Patient-Reported Outcome Measurement Information System Depression and Anxiety in Elective Knee Surgery Patients.

Mental health has been shown to play an important role in patient-reported outcomes (PRO); however, there is a general lack of literature describing patient-reported outcome measurement information system (PROMIS) depression and anxiety computer adaptive tests in elective knee surgery patients. The purpose of our study was to assess the prevalence of depression and anxiety symptoms before and after elective knee surgery and to determine whether these symptoms influence postoperative functional outcomes. An institutional review board-approved prospective orthopaedic registry was retrospectively queried for patients undergoing elective knee surgery from June 2015 to November 2018. Electronic surveys collecting patient demographic information and PROs were administered pre- and postoperatively. Of the 663 patients that completed baseline questionnaires, 466 completed 2-year follow-up (70.3%). PROs included PROMIS depression, PROMIS anxiety, International Knee Documentation Committee Subjective Knee Form (IKDC), and PROMIS physical function (PF). Wilcoxon rank sum and Spearman's rank order correlation were utilized to determine associations between variables. Multivariable analysis was used to control for confounding variables. Average PROMIS depression and anxiety scores significantly improved 2 years after surgery. PROMIS depression and anxiety scores significantly correlated with each other. PROMIS depression and anxiety scores significantly correlated with PROMIS PF and IKDC scores. After controlling for confounders on multivariable analysis, worse 2-year PROMIS anxiety was predictive of less functional improvement and worse 2-year PF and IKDC, while worse 2-year PROMIS depression was predictive of less improvement in IKDC. This study confirms the important relationship between mental health and functional outcomes. Given that psychiatric comorbidities are potentially modifiable with treatment, proper recognition could potentially lead to better orthopaedic outcomes. In addition, the prevalence of depression and anxiety symptoms postoperatively, as documented by PROMIS computer adaptive tests, may act as a barrier to achieving optimal functional outcomes after elective knee surgery. LEVEL OF EVIDENCE: Level III.

Relationship Between Sever Disease and Skeletal Maturity.

BACKGROUND: Sever disease is a common condition in active, growing children. This condition presents as pain in the heel and is thought to be an overuse condition of the calcaneal apophysis. There are currently no defined radiographic diagnostic criteria for evaluation of Sever disease, with radiographs generally showing normal appearance of the calcaneal apophysis. A better understanding of the relationship of Sever disease and skeletal maturity may allow for improved interpretation of radiographs when trying to diagnose this condition. METHODS: ICD-9 code 732.5 was used to search for patients diagnosed with Sever disease from 2007 to 2015 at a single hospital. For every patient with Sever disease with available calcaneal imaging within 40 days of diagnosis, heel x-rays were staged for calcaneal maturity score using a previously described calcaneal skeletal maturity assessment system. Controls matched by age, race, and sex were evaluated for calcaneal stage to compare with the Sever patients. RESULTS: The chart review yielded 78 patients diagnosed with Sever disease by the orthopaedic attending, 39 of which have x-rays around the time of diagnosis. Calcaneal scores averaged 2.2±0.8 for all patients, 2.1±0.9 for male individuals, and 2.3±0.8 for female individuals. The average age for male individuals was 10.4±1.9 years and for female individuals, 9.2±2.2 years. The ages of diagnosis were similar for patients with and without x-rays. Twenty-two of 39 patients with Sever disease were calcaneal stage 2, and 37 of 39 were stages 1, 2, or 3. We calculated the absolute difference from stage 2 for the Sever and control groups. Mean difference from stage 2 was 0.51±0.68 for the Sever patients and 0.95±0.79 for control patients (P=0.01). CONCLUSION: Sever disease occurs in a very narrow range of skeletal maturity, as measured by the calcaneal skeletal maturity assessment system and our observations with chronological age. When compared with age-matched and race-matched controls, stage 2 was seen more frequently in the Sever patients. If a child is not within calcaneal stages 1, 2, or 3, then a different diagnosis should be considered. LEVEL OF EVIDENCE: Level III-retrospective case-control study.

Applicability of the Calcaneal Apophysis Ossification Staging System to the Modern Pediatric Population.

