A Comparison of 2 Abbreviated Methods for Assessing Adolescent Bone Age: The Shorthand Bone Age Method and the SickKids/Columbia Method.

BACKGROUND: Radiographic assessment of bone age is critically important to decision-making on the type and timing of operative interventions in pediatric orthopaedics. The current widely accepted method for determining bone age is time and resource-intensive. This study sought to assess the reliability and accuracy of 2 abbreviated methods, the Shorthand Bone Age (SBA) and the SickKids/Columbia (SKC) methods, to the widely accepted Greulich and Pyle (GP) method. METHODS: Standard posteroanterior radiographs of the left hand of 125 adolescent males and 125 adolescent females were compiled, with bone ages determined by the GP method ranging from 9 to 16 years for males and 8 to 14 years for females. Blinded to the chronologic age and GP bone age of each child, the bone age for each radiograph was determined using the SBA and SKC methods by an orthopaedic surgery resident, 2 pediatric orthopaedic surgeons, and a musculoskeletal radiologist. Measurements were then repeated 2 weeks later after rerandomization of the radiographs. Intrarater and interrater reliability for the 2 abbreviated methods as well as the agreement between all 3 methods were calculated using weighted κ values. Mean absolute differences between methods were also calculated. RESULTS: Both bone age methods demonstrated substantial to almost perfect intrarater reliability, with a weighted κ ranging from 0.79 to 0.93 for the SBA method and from 0.82 to 0.96 for the SKC method. Interrater reliability was moderate to substantial (weighted κ: 0.55 to 0.84) for the SBA method and substantial to almost perfect (weighted κ: 0.67 to 0.92) for the SKC method. Agreement between the 3 methods was substantial for all raters and all comparisons. The mean absolute difference, been GP-derived and SBA-derived bone age, was 7.6±7.8 months, as compared with 8.8±7.4 months between GP-derived and SKC-derived bone ages. CONCLUSIONS: The SBA and SKC methods have comparable reliability, and both correlate well to the widely accepted GP methods and to each other. However, they have relatively large absolute differences when compared with the GP method. These methods offer simple, efficient, and affordable estimates for bone age determination, but at best provide an estimate to be used in the appropriate setting. LEVEL OF EVIDENCE: Diagnostic study-level III.

Predictors of Acute Hematologic Toxicity in Women Receiving Extended-Field Chemoradiation for Cervical Cancer: Do Known Pelvic Radiation Bone Marrow Constraints Apply?

Purpose: Patients with cervical cancer who are at high risk for para-aortic lymphatic involvement may receive extended-field chemoradiation (EF-CRT), with inclusion of the para-aortic region. Increased radiation to bone marrow (BM) may heighten hematologic toxicity (HT) and affect timely delivery of chemoradiation. Factors associated with HT in this setting have not been well studied. Methods and Materials: This study was a retrospective analysis of women treated with EF-CRT from 2012 to 2018 with platinum-based chemotherapy. Factors including age, body mass index (BMI), race, Charlson Comorbidity Index (CCI), and nadirs for white blood cell count, absolute neutrophil count, hemoglobin, and platelet count were collected. The BM metrics included V5Gy, V10Gy, V15Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy and V45Gy (VxGy was defined as the percentage of BM volume receiving x Gy). Hematologic toxicity was defined as grade ≥2 (Cooperative Group Common Toxicity Criteria) leukopenia, anemia, neutropenia, or thrombocytopenia. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the χ2 test, the Fisher exact test, and logistic regression. Previously published dosimetric BM constraints were examined as detailed in each respective study. Results: Fifty-two women underwent EF-CRT with cisplatin. UVA showed no association between HT and age, BMI, or CCI. When accounting for race, V5Gy ≥98% was associated with grade ≥2 leukopenia (P = .02) and grade ≥2 HT (P = .05). Most previously described radiation metrics were not reproduced in our cohort, but a similar constraint, V20Gy <70%, was associated with reduced leukopenia of grade ≥2 on UVA (P = .02) and MVA (P < .05). Conclusions: Acute HT in patients receiving EF-CRT was associated with large volumes of low-dose radiation to the BM and was also associated with race. Restricting the BM V20Gy to less than 70% to 75% may be beneficial in reducing HT, but other pelvic radiation BM constraints may not be applicable to this population.

