A pragmatic randomized prospective trial of cooled radiofrequency ablation of the medial branch nerves versus facet joint injection of corticosteroid for the treatment of lumbar facet syndrome: 12 month outcomes.

BACKGROUND: Lumbar medial branch radiofrequency ablation (LRFA) and intraarticular facet steroid injections (FJI) are commonly performed for recalcitrant facet joint-mediated pain. However, no study has compared clinical outcomes of the two treatments in patients selected using dual medial branch blocks (MBBs) with an 80% relief threshold. OBJECTIVE: Compare the effectiveness of cooled LRFA (C-LRFA) to FIJ as assessed by pain and functional improvements. DESIGN: Prospective randomized comparative trial. METHODS: Patients with dual MBB-confirmed facet joint-mediated pain were randomized to receive C-LRFA or FIJ. Outcomes were assessed at 1, 3, 6, and 12 months. The primary outcome was ≥50% improvement in numerical pain rating scale (NPRS) score at 3 months. Secondary outcