Muscle and Bone Impairment in Infantile Nephropathic Cystinosis: New Concepts

Cystinosis Metabolic Bone Disease (CMBD) has emerged during the last decade as a well-recognized, long-term complication in patients suffering from infantile nephropathic cystinosis (INC), resulting in significant morbidity and impaired quality of life in teenagers and adults with INC. Its underlying pathophysiology is complex and multifactorial, associating complementary, albeit distinct entities, in addition to ordinary mineral and bone disorders observed in other types of chronic kidney disease. Amongst these long-term consequences are renal Fanconi syndrome, hypophosphatemic rickets, malnutrition, hormonal abnormalities, muscular impairment, and intrinsic cellular bone defects in bone cells, due to CTNS mutations. Recent research data in the field have demonstrated abnormal mineral regulation, intrinsic bone defects, cysteamine toxicity, muscle wasting and, likely interleukin-1-driven inflammation in the setting of CMBD. Here we summarize these new pathophysiological deregulations and discuss the crucial interplay between bone and muscle in INC. In future, vitamin D and/or biotherapies targeting the IL1β pathway may improve muscle wasting and subsequently CMBD, but this remains to be proven.

A 24-month retrospective update: follow-up hospitalization charges and readmissions in US lumbar fusion surgeries using a cellular bone allograft (CBA) versus recombinant human bone morphogenetic protein-2 (rhBMP-2)

Background The objectives of this study were to build upon previously-reported 12-month findings by retrospectively comparing 24-month follow-up hospitalization charges and potentially-relevant readmissions in US lumbar fusion surgeries that employed either recombinant human bone morphogenetic protein-2 (rhBMP-2) or a cellular bone allograft comprised of viable lineage-committed bone cells (V-CBA) via a nationwide healthcare system database. Methods A total of 16,172 patients underwent lumbar fusion surgery using V-CBA or rhBMP-2 in the original study, of whom 3,792 patients (23.4%) were identified in the current study with all-cause readmissions during the 24-month follow-up period. Confounding baseline patient, procedure, and hospital characteristics found in the original study were used to adjust multivariate regression models comparing differences in 24-month follow-up hospitalization charges (in 2020 US dollars) and lengths of stay (LOS; in days) between the groups. Differences in potentially-relevant follow-up readmissions were also compared, and all analyses were repeated in the subset of patients who only received treatment at a single level of the spine. Results The adjusted cumulative mean 24-month follow-up hospitalization charges in the full cohort were significantly lower in the V-CBA group ($99,087) versus the rhBMP-2 group ($124,389; P < 0.0001), and this pattern remained in the single-level cohort (V-CBA = $104,906 vs rhBMP-2 = $125,311; P = 0.0006). There were no differences between groups in adjusted cumulative mean LOS in either cohort. Differences in the rates of follow-up readmissions aligned with baseline comorbidities originally reported for the initial procedure. Subsequent lumbar fusion rates were significantly lower for V-CBA patients in the full cohort (10.12% vs 12.00%; P = 0.0002) and similar between groups in the single-level cohort, in spite of V-CBA patients having significantly higher rates of baseline comorbidities that could negatively impact clinical outcomes, including bony fusion. Conclusions The results of this study suggest that use of V-CBA for lumbar fusion surgeries performed in the US is associated with substantially lower 24-month follow-up hospitalization charges versus rhBMP-2, with both exhibiting similar rates of subsequent lumbar fusion procedures and potentially-relevant readmissions.

Immediate Mandibular Reconstruction Using a Cellular Bone Allograft Following Tumor Resection in a Pediatric Patient

Reconstruction of large segmental mandibular defects presents a challenge for oral and maxillofacial surgeons, particularly in the skeletally immature pediatric patient. Autogenous bone graft is historically preferred; however, harvest of autograft requires a second surgical site, risking donor-site complications as well as the potential for long-term complications in the growing child. Here, we present the first known report of a pediatric patient who underwent immediate mandibular reconstruction of a 6.5-cm long segmental defect using a cellular bone allograft (VF-CBA) combined with custom-fabricated guides and plates following tumor resection. The use of VF-CBA, along with the custom guides and plates, eliminated the need for autograft harvest in a child, enabled an entirely intraoral approach, avoiding the creation of a cutaneous scar, and reduced the total operative time, resulting in a fast recovery and improved patient satisfaction. By 7 months postoperative, the patient’s mandible was fully healed with solid osseous consolidation. These results support VF-CBA combined with custom intraoral guides and plates as an effective treatment option for reconstruction of large segmental mandibular defects in a pediatric patient.