Patient-Proxy and Societal Perspectives of Quality-of-Life Utilities in Children With Cleft Lip and Palate Managed With Surgical Repair vs No Repair in Ethiopia.

Importance: In Ethiopia, more than 70% of infants with cleft lip and/or palate (CL/P) lack access to surgery. Infants who are untreated can experience severe malnutrition and extreme social stigma resulting in abandonment. Utilities are standardized measures of health-related quality of life (HRQOL) that inform health care resource allocation. However, CL/P utilities are missing from low- and middle-income countries (LMICs). Objective: To elicit utilities for untreated and surgically treated children with CL/P with consideration for social determinants of health from patient-proxy and societal participants. Design, Setting, and Participants: This cross-sectional study used patient proxies and societal participants in Addis Ababa, Ethiopia, from July 1, 2019, to January 30, 2020. Eligible patient proxies were caregivers of children younger than 18 years with nonsyndromic CL/P who were untreated or received surgery. Proxies were necessary as most patients were 0 to 4 years old and cannot reliably self-report. Eligible societal participants were 18 years and older with no family history of CL/P. Exposures: Surgical treatment and social determinants of health. Main Outcomes and Measures: Participants measured utilities using the visual analog scale (VAS), time trade-off (TTO), and standard gamble (SG). Results: In this study, 312 patient proxies and 135 societal participants were recruited. Mean (SD) utilities for untreated CL/P ranged from 0.57 (0.23) to 0.70 (0.22) from patient proxies and from 0.35 (0.21) to 0.8 (0.23) from societal participants, depending on utility instrument and cleft type. Surgical treatment was associated with a better HRQOL from the patient-proxy perspective (VAS, 0.17; 95% CI, 0.09 to 0.26; TTO, 0.15; 95% CI, 0.05 to 0.25) from the societal perspective (VAS, 0.21; 95% CI, 0.16 to 0.26; TTO, 0.17; 95% CI, 0.13 to 0.22; SG, 0.11; 95% CI, 0.06 to 0.15). Social determinants of health that were associated with patient-proxy utilities were income above the national mean (VAS, 0.10; 95% CI, 0.02 to 0.17; TTO, 0.11; 95% CI, 0.02 to 0.20), and religion (Christian vs other: TTO, -0.10; 95% CI, -0.17 to -0.03). From the societal perspective, the association between treatment and utilities was smaller in females compared with males (TTO, -0.05; 95% CI, -0.10 to -0.01). Conclusions and Relevance: The findings of this study suggest that CL/P disease severity and surgical impact in Ethiopia were undervalued by previous estimates from high-income countries and were associated with social determinants of health. Utility studies from participants from LMICs are feasible and necessary for representing HRQOL in LMICs and addressing health inequalities.

Opioid Use in Patients With Cervical Cancer at Two Urban Medical Centers.

Purpose: Patients with cervical cancer are at high risk for opioid use. This study aimed to characterize opioid prescribing patterns at 2 urban hospitals. Methods and Materials: Data from patients with cervical cancer treated with curative intent from 2011 to 2018 were retrospectively collected. Women with unrelated chronic opioid use before diagnosis, persistent/recurrent disease at 3 months after initiation of treatment, or initiation of opioids >6 months after treatment were excluded. Demographics, disease characteristics, treatment, and outpatient prescription practices were collected. Endpoints included duration of opioid use ≥6 and ≥12 months. Results: There were 106 women included, of whom 83% received definitive radiation. Most patients (n = 91, 85.8%) received outpatient opioids. Most common timing of prescriptions were before cancer therapy (35.9%), postprocedure (26.4%), and during radiation therapy (17.0%). Median duration was 3 (interquartile range, 1-11) months; 35.2% of these patients received opioids ≥6 months and 22% received opioids ≥12 months. Greater International Federation of Gynaecology and Obstetrics (FIGO) stage, recurrent/residual disease, initiation of opioids before treatment, history of depression or anxiety, and use of gabapentin or steroids were associated with long-term opioid use. Conclusions: Most patients were prescribed outpatient opioids, many of whom used opioids for 12 months. Improvement in provider communication and education, increased posttreatment monitoring, and further evaluation of nonopioid therapies are needed in this patient population to reduce long-term opioid use.

Complications of Elongating Intramedullary Rods in the Treatment of Lower Extremity Fractures for Osteogenesis Imperfecta: A Meta-Analysis of 594 Patients in 40 Years.

