEVs (CR-sEVs) enhance the cyclic adenosine monophosphate signaling pathway in macrophage (Mφ) via platelet factor 4 delivery, thereby inhibiting Mφ M1 polarization. Subsequently, a triphasic microneedle (MN) scaffold with a tip, stem, and base is designed for the local delivery of CR-sEVs (CR-sEVs/MN) at the tendon-to-bone junction, incorporating tendon-derived decellularized extracellular matrix in the base to facilitate tendon repair. CR-sEVs/MN mitigates inflammation, promotes fibrocartilage regeneration, and enhances tendon healing, thereby improving biomechanical strength and shoulder joint function in a rat RCR model. Combining CR-sEVs with this triphasic microneedle delivery system presents a promising strategy for enhancing tendon-to-bone healing in clinical settings.
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BACKGROUND: The purpose of the present study was to retrospectively compare the clinical and radiological outcomes of arthroscopic suture anchor fixation and open screw fixation for acute large anterior glenoid rim fractures. METHODS: This study enrolled patients with acute large anterior glenoid rim fractures treated with arthroscopic suture anchor fixation (group A) or open screw fixation (group O) from January 2013 to June 2020 with a minimum follow-up ofï¼2 years. The Subjective Shoulder Value (SSV), American Shoulder and Elbow Surgeons (ASES) score, Rowe score, Constant score, range of motion (ROM), recurrent instability rate, and complications were recorded as clinical results. The quality of the postoperative reduction, reconstructed glenoid sizes, rate of fracture healing, and progression of osteoarthritis (OA) were evaluated as radiological outcomes. RESULTS: This retrospective study included 66 patients, including 37 in Group A and 29 in Group O with a mean follow-up of 46.9 (range, 24.3-94.2) months and a mean patient age of 46.8 (range, 21-69) years. No significant differences were found in the clinical outcomes between the two groups. A significant ROM limitation in all planes was found in both groups and group O showed more limitations in external rotation at the side (ERs) (18° vs. 10°, P = 0.002). The reduction quality was better in group O (P < 0.001). However, there was no significant difference between the two groups in terms of reconstructed glenoid size (101.6% ± 4.6% vs. 100.6% ± 7.1%, P = 0.460) and the rate of OA progression (26.9% vs. 20%, P = 0.525). CONCLUSION: Arthroscopic suture anchor fixation and open screw fixation achieved similar clinical outcomes, reconstructed glenoid sizes, and OA progression in patients with acute large anterior glenoid rim fractures. Arthroscopic suture fixation showed a poorer quality of reduction but less ERs limitations.
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PURPOSE: This study aims to evaluate the clinical and radiological outcomes of the arthroscopic autologous iliac crest grafting (AICG) procedure with an adjustable-loop suspensory fixation device in the treatment of anterior shoulder instability (ASI) with glenoid bone defects. METHODS: A retrospective review was conducted on the patients who underwent arthroscopic AICG with an adjustable-loop suspensory fixation device from January 2017 to December 2020. Patients with traumatic ASI, significant glenoid bone defects, and a minimum follow-up of 24 months were included. Patient-reported outcomes (PROs), including the Oxford Shoulder Instability Score (OSIS), the Rowe score, the Walch-Duplay score, the Constant score, and the Visual Analogue Score (VAS), were compared preoperatively and postoperatively. Radiological assessments using computed tomography (CT) were performed before and after the procedure. Additional data on active range of motion, recurrence events, and complications were recorded. RESULTS: A total of 42 patients were included in the study, with a mean follow-up time of 35.2 months ranging from 25.1 to 55.9 months. Mean preoperative OSIS, Rowe score, Walch-Duplay score, and Constant score significantly improved from 24.4±7.2, 25.0±9.0, 25.2±9.8, 87.5±7.1 to 42.4±4.9, 92.4±8.1, 87.9±8.3, 93.6±4.5 at the last follow-up, respectively. All patients exceeded the minimal clinically important difference (MCID) for OSIS, Rowe, and Walch-Duplay scores. The graft union rate was 100%, and the glenoid area increased significantly from 82.5% preoperatively to 100.1% at the final follow-up. No patient experienced a recurrence of instability. Two recorded complications included one case of dysesthesia around the donor site and one case of postoperative shoulder stiffness. CONCLUSIONS: The outcomes of the arthroscopic AICG procedure, which utilizes an adjustable-loop suspensory fixation device, demonstrated stable bone graft fixation, high rates of graft integration, favorable clinical results, and a low incidence of complications. Moreover, the remodeling of the graft during the follow-up period significantly restored the width and concavity of the inferior glenoid, contributing to the overall recovery. LEVEL OF EVIDENCE: Level IV, retrospective case series.