BACKGROUND: The calcaneal apophysis ossification staging system is a novel method for assessing skeletal maturity. However, it was created using the same historic patient population that was used to create the Greulich and Pyle atlas of the hand and wrist, predominantly white children. It is unclear if the calcaneal apophysis ossification staging system is still applicable to the modern pediatric population and to children of other races. METHODS: We retrospectively studied 1327 benign lateral foot x-rays from modern white and black children. Calcaneal stage was determined and age, race, and sex were collected for each patient. A 2-tailed Student t test was used to compare between cohorts the differences in age for each calcaneal stage. RESULTS: Mean age was 11.55±4.39 years. Modern white females graded as stage 3 and 4 were significantly delayed in their bone age (stage 3 P<0.002; stage 4 P<0.003) when compared with their historic counterparts. Skeletal maturity was consistent between modern and historic white males for stages 1 to 4. Modern black females graded as stage 1 to 4 were significantly advanced in their skeletal age when compared with modern white females (stage 1 P<0.038; stage 2 P<0.005; stage 3 P<0.002; stage 4 P<0.002). Modern black males graded as stages 1, 3, and 4 were also significantly advanced in their bone age when compared with their modern white counterparts (stage 1 P<0.003; stage 3 P<0.012; stage 4 P<0.029). CONCLUSIONS: Modern white females mature more slowly in the later stages when compared with their historic counterparts. No significant difference is seen between modern and historic white males. Modern black females and males were skeletally advanced compared with modern white females and males. We have shown that the calcaneal ossification staging system can be used to assess for skeletal maturity in the modern pediatric population with only mild corrections for white females and more significant adjustments for black females and males. LEVEL OF EVIDENCE: Level III-retrospective chart review.

The Association Between Body Mass Index and the Prevalence, Severity, and Frequency of Low Back Pain: Data From the Osteoarthritis Initiative.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To determine whether there is an association between body mass index (BMI) and the prevalence, severity, and frequency of low back pain and identify other potential patient risk factors for the development of low back pain. SUMMARY OF BACKGROUND DATA: Many studies have implicated that a high BMI is a risk factor for low back pain. However, few studies have examined the association between increased BMI and the prevalence, severity, and frequency of low back pain. METHODS: Data from the Osteoarthritis Initiative, a multicenter, prospective study of knee osteoarthritis, were used to conduct this study, which included 4796 patients. BMI was categorized according to the World Health Organization classification and the prevalence, severity, and frequency of low back pain were assessed. Logistic regression was performed to identify additional patient risk factors associated with low back pain. RESULTS: The prevalence of low back pain was found to be significantly higher in patients with an elevated BMI compared to those with normal or underweight BMI and demonstrated a stepwise increase with each BMI category. Approximately 47.4% of patients with normal or underweight BMI complained of low back pain compared with 72.8% of morbidly obese patients (P < 0.0001). No association was seen between BMI and the frequency or severity of low back pain episodes. Osteoarthritis of the back and depression were patient variables found to be associated with all three measures (prevalence, severity, and frequency) of low back pain. CONCLUSION: Elevated BMI is strongly associated with an increased prevalence of low back pain. Depression and osteoarthritis of the back are associated with the prevalence, severity, and frequency of low back pain. LEVEL OF EVIDENCE: 3.

Axial and appendicular body proportions for evaluation of limb and trunk asymmetry.

Background and purpose - When children with irregular body proportions or asymmetric limbs present, it may be unclear where the pathology is located. An improved understanding of the clinical ratio between upper extremity, lower extremity, and spine length may help elucidate whether there is disproportion between the trunk and limbs, and whether there is a reduction deficit of the shorter limb rather than hypertrophy of the longer limb. Patients and methods - We used the Brush Foundation study of child growth and development, which was a prospective, longitudinal study of healthy children between the 1930s and the 1950s, and we collected serial clinical measurements for 290 children at 3,326 visits. Children ranged from 2 to 20 years of age during the study period. Linear and quadratic regression were used to construct nomographs and 95% prediction intervals for anthropometric body proportions. Results - The maximum anterior superior iliac spine height to sitting height ratio occurred at 12.4 years in females and at 14.17 years in males. Overall, the ratio of arm length to sitting height was 0.76 (SD 0.06), the ratio of arm length to anterior superior iliac spine height was 0.76 (SD 0.03), and the ratio of anterior superior iliac spine height to sitting height was 0.98 (SD 0.13). When comparing ratios between arm length, anterior superior iliac spine height, and sitting height, the smallest variance between appendicular proportions was found in the arm length to anterior superior iliac spine height ratio. Interpretation - We recommend comparisons between total arm length and anterior superior iliac spine height to distinguish limb reduction deficits from hemi-hypertrophy, with sitting height being used only if combined upper and lower extremity discrepancy is noted.

Does Tobacco Use Attenuate Benefits of Early Decompression in Patients With Cervical Myelopathy?