BACKGROUND: Osteogenesis imperfecta is a collagen mutation-related disease characterized by bone fragility and other extraskeletal manifestations. Intramedullary fixation for deformity correction or fracture is the standard care. Elongating rods are designed to accommodate growth, with the aim of preventing additional operations and/or complications associated with nonelongating rods. Although elongating rods have been in use for many years, estimates of the clinical outcomes vary. We conducted a systematic review and meta-analysis to synthesize the literature on outcomes of elongating rods and nonelongating rods. Meta-analysis was used to compare the complication rates and reoperation rates. METHODS: We conducted the literature search, systematic review, and meta-analysis in accordance with Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. Comparative cohort studies and large case series detailing complication rates and reoperation rates of elongating and nonelongating rods were included. Random effect models were used to summarize the complication rates and reoperation rates of intramedullary rod procedures. RESULTS: A total of 397 studies were identified and 24 studies were included in the final cohort. Compared with rates from nonelongating rods, osteogenesis imperfecta Patients using elongating rods had a complication rate of 61% and a reoperation rate of 78%. Reoperation rates dropped with succeeding generations of elongating rods. Pooling data from 600 patients, we identified a 9% complication rate per rod per follow up year and 5% reoperation rate per rod and per follow up year in the cohort of elongating rod fixation. The Bailey-Dubow rod had the highest complication rate per rod per follow up year (12%), largely because of its T piece relate problems. The most popular fixator Fassier-Duval rod had a complication rate per rod per follow up year of 9%. About 68% of complications were mechanical-biological related. CONCLUSION: Pooling data from published literature demonstrates the advantage of elongating rods over nonelongating rods. However, as high as 9% complication rate per rod per follow up year was associated with elongating fixation. Notably, most complications are both mechanical and biological related. LEVEL OF EVIDENCE: Level III.

Primary Synovial Osteochondromatosis of the Shoulder in Pediatric Patient: Case Report and Review of the Literature.

We report a primary synovial osteochondromatosis in a 6-year-old male with a 1-year history of shoulder pain and stiffness. The patient underwent surgical treatment, resulting in significant improvement in range of motion and functional status. Primary synovial osteochondromatosis of the shoulder is a rare benign condition that can result in shoulder pain, stiffness, and locking. MRI helps identify these lesions within the affected joint. Removal of loose bodies often alleviates symptoms and allows for improved range of motion with satisfactory results.

Local Control and Use of External Beam Parametrial Boost in the Era of Image-Guided Brachytherapy for Locally Advanced Cervical Cancer.

OBJECTIVE: Historically, external beam parametrial boost (EBPB) has been used in locally advanced cervical cancers to supplement radiation dose. However, it has become controversial in the era of image-guided brachytherapy. Modern 3D imaging and brachytherapy techniques have improved delineation and coverage of tumor. Outcomes with and without parametrial boost were analyzed. METHODS: Women with cervical cancer involving the parametria (clinically or radiographically) diagnosed between 2001 and 2017 were identified. Clinicopathologic and treatment features, survival and patterns of failure data were collected. Univariate and multivariable data analysis was performed to evaluate association of these variables, including parametrial boost, with local failure-free survival and overall survival. Competing risks analysis was performed for cumulative incidence of local failure, with death and other failures treated as competing events. RESULTS: A total of 100 women were identified (median follow-up 26.8 mo). Forty-one (41%) received EBPB; these patients were less likely to have received magnetic resonance imaging, positron emission tomography, interstitial, or high-dose rate brachytherapy. Magnetic resonance imaging, positron emission tomography, dose rate, and treatment era were highly correlated (Cramer's V: 0.43 to 0.68, P<0.01). Two-year overall survival and local failure were 78% and 12% for the entire cohort. While the use of EBPB was not associated with any outcome on multivariable analysis, treatment year after 2009 was highly associated with improved outcomes in all models. CONCLUSIONS: In this study, omission of EBPB did not compromise local control or survival in the modern era, supporting a decreased need for standardized use of parametrial boost.

Tibial tuberosity ossification predicts reoperation for growth disturbance in distal femoral physeal fractures.