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BACKGROUND: Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study. METHODS: Herein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats. RESULTS: We discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence. CONCLUSION: In conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.
Subject(s)
AMP-Activated Protein Kinases , Cellular Senescence , Exosomes , Ferroptosis , NF-E2-Related Factor 2 , Phospholipid Hydroperoxide Glutathione Peroxidase , Regeneration , Signal Transduction , Stem Cells , Tendons , Animals , Ferroptosis/physiology , Exosomes/metabolism , Exosomes/physiology , NF-E2-Related Factor 2/metabolism , Cellular Senescence/physiology , Rats , Signal Transduction/physiology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Regeneration/physiology , AMP-Activated Protein Kinases/metabolism , Stem Cells/metabolism , Stem Cells/physiology , Tendons/metabolism , Tendons/physiology , Male , Blood Platelets/metabolism , Rats, Sprague-Dawley , Rotator Cuff Injuries/metabolism , Rotator Cuff Injuries/therapy , Rotator Cuff Injuries/pathology , Disease Models, AnimalABSTRACT
WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).
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Background: Knee osteoarthritis (KOA) is a common musculoskeletal condition that affects dynamic balance control and increases the risk of falling during walking. However, the mechanisms underlying this are still unclear. Diminished ankle proprioception during walking has been found to be related to fear of falling in older adults, with a gender difference in incidence of falling. This study aimed to determine 1) whether ankle inversion proprioceptive acuity during walking is impaired in patients with KOA; and 2) whether there is any difference between genders. Methods: Thirty-two patients with KOA (F:M = 17:15, Median age = 52.5, BMI = 22.3 ± 3.0) and 34 healthy controls without KOA (HC) (F:M = 17:17; median age = 49.0, BMI = 22.5 ± 2.7) were recruited. In patients with KOA, ankle inversion proprioceptive acuity was measured on the affected side using the ankle inversion discrimination apparatus for walking (AIDAW), whilst HC were assessed on a randomly selected side. Two-way (2*2) analysis of variance (ANOVA) was performed to determine the main effects and interaction between gender and KOA condition. Results: Two-way ANOVA showed a significant KOA main effect (F = 26.6, p < 0.001, Æp 2 = 0.3) whereby AIDAW scores during walking for individuals with KOA were significantly lower than those without KOA (KOA vs. HC: 0.746 ± 0.057 vs. 0.807 ± 0.035). There was neither a gender main effect nor interaction (both p > 0.05). Conclusion: Individuals with KOA demonstrated lower ankle proprioception scores during walking compared to their healthy counterparts, with a similar level of impairment in ankle proprioceptive acuity between male and female patients. A low score may contribute to an increased risk of falling in the KOA population. The current findings suggest the need for global concern about lower limb proprioception in the clinical management of KOA.
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Background: The stability ratio (SR) is used to assess the stability of the glenoid in anterior shoulder instability (ASI). However, the association between the SR and postoperative clinical function and instability recurrence after arthroscopic Bankart repair is unknown. Hypothesis: Patients with a higher SR would have better postoperative clinical scores and a lower incidence of recurrent instability than patients with a lower SR after arthroscopic Bankart repair. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 62 patients who underwent arthroscopic Bankart repair for ASI between 2013 and 2019 were enrolled. All patients had at least 2 years of follow-up data. The preoperative SR was calculated via biomechanical testing based on patient-specific 3-dimensional glenoid models, and patients were evenly divided into 2 groups: high SR (≥16.13%) and low SR (<16.13%). Baseline information (patient characteristics, clinical history, bone defect area [BDA], and SR), clinical scores at the final follow-up (Single Assessment Numerical Evaluation, Western Ontario Shoulder Index, and American Shoulder and Elbow Surgeons), and instability recurrence were compared between the 2 groups. Results: No significant differences were found in the baseline information between the high- and low-SR groups, except for the BDA (8.5% [high-SR group] vs 11.9% [low-SR group]; P = .01). No patients in the high-SR group had recurrent instability, while 6 patients (19.4%) had recurrent instability in the low-SR group (P = .02). Patients in the high-SR group had superior clinical outcomes compared with those in the low-SR group in terms of postoperative Western Ontario Shoulder Index scores (median, 205 vs 410, respectively; P = .006) and American Shoulder and Elbow Surgeons scores (median, 98.3 vs 95, respectively; P = .02). Conclusion: In the present study, the SR was significantly associated with postoperative clinical function and recurrence of instability after arthroscopic Bankart repair in patients with ASI.