STUDY DESIGN: A retrospective cohort. OBJECTIVE: This study investigates the interplay between duration of preoperative symptoms and smoking status with respect to postoperative outcomes in patients with cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Many studies have established the harms of smoking and several have identified the benefits of early decompression in patients with cervical myelopathy, but to our knowledge, none have assessed the relationship between these two variables. METHODS: The medical records of all 212 patients operated on by the senior author between March 2005 and July 2012 were reviewed. Inclusion criteria were the diagnosis of CSM with a Nurick score, surgical intervention, and at least 2 years of follow-up. Patients were categorized according to smoking status and quantification of tobacco use by packs per day and pack-years, and duration of symptoms according to thresholds of 6, 12, or 24 months. Age, sex, preoperative Nurick score, duration of preoperative symptoms, duration of follow-up, procedure performed, prior surgery, number of levels operated on, diabetes status, ethanol use, and signal change on preoperative magnetic resonance imaging were also recorded for ordered logistical regression analysis. RESULTS: One hundred twenty-five patients met all criteria. Eighty patients were smokers and 45 were nonsmokers. The median change in Nurick score for nonsmokers was 2 compared with 1 in smokers. Nonsmokers had a statistically significant likelihood of decreased change in Nurick score for symptom duration of greater than 24 months (odds ratio = 0.06, P = 0.0025). Smokers did not show a significant difference in the change in Nurick score for any threshold of symptom duration. CONCLUSION: Increased duration of symptoms significantly affects outcomes in surgical decompression of CSM. A history of cigarette use may attenuate the benefit of early decompression and results in lower improvement in Nurick score regardless of symptom duration. LEVEL OF EVIDENCE: 3.

MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma.

The molecular mechanisms underlying the aggressive behavior of MYCN driven neuroblastoma (NBL) is under intense investigation; however, little is known about the impact of this family of transcription factors on the splicing program. Here we used high-throughput RNA sequencing to systematically study the expression of RNA isoforms in stage 4 MYCN-amplified NBL, an aggressive subtype of metastatic NBL. We show that MYCN-amplified NBL tumors display a distinct gene splicing pattern affecting multiple cancer hallmark functions. Six splicing factors displayed unique differential expression patterns in MYCN-amplified tumors and cell lines, and the binding motifs for some of these splicing factors are significantly enriched in differentially-spliced genes. Direct binding of MYCN to promoter regions of the splicing factors PTBP1 and HNRNPA1 detected by ChIP-seq demonstrates that MYCN controls the splicing pattern by direct regulation of the expression of these key splicing factors. Furthermore, high expression of PTBP1 and HNRNPA1 was significantly associated with poor overall survival of stage4 NBL patients (p ≤ 0.05). Knocking down PTBP1, HNRNPA1 and their downstream target PKM2, an isoform of pro-tumor-growth, result in repressed growth of NBL cells. Therefore, our study reveals a novel role of MYCN in controlling global splicing program through regulation of splicing factors in addition to its well-known role in the transcription program. These findings suggest a therapeutically potential to target the key splicing factors or gene isoforms in high-risk NBL with MYCN-amplification.

Characterization of the metastatic phenotype of a panel of established osteosarcoma cells.

Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients. In this study, we collected 18 OS cell lines, confirmed their expression of bone markers and complex karyotypes, and characterized their in vivo tumorgenicity and metastatic potential. Since prior reports included conflicting descriptions of the metastatic and in vivo phenotypes of these models, there was a need for a comparative assessment of metastatic phenotypes using identical procedures in the hands of a single investigative group. We expect that this single characterization will accelerate the study of this metastatic cancer. Using these models we evaluated the expression of six previously reported metastasis-related OS genes. Ezrin was the only gene consistently differentially expressed in all the pairs of high/low metastatic OS cells. We then used a subtractive gene expression approach of the high and low human metastatic cells to identify novel genes that may be involved in OS metastasis. PHLDA1 (pleckstrin homology-like domain, family A) was identified as one of the genes more highly expressed in the high metastatic compared to low metastatic cells. Knocking down PHLDA1 with siRNA or shRNA resulted in down regulation of the activities of MAPKs (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs). Reducing the expression of PHLDA1 also delayed OS metastasis progression in mouse xenograft models.

Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534).

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.

Identification of potent Yes1 kinase inhibitors using a library screening approach.

Yes1 kinase has been implicated as a potential therapeutic target in a number of cancers including melanomas, breast cancers, and rhabdomyosarcomas. Described here is the development of a robust and miniaturized biochemical assay for Yes1 kinase that was applied in a high throughput screen (HTS) of kinase-focused small molecule libraries. The HTS provided 144 (17% hit rate) small molecule compounds with IC50 values in the sub-micromolar range. Three of the most potent Yes1 inhibitors were then examined in a cell-based assay for inhibition of cell survival in rhabdomyosarcoma cell lines. Homology models of Yes1 were generated in active and inactive conformations, and docking of inhibitors supports binding to the active conformation (DFG-in) of Yes1. This is the first report of a large high throughput enzymatic activity screen for identification of Yes1 kinase inhibitors, thereby elucidating the polypharmacology of a variety of small molecules and clinical candidates.