PURPOSE: Distal femoral physeal fractures (DFPF) can cause growth disturbance that requires further surgical intervention. The aim of this study is to determine if Tibial Tuberosity Ossification Stage (TTOS) at the time of injury predicts secondary surgery for growth disturbance in patients who have sustained a DFPF. METHODS: We retrospectively investigated all patients who had operative treatment for a DFPF at a single centre over a 17-year period. Regression analysis was performed investigating associations between secondary surgery to treat growth disturbance and TTOS, age, Salter-Harris fracture classification type, mode of fixation or mechanism of injury. RESULTS: In all, 85 consecutive patients were identified. A total of 74 met the inclusion criteria. The mean age at time of injury was 13.1 years (2.0 to 17.1). Following fixation, 30 patients (41%) underwent further surgery to treat growth disturbance. Absence of tibial tuberosity fusion to the metaphysis was significantly associated with the need for further surgery (p < 0.001). Odds of requiring secondary surgery after tibial tuberosity fusion to metaphysis (compared with not fused) were 0.12 (95% confidence interval (CI) 0.04 to 0.34). The estimate of the effect of TTOS on reoperation rates did not vary when adjusted for gender, mechanism, fixation and Salter-Harris type. When accounting for age, the odds of any further operation if the tibial tuberosity is fused to the metaphysis (compared with not fused) were 0.28 (95% CI 0.08 to 0.94). CONCLUSION: TTOS at the time of injury is a predictor of further surgery to treat growth disturbance in paediatric distal femoral fractures. LEVEL OF EVIDENCE: Diagnostic Level II.

Osteofibrous Dysplasia of the Tibia in Children: Outcome Without Resection.

BACKGROUND: The proposed association between osteofibrous dysplasia and adamantinoma has led some to advocate resection of the entire lesion, which can require major subsequent reconstruction. However, this link remains unproven and there is some support in more recent literature for a less aggressive approach. This study aims to describe our experience managing pediatric tibial osteofibrous dysplasia with such an approach and to report functional outcomes in children treated thus. METHODS: A total of 28 cases of osteofibrous dysplasia in 25 patients were managed at a referral center for pediatric bone tumors with observation in the first instance, then limited surgical intervention if required to address pain and deformity. Surgery aimed to restore stability and alignment without excising the lesion. Clinical records provided basic clinical outcome measures involving walking, recreation, orthoses and school/work participation and patients provided a Musculoskeletal Tumour Society score (MSTS) where contactable. RESULTS: Mean age at presentation was 6.0 years and mean follow-up was 8.3 years. Only 8 patients required surgery. According to basic outcome measures, 13 patients were symptom-free. About 15 patients (17 cases) provided a MSTS and the mean score was 24 of 30. No transformation to adamantinoma was observed. Those who presented at a younger age and with bilateral disease more often required surgery and remained symptomatic. CONCLUSIONS: A less aggressive approach to pediatric tibial osteofibrous dysplasia achieves good functional outcomes and patient satisfaction in most cases. Surgery is required in the minority of cases. Transformation to adamantinoma was not observed in this series. We recommend patient education, clinical observation and reactive intervention if required, rather than proactive resection and reconstruction. LEVEL OF EVIDENCE: Level IV-case series.

Should Proximal Femoral Implants be Removed Prophylactically or Reactively in Children With Cerebral Palsy?

BACKGROUND: Implants are commonly used to stabilize proximal femoral osteotomies in children with cerebral palsy (CP). Removal of implants is common practice and believed to avoid infection, fracture, or pain that might be associated with retained hardware. There is little evidence to support a prophylactic strategy over a reactive approach based on symptoms. The aim of this study was to compare the outcomes of prophylactic and reactive approaches to removal of proximal femoral implants in children with CP. METHODS: An intention-to-treat model was used to compare 2 institutions that followed a prophylactic (within ∼1 y) and reactive (following complication/symptoms) approach to hardware removal, respectively. Patients with CP who had femoral implants placed at or before age 16, and had ≥2-year postsurgical follow-up were included. Demographics, surgical details, reasons for removal, and complications were recorded. χ and t tests were used. RESULTS: Six hundred twenty-one patients (prophylactic=302, reactive=319) were followed for an average of 6 years (range, 2 to 17 y). Two hundred eighty-seven (95%) implants were removed in the prophylactic group at 1.2 years. In the reactive group, 64 (20%) implants were removed at an average of 4.2 years. Reasons for removal included pain; infection; fracture; or for repeat reconstruction. The rate of unplanned removals due to fracture or infection was higher in the reactive group (4.7% vs. 0.7%, P=0.002), but there was no difference in the rate of complications during/after removal between the 2 groups (1.7% vs. 3.1%; P=0.616). No specific risk factor associated with unplanned removal could be identified; but children under 8 years old seemed more likely to undergo later removal (odds ratio 1.98; 95% confidence interval, 0.99-3.99). CONCLUSIONS: Eighty percent of patients in the reactive removal strategy avoided surgery. This group did have a 4% higher rate of fracture or infection necessitating unplanned removal but these were successfully treated at time of removal with no difference in complication rates associated with removal between both groups. One would need to remove implants from 25 patients to avoid 1 additional complication, providing some support for a reactive approach to removal of proximal femoral implants in this population. LEVEL OF EVIDENCE: Level III-therapeutic.