Lumbar spine fusion outcomes using a cellular bone allograft with lineage-committed bone-forming cells in 96 patients

Background Instrumented posterior lumbar fusion (IPLF) with and without transforaminal interbody fusion (TLIF) is a common treatment for low back pain when conservative interventions have failed. Certain patient comorbidities and lifestyle risk factors, such as obesity and smoking, are known to negatively affect these procedures. An advanced cellular bone allograft (CBA) with viable osteogenic cells (V-CBA) has demonstrated high fusion rates, but the rates for patients with severe and/or multiple comorbidities remain understudied. The purpose of this study was to assess fusion outcomes in patients undergoing IPLF/TLIF using V-CBA with baseline comorbidities and lifestyle risk factors known to negatively affect bone fusion. Methods This was a retrospective study of de-identified data from consecutive patients at an academic medical center who underwent IPLF procedures with or without TLIF, and with V-CBA. Baseline patient and procedure characteristics were assessed. Radiological outcomes included fusion rates per the Lenke scale. Patient-reported clinical outcomes were evaluated via the Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) for back and leg pain. Operating room (OR) times and intraoperative blood loss rates were also assessed. Results Data from 96 patients were assessed with a total of 222 levels treated overall (mean: 2.3 levels) and a median follow-up time of 16 months (range: 6 to 45 months). Successful fusion (Lenke A or B) was reported for 88 of 96 patients (91.7%) overall, including in all IPLF-only patients. Of 22 patients with diabetes in the IPLF+TLIF group, fusion was reported in 20 patients (90.9%). In IPLF+TLIF patients currently using tobacco (n = 19), fusion was reported in 16 patients (84.3%), while in those with a history of tobacco use (n = 53), fusion was observed in 48 patients (90.6%). Successful fusion was reported in all 6 patients overall with previous pseudarthrosis at the same level. Mean postoperative ODI and VAS scores were significantly reduced versus preoperative ratings. Conclusion The results of this study suggest that V-CBA consistently yields successful fusion and significant decreases in patient-reported ODI and VAS, despite patient comorbidities and lifestyle risk factors that are known to negatively affect such bony healing.

Commercial Bone Grafts Claimed as an Alternative to Autografts: Current Trends for Clinical Applications in Orthopaedics

In the last twenty years, due to an increasing medical and market demand for orthopaedic implants, several grafting options have been developed. However, when alternative bone augmentation materials mimicking autografts are searched on the market, commercially available products may be grouped into three main categories: cellular bone matrices, growth factor enhanced bone grafts, and peptide enhanced xeno-hybrid bone grafts. Firstly, to obtain data for this review, the search engines Google and Bing were employed to acquire information from reports or website portfolios of important competitors in the global bone graft market. Secondly, bibliographic databases such as Medline/PubMed, Web of Science, and Scopus were also employed to analyse data from preclinical/clinical studies performed to evaluate the safety and efficacy of each product released on the market. Here, we discuss several products in terms of osteogenic/osteoinductive/osteoconductive properties, safety, efficacy, and side effects, as well as regulatory issues and costs. Although both positive and negative results were reported in clinical applications for each class of products, to date, peptide enhanced xeno-hybrid bone grafts may represent the best choice in terms of risk/benefit ratio. Nevertheless, more prospective and controlled studies are needed before approval for routine clinical use.

Investigating the efficacy of allograft cellular bone matrix for spinal fusion: a systematic review of the literature

OBJECTIVE The use of allograft cellular bone matrices (ACBMs) in spinal fusion has expanded rapidly over the last decade. Despite little objective data on its effectiveness, ACBM use has replaced the use of traditional autograft techniques, namely iliac crest bone graft (ICBG), in many centers. METHODS In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review was conducted of the PubMed, Cochrane Library, Scopus, and Web of Science databases of English-language articles over the time period from January 2001 to December 2020 to objectively assess the effectiveness of ACBMs, with an emphasis on the level of industry involvement in the current body of literature. RESULTS Limited animal studies (n = 5) demonstrate the efficacy of ACBMs in spinal fusion, with either equivalent or increased rates of fusion compared to autograft. Clinical human studies utilizing ACBMs as bone graft expanders or bone graft substitutes (n = 5 for the cervical spine and n = 8 for the lumbar spine) demonstrate the safety of ACBMs in spinal fusion, but fail to provide conclusive level I, II, or III evidence for its efficacy. Additionally, human studies are plagued with several limiting factors, such as small sample size, lack of prospective design, lack of randomization, absence of standardized assessment of fusion, and presence of industry support/relevant conflict of interest. CONCLUSIONS There exist very few objective, unbiased human clinical studies demonstrating ACBM effectiveness or superiority in spinal fusion. Impartial, well-designed prospective studies are needed to offer evidence-based best practices to patients in this domain.