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PURPOSE: Reverse shoulder arthroplasty has demonstrated excellent clinical efficacy for patients with shoulder joint diseases and is increasingly in demand. Traditional surgery faces challenges such as limited exposed surfaces and a narrow field of vision, leading to a shorter prosthesis lifespan and a higher risk of complications. In this study, an optical navigation system was proposed to assist surgeons in real-time tracking of the surgical scene. METHODS: Our optical navigation system was developed using the NDI Polaris Spectra device and several open-source platforms. The first step involved using the preoperative medical image to plan screw implantation paths. Real-time tracking of the patient phantom or cadaver and the surgical instrument was achieved through registration and calibration algorithms. Surgeons were guided on drilling through visualization methods. Postoperative results were compared with the planned implantation paths, and an algorithm was introduced to correct errors caused by the incorrect beginning points. RESULTS: Experiments involved three scapula cadavers and their corresponding phantoms with identical anatomy. For each experiment, three holes were completed with drills with diameters of 3.2 mm and 8.0 mm, respectively. Comparisons between the postoperative actual screw implantation paths and the preoperative planned implantation paths revealed an entry error of 1.05 ± 0.15 mm and an angle error of 2.47 ± 0.55° for phantom experiments. For cadaver experiments, the entry error was 1.53 ± 0.22 mm, and the angle error was 4.91 ± 0.78°. CONCLUSION: Our proposed optical navigation system successfully achieved real-time tracking of the surgical site, encompassing the patient phantom or cadaver and surgical instrument, thereby aiding surgeons in achieving precise surgical outcomes. Future study will explore the integration of robots to further enhance surgical efficiency and effectiveness.
Subject(s)
Arthroplasty, Replacement, Shoulder , Cadaver , Phantoms, Imaging , Humans , Arthroplasty, Replacement, Shoulder/methods , Arthroplasty, Replacement, Shoulder/instrumentation , Surgical Navigation Systems , Algorithms , Surgery, Computer-Assisted/methods , Surgery, Computer-Assisted/instrumentation , Bone ScrewsABSTRACT
Musculoskeletal disorders are the leading causes of physical disabilities worldwide. The poor self-repair capacity of musculoskeletal tissues and the absence of effective therapies have driven the development of novel bioengineering-based therapeutic approaches. Adipose-derived stem cell (ADSC)-based therapies are being explored as new regenerative strategies for the repair and regeneration of bone, cartilage, and tendon owing to the accessibility, multipotency, and active paracrine activity of ADSCs. In this review, recent advances in ADSCs and their optimization strategies, including ADSC-derived exosomes (ADSC-Exos), biomaterials, and genetic modifications, are summarized. Furthermore, the preclinical and clinical applications of ADSCs and ADSC-Exos, either alone or in combination with growth factors or biomaterials or in genetically modified forms, for bone, cartilage, and tendon regeneration are reviewed. ADSC-based optimization strategies hold promise for the management of multiple types of musculoskeletal injuries. The timely summary and highlights provided here could offer guidance for further investigations to accelerate the development and clinical application of ADSC-based therapies in musculoskeletal regeneration.
Subject(s)
Adipose Tissue , Exosomes , Adipose Tissue/metabolism , Adipocytes , Regeneration , Biocompatible Materials , Exosomes/metabolism , Stem Cells/metabolismABSTRACT
Rotator cuff tears are a prevalent musculoskeletal problem that affect many individuals and may result in substantial social and health-related expenses. Moreover, the muscular fat infiltration and dystrophy associated with rotator cuff tears have been persistent challenges in rotator cuff surgical repair and postoperative rehabilitation. In this study, an in situ-formed injectable sodium alginate (SA) and bioglass (BG) hydrogel consisting of poly (lactic-co-glycolic acid) (PLGA) microspheres containing metformin (SA/BG-PLGA-Met) was developed for the prevention of muscular fat infiltration and dystrophy. Metformin and silicon ions were slowly released by the combined hydrogel, resulting in long-term biological effects. Moreover, the hydrogel displayed excellent degradability and biocompatibility. Extracts of SA/BG-PLGA-Met inhibited the adipogenesis of 3T3-L1 cells and stimulated the myogenic differentiation of C2C12 cells in vitro. In a mouse model of rotator cuff degeneration, the SA/BG-PLGA-Met hydrogel inhibited fat infiltration and dystrophy of the supraspinatus muscle. Overall, the SA/BG-PLGA-Met hydrogel, as a novel biomaterial, has great clinical potential for preventing rotator cuff muscle fat infiltration and atrophy.
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Injectable hydrogels find extensive application in the treatment of diabetic wound healing. However, traditional bulk hydrogels are significantly limited due to their nano-porous structure, which obstructs cell migration and tissue infiltration. Moreover, regulating inflammation and matrix metalloproteinase -9 (MMP-9) expression in diabetic wounds is crucial for enhancing wound healing. This study marks the first instance of introducing an efficient, scalable, and simple method for producing microfiber-gel granules encapsulating bioceramics powders. Utilizing this method, an injectable microporous granular microgel-fiber hydrogel (MFgel) is successfully developed by assembling microgel-fibers made from hyaluronic acid (HA) and sodium alginate (SA) loaded with small interfering RNA (siRNA) and bioglass (BG) particles. Compared to traditional hydrogels (Tgel), MFgel possesses a highly interconnected network with micron-sized pores, demonstrating favorable properties for cell adhesion and penetration in in vitro experiments. Additionally, MFgel exhibits a higher compressive modulus and superior mechanical stability. When implanted subcutaneously in mice, MFgel promotes cellular and tissue infiltration, facilitating cell proliferation. Furthermore, when applied to skin defects in diabetic rats, MFgel not only effectively regulates inflammation and suppresses MMP-9 expression but also enhances angiogenesis and collagen deposition, thereby significantly accelerating diabetic wound healing. Taken together, this hydrogel possesses great potential in diabetic wound healing applications.
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Osteoporotic tendon-to-bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose-derived stem cells (sEVs) (MHA-sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA-sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA-sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA-sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell-hydrogel interaction studies reveal that the alignment of microfiber gels in MHA-sEVs induces tenogenic differentiation of tendon-derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor-kappaB (NF-κb) signaling pathway. Taken together, MHA-sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH.
Subject(s)
Extracellular Vesicles , Hydrogels , Rats , Animals , Hydrogels/chemistry , Rats, Sprague-Dawley , Tendons , Extracellular Vesicles/metabolism , Inflammation/metabolismABSTRACT
Healing of a damaged tendon-to-bone enthesis occurs through the formation of fibrovascular scar tissue with greatly compromised histological and biomechanical properties instead of the regeneration of a new enthesis due to the lack of graded tissue-engineering zones in the interface during the healing process. In the present study, a structure-, composition-, and mechanics-graded biomimetic scaffold (GBS) coated with specific decellularized extracellular matrix (dECM) (GBS-E) aimed to enhance its cellular differentiation inducibilities was fabricated using a three-dimensional (3-D) bioprinting technique. In vitro cellular differentiation studies showed that from the tendon-engineering zone to the bone-engineering zone in the GBS, the tenogenic differentiation inducibility decreased in correspondence with an increase in the osteogenic differentiation inducibility. The chondrogenic differentiation inducibility peaked in the middle, which was in consistent with the graded cellular phenotypes observed in a native tendon-to-bone enthesis, while specific dECM coating from the tendon-engineering zone to the bone-engineering zone (tendon-, cartilage-, and bone-derived dECM, respectively) further enhanced its cellular differentiation inducibilities (GBS-E). In a rabbit rotator cuff tear model, histological analysis showed that the GBS-E group exhibited well-graded tendon-to-bone differentiated properties in the repaired interface that was similar to a native tendon-to-bone enthesis at 16 weeks. Moreover, the biomechanical properties in the GBS-E group were also significantly higher than those in other groups at 16 weeks. Therefore, our findings suggested a promising tissue-engineering strategy for the regeneration of a complex enthesis using a three-dimensional bioprinting technique.
Subject(s)
Bioprinting , Decellularized Extracellular Matrix , Animals , Rabbits , Osteogenesis , Biomimetics , Tendons , Extracellular Matrix , Tissue ScaffoldsABSTRACT
Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, was recently approved for FGFR2 rearrangement-positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14 C-futibatinib single oral 20-mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half-life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine-conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14 C-futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1-aminobenzotriazole (a pan-cytochrome P450 inhibitor), and glutathione- and cysteine-conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O-desmethylation and glutathione conjugation, with cytochrome P450 enzyme-mediated desmethylation as the main oxidation pathway. 14 C-futibatinib was well tolerated in this Phase 1 study.
Subject(s)
Protein Kinase Inhibitors , Pyrazoles , Humans , Healthy Volunteers , Pyrazoles/adverse effects , Cytochrome P-450 Enzyme System , MetabolomeABSTRACT
Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P-glycoprotein (P-gp) substrate and inhibitor. Futibatinib also showed time-dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug-drug interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P-gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug-drug interaction studies with P-gp-specific substrates and inhibitors are planned.
Subject(s)
Cytochrome P-450 CYP3A , Rifampin , Adult , Humans , Cytochrome P-450 CYP3A/metabolism , Rifampin/pharmacokinetics , Itraconazole/pharmacology , Midazolam/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Cytochrome P-450 CYP3A Inducers/pharmacology , Drug InteractionsABSTRACT
BACKGROUND: Adipose-derived stem cell (ADSC) sheets have been shown to promote tendon-to-bone healing. However, conventional laboratory preparation methods for ADSC sheets are time-consuming and risky, which precludes their diverse clinical applications. PURPOSE: To explore the utility of off-the-shelf cryopreserved ADSC sheets (c-ADSC sheets) for rotator cuff tendon-to-bone healing. STUDY DESIGN: Controlled laboratory study. METHODS: The ADSC sheets were cryopreserved and thawed for live/dead double staining, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, scanning electron microscopy observation, and biomechanical testing. Clone formation, proliferative capacity, and multilineage differentiation of ADSCs within the c-ADSC sheets were assayed to explore the effect of cryopreservation on stem cell properties. A total of 67 rabbits were randomly divided into 4 groups: normal group (without supraspinatus tendon tears; n = 7), control group (repair alone; n = 20), fresh ADSC (f-ADSC) sheet group (repair; n = 20), and c-ADSC sheet group (repair; n = 20). Rabbit bilateral supraspinatus tendon tears were induced to establish a chronic rotator cuff tear model. Gross observation, micro-computed tomography analysis, histological or immunohistochemical tests, and biomechanical tests were conducted at 6 and 12 weeks after repair. RESULTS: No significant impairment was seen in the cell viability, morphology, and mechanical properties of c-ADSC sheets when compared with f-ADSC sheets. The stem cell properties of ADSC sheets also were preserved by cryopreservation. At 6 and 12 weeks after the repair, the f-ADSC and c-ADSC sheet groups showed superior bone regeneration, higher histological scores, larger fibrocartilage areas, more mature collagen, and better biomechanical results compared with the control group. No obvious difference was seen between the f-ADSC and c-ADSC sheet groups in terms of bone regeneration, histological score, fibrocartilage formation, and biomechanical tests. CONCLUSION: c-ADSC sheets, an off-the-shelf scaffold with a high potential for clinical translational application, can effectively promote rotator cuff tendon-to-bone healing. CLINICAL RELEVANCE: Programmed cryopreservation of ADSC sheets is an efficient off-the-shelf scaffold for rotator cuff tendon-to-bone healing.
Subject(s)
Rotator Cuff Injuries , Animals , Rabbits , Rotator Cuff Injuries/therapy , X-Ray Microtomography , Wound Healing , Tendons , Cryopreservation , Stem Cells , Biomechanical PhenomenaABSTRACT
PURPOSE: To compare the functional outcomes, range of motion (ROM), recurrence rates, and complication rates of arthroscopic autologous iliac crest grafting (AICG) and Remplissage plus Bankart repair (RB) for anterior shoulder instability with bipolar bone defects. METHODS: This study enrolled patients undergoing arthroscopic AICG or RB with 13.5-25% glenoid bone defect combined with Hill-Sachs lesion between January 2013 and April 2020, who had a minimum 2-year follow-up. Patient-reported outcomes were evaluated by Subjective Shoulder Value (SSV), Oxford Shoulder Instability Score (OSIS), Rowe score, Constant score, and visual analog scale (VAS) for pain. Active ROM, return to sports, recurrence, self-reported apprehension, and complications were recorded. RESULTS: This study included 60 patients, including 28 AICG (Group A) and 32 RB (Group R). Mean glenoid bone defect was similar (17.7% ± 3.1% vs 16.6% ± 2.4%; P = .122). Both groups showed significant postoperative improvement in Rowe score, SSV, OSIS, and Constant score. No significant difference was found in postoperative Rowe Score (87.7 vs 85.2; P = .198). A total of 20/28 (71.4%) patients in Group A versus 26/32 (81.3%) patients in Group R met the Patient Acceptable Symptomatic State determined by VAS pain score (P = .370). Both groups showed high return-to-sports rates (67.8% vs 71.8%; P = .735) and slightly decreased ROM. There were two cases of recurrence in Group A versus one in Group R (P = .594). Group R had insignificantly higher positive self-reported apprehension rate (40.6% vs 17.9%; P = .055). CONCLUSIONS: For anterior shoulder instability with bipolar bone defects, both arthroscopic AICG and RB can result in satisfactory clinical outcomes, good postoperative ROM, and low recurrence and complication rates. LEVEL OF EVIDENCE: Level III, retrospective cohort study.