Case report: Intraoperative thrombosis cardiac arrest in extended right hepatectomy involving use of local haemostatic agent in intraoperative cell salvage (ICS) and administration of recombinant activated factor VII (rFVIIa).

INTRODUCTION: In modern surgical era, local haemostatic agents and blood components such as recombinant activated factor VII (rFVIIa) have expanded surgeons' armamentarium in controlling "surgical" and "nonsurgical bleeding". We report a case of intraoperative thrombosis and cardiac arrest involving use of local haemostatic agent in intraoperative cell salvage and rFVIIa administration in extended right hepatectomy. PRESENTATION OF CASE: A 46-year-old lady underwent extended right hepatectomy using cardiopulmonary bypass (CPB) and autotransfusion with ICS for metastatic gastrointestinal stromal tumour. She became extremely coagulopathic following weaning of CPB despite an array of fluid and blood products replacements. Decision to administer rFVIIa as a measure to arrest bleeding was unsuccessful. Extensive systemic thrombosis occurred which resulted in cardiac arrest and mortality. DISCUSSION: The thromboembolic event was unclear but likely multifactorial. Two important hypotheses were the administration of rFVIIa and use of local haemostatic agent in ICS. CONCLUSION: Reported incidence of thromboembolism with use of rFVIIa in refractory bleeding is variable. More randomised controlled trials are needed to ascertain the efficacy and safety profile of the haemostatic agent. At present, off-label use of rFVIIa should be guided by the risk:benefit profile on a case-to-case basis. The authors also feel strongly against the use of local haemostatic gel in conjunction with ICS due to potential systemic circulation of the thrombin.

Disruption of the PTHLH regulatory landscape results in features consistent with hyperparathyroid disease.

Parathyroid hormone like hormone (PTHLH) signaling is essential for the proper formation of bone and its elevation or disruption has been directly implicated in several different skeletal dysplasias. We report a patient with a 2.802 Mb deletion upstream of the PTHLH coding sequence who presents with multiple fractures, metaphyseal changes, and overall features consistent with hyperparathyroid like disease. Analysis of the deleted region revealed the loss of putative regulatory regions adjacent to PTHLH and the possible gain of a limb enhancer. Furthermore, PTHLH expression appeared to be mis-regulated in fibroblasts derived from the patient. Altogether, we find that the disruption of the regulatory landscape of PTHLH likely results in its inappropriate expression and this novel clinical presentation.

The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones.

OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear. METHODS AND RESULTS: We find that GPR142 is expressed not only in ß- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity. CONCLUSIONS: GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon.

Interdisciplinary Oncology Education: a National Survey of Trainees and Program Directors in the United States.

Oncologists must have a strong understanding of collaborating specialties in order to deliver optimal cancer care. The objective of this study was to quantify current interdisciplinary oncology education among oncology training programs across the USA, identify effective teaching modalities, and assess communication skills training. Web-based surveys were sent to oncology trainees and program directors (PDs) across the USA on April 1, 2013 and October 8, 2013, respectively. Question responses were Yes/No, five-point Likert scales (1 = not at all, 2 = somewhat, 3 = moderately, 4 = quite, 5 = extremely), or free response. Respondents included the following (trainees/PDs): 254/55 medical oncology, 160/42 surgical oncology, 102/24 radiation oncology, and 41/20 hospice and palliative medicine (HPM). Trainees consistently reported lower rates of interdisciplinary education for each specialty compared with PDs as follows: medical oncology 57 vs. 77% (p < 0.01), surgical oncology 30 vs. 44% (p < 0.01), radiation oncology 70 vs. 89% (p < 0.01), geriatric oncology 19 vs. 30% (p < 0.01), and HPM 55 vs. 74% (p < 0.01). The predominant teaching method used (lectures vs. rotations vs. tumor board attendance vs. workshop vs. other) varied according to which discipline was being taught. The usefulness of each teaching method was rated statistically different by trainees for learning about select disciplines. Furthermore, statistically significant differences were found between PDs and trainees for the perceived usefulness of several teaching modalities. This study highlights a deficiency of interdisciplinary education among oncology training programs in the USA. Efforts to increase interdisciplinary education opportunities during training may ultimately translate into improved collaboration and quality of cancer care.