Existing clinical evidence on the use of cellular bone matrix grafts in spinal fusion: updated systematic review of the literature

OBJECTIVE Spinal fusion surgery is increasingly common; however, pseudarthrosis remains a common complication affecting as much as 15% of some patient populations. Currently, no clear consensus on the best bone graft materials to use exists. Recent advances have led to the development of cell-infused cellular bone matrices (CBMs), which contain living components such as mesenchymal stem cells (MSCs). Relatively few clinical outcome studies on the use of these grafts exist, although the number of such studies has increased in the last 5 years. In this study, the authors aimed to summarize and critically evaluate the existing clinical evidence on commercially available CBMs in spinal fusion and reported clinical outcomes. METHODS The authors performed a systematic search of the MEDLINE and PubMed electronic databases for peer-reviewed, English-language original articles (1970–2020) in which the articles’ authors studied the clinical outcomes of CBMs in spinal fusion. The US National Library of Medicine electronic clinical trials database (www.ClinicalTrials.gov) was also searched for relevant ongoing clinical trials. RESULTS Twelve published studies of 6 different CBM products met inclusion criteria: 5 studies of Osteocel Plus/Osteocel (n = 354 unique patients), 3 of Trinity Evolution (n = 114), 2 of ViviGen (n = 171), 1 of map3 (n = 41), and 1 of VIA Graft (n = 75). All studies reported high radiographic fusion success rates (range 87%–100%) using these CBMs. However, this literature was overwhelmingly limited to single-center, noncomparative studies. Seven studies disclosed industry funding or conflicts of interest (COIs). There are 4 known trials of ViviGen (3 trials) and Bio4 (1 trial) that are ongoing. CONCLUSIONS CBMs are a promising technology with the potential of improving outcome after spinal fusion. However, while the number of studies conducted in humans has tripled since 2014, there is still insufficient evidence in the literature to recommend for or against CBMs relative to cheaper alternative materials. Comparative, multicenter trials and outcome registries free from industry COIs are indicated.

Quizartinib with decitabine and venetoclax (triplet) is highly active in patients with FLT3-ITD mutated acute myeloid leukemia (AML).

e19019 Background: The outcomes in patients (pts) with newly diagnosed FLT3 mutated AML who are ineligible for intensive induction chemotherapy are poor. Added to a low intensity chemotherapy backbone, FLT3 inhibitors, such as midostaurin, sorafenib, and quizartinib, result in median OS of 8-17 months in the frontline (Gallogly ASH 2017, Ohanian AJH 2018, Swaminathan ASH 2017), and 4-8 months in relapsed/refractory (R/R) settings (Yilmaz JHO 2020, Ravandi Blood 2013). Quizartinib, a potent second generation FLT3 inhibitor demonstrated synergy with venetoclax (VEN) (a BCL-2 inhibitor) in AML cell lines and PDX models (Mali Haematologica 2020). We designed this study to evaluate the safety and efficacy of quizartinib, venetoclax, and decitabine combination in pts with R/R or newly diagnosed FLT3 mutated AML. Methods: Frontline cohort included pts who are ineligible for intensive induction chemotherapy, and R/R cohort included pts who received 5 or less prior treatments. All patients had a performance status of ECOG ≤2, adequate organ functions, and QTcF <450 msec prior to therapy. All pts underwent day 14 bone marrow, and venetoclax (400 mg/day) was put on hold in patients with bone marrow blasts ≤ 5% (or marrow aplasia). Those with day14 bone marrow blast >5% continued venetoclax for 21 days during cycle 1. All pts induced with 10 days of decitabine (20 mg/m2). In subsequent cycles, decitabine administered for 5 days. Quizartinib (30 or 40 mg/day) was administered daily continuously. Results: 21 pts were enrolled and 17 pts evaluable at the time of this report (4 are still within cycle 1). Of 13 pts with R/R AML (median 3 [range 1-5] prior therapies, 85% with ≥1 prior FLT3 inhibitor), 9 (69%) achieved CRc (2 CR, 7 CRi) with 4/9 and 5/9 responders FLT3-PCR and multicolor flow cytometry (MFC) negative, respectively. Thirty and 60-day mortality rates were 0% and 8%. Of 4 patients with newly diagnosed AML (median age 72), all achieved CRc (2 CR, 2 CRi) with 4/4 and 2/3 responders FLT3-PCR and MFC negative, respectively. 60-day mortality was 0% in the frontline cohort. No pts developed a dose limiting toxicity (DLT) with 30 mg/day quizartinib, however with the 40mg/day quizartinib 2 pts developed hematologic DLT (grade ≥3 neutropenia with a <5% cellular bone marrow lasting ≥42 days). Hence, quizartinib 30 mg/day dose was determined as recommended phase 2 dose for the triplet. Grade 3/5 non-hematologic toxicities in >2 pts included lung infections (N=9) and neutropenic fever (N=6). No QTcF prolongations >450 msec were noted. With a median follow-up of 7.2 months, the median OS was not reached in frontline cohort and was 7.1 months in R/R cohort. 2/4 and 5/9 responders underwent ASCT in frontline and R/R cohorts, respectively. All frontline pts were alive at the last follow-up; 3 were in CR and 1 relapsed disease. Of 9 responders in R/R cohort, 4 were alive (3 CR, 1 relapse) and 5 died (4 relapse, 1 CR). Conclusions: Decitabine + venetoclax + quizartinib is highly active in R/R FLT3-ITD mutated AML pts, with CRc rates of 69% and the median OS of 7.1 months. Accrual to the triplet continues and updated clinical and correlative data will be presented. Clinical trial information: NCT03661307.