Subject(s)
Bankart Lesions , Joint Instability , Shoulder Dislocation , Shoulder Joint , Humans , Shoulder/surgery , Shoulder Joint/surgery , Shoulder Dislocation/surgery , Retrospective Studies , Joint Instability/surgery , Ilium , Arthroscopy/methods , Recurrence , Bankart Lesions/surgery , PainABSTRACT
BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).
Subject(s)
Antineoplastic Agents , Bile Duct Neoplasms , Bile Ducts, Intrahepatic , Cholangiocarcinoma , Protein Kinase Inhibitors , Receptor, Fibroblast Growth Factor, Type 2 , Aged , Humans , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/pathology , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Quality of Life , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Antineoplastic Agents/administration & dosageABSTRACT
Futibatinib, a fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being investigated for FGFR-aberrant tumors. A 4-period, crossover, phase 1 thorough QT/QTc study compared effects on Fridericia heart rate-corrected QT (QTcF) interval of single doses of futibatinib 20 and 80 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin (positive control) in healthy subjects. The study objective was to assess the time-matched difference in change from baseline in QTcF (ddQTcF) between futibatinib and placebo. In addition, changes from baseline in QTcF and other electrocardiogram (ECG) parameters, pharmacokinetics, ECG morphology, and safety were assessed. Forty-eight subjects were randomized. ddQTcF upper limits of 2-sided 90%CIs remained <10 milliseconds (clinical threshold) for both futibatinib doses at all time points (range, 2.0-4.5 milliseconds). Assay sensitivity was demonstrated by lower limits of 2-sided 97.5%CIs of the dQTcF difference between moxifloxacin and placebo of >5 milliseconds. Futibatinib exposure increased in a dose-dependent manner, and no significant relationship was detected between plasma futibatinib concentration and ddQTcF. There were no significant effects on heart rate, other ECG parameters, or ECG morphology. No serious adverse events occurred. Futibatinib did not prolong QTcF or affect other cardiac measures at therapeutic or supratherapeutic doses.
Subject(s)
Fluoroquinolones , Heart , Humans , Moxifloxacin/adverse effects , Fluoroquinolones/adverse effects , Healthy VolunteersABSTRACT
Futibatinib, an oral, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being evaluated for FGFR-aberrant tumors. Two open-label phase 1 studies evaluated the effects of high-fat, high-calorie food and concomitant proton pump inhibitors (PPIs; lansoprazole) on single-dose futibatinib (20 mg) pharmacokinetics and safety in healthy adults. In the food effect study (N = 17), subjects received futibatinib under fed and fasted conditions, separated by a 7-day washout. In the PPI study (N = 20), subjects received futibatinib alone, underwent a 2-day washout, and then received lansoprazole 60 mg once daily for 5 days, with futibatinib also administered on day 5. Under fed versus fasted conditions, futibatinib bioavailability was 11.2% lower (area under the plasma concentration-time curve from time 0 to infinity geometric mean ratio 88.8%; 90% confidence interval, 79.8%-98.9%), and median time to maximum plasma concentration was significantly delayed (4.0 vs 1.5 hours; P < .0001). There were no significant differences in futibatinib exposure between futibatinib plus lansoprazole and futibatinib alone. No serious adverse events occurred in either study. These findings suggest that food and PPIs are unlikely to have clinically meaningful impacts on futibatinib bioavailability. Thus, futibatinib may be used with or without food and concomitantly with acid-reducing agents.