Duodenal-jejunal bypass surgery induces hepatic lipidomic alterations associated with ameliorated hepatic steatosis in mice.

OBJECTIVE: Bariatric surgery induces weight loss and improvement of insulin resistance; one aspect of both is an amelioration of hepatic steatosis. This study was undertaken to assess the changes in the hepatic lipidome after duodenal-jejunal bypass (DJB) surgery. METHODS: A DJB surgical model was developed and characterized in diet-induced obese mice. In comparison with sham-operated mice, an unbiased lipidomic profiling of hepatic lipids was performed together with measurements of gene expression within key pathways of hepatic lipid metabolism. RESULTS: In the liver of DJB mice, a dramatic reduction (by 77%) in hepatic triacylglycerols was observed. Global lipidomic profiling identified marked decreases of triacylglycerols comprised of medium length fatty acids and with low double bond content. Specific diacylglycerol species were also among the most dramatic decreases in hepatic lipids, whereas lysophosphatidic acids and phosphatidic acids were increased. Expression of fatty acid transporter and lipogenic genes was down-regulated. CONCLUSIONS: From in-depth analysis of hepatic lipid composition, specific lipid intermediates were identified that are preferentially changed following DJB surgery. These changes were most likely due to DJB-induced weight loss, and only further studies will be able to distinguish weight loss-dependent from weight loss-independent changes.

ß-Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications.

Tibial pseudarthrosis causes substantial morbidity in patients with neurofibromatosis type 1 (NF1). We studied tibial pseudarthrosis tissue from patients with NF1 and found elevated levels of ß-catenin compared to unaffected bone. To elucidate the role of ß-catenin in fracture healing, we used a surgically induced tibial fracture model in conditional knockout (KO) Nfl (Nf1(flox/flox)) mice. When treated with a Cre-expressing adenovirus (Ad-Cre), there was a localized knockdown of Nf1 in the healing fracture and a subsequent development of a fibrous pseudarthrosis. Consistent with human data, elevated ß-catenin levels were found in the murine fracture sites. The increased fibrous tissue at the fracture site was rescued by local treatment with a Wingless-type MMTV integration site (Wnt) antagonist, Dickkopf-1 (Dkk1). The murine pseudarthrosis phenotype was also rescued by conditional ß-catenin gene inactivation. The number of colony-forming unit osteoblasts (CFU-Os), a surrogate marker of undifferentiated mesenchymal cells able to differentiate to osteoblasts, correlated with the capacity to form bone at the fracture site. Our findings indicate that the protein level of ß-catenin must be precisely regulated for normal osteoblast differentiation. An up-regulation of ß-catenin in NF1 causes a shift away from osteoblastic differentiation resulting in a pseudarthrosis in vivo These results support the notion that pharmacological modulation of ß-catenin can be used to treat pseudarthrosis in patients with NF1.-Ghadakzadeh, S., Kannu, P., Whetstone, H., Howard A., Alman, B. A. ß-catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications.

Tibial hemimelia associated with GLI3 truncation.

Tibial hemimelia is a rare, debilitating and often sporadic congenital deficiency. In syndromic cases, mutations of a Sonic hedgehog (SHH) enhancer have been identified. Here we describe an ~5 kb deletion within the SHH repressor GLI3 in two patients with bilateral tibial hemimelia. This deletion results in a truncated GLI3 protein that lacks a DNA-binding domain and cannot repress hedgehog signaling. These findings strengthen the concept that tibial hemimelia arises because of failure to restrict SHH activity to the posterior aspect of the limb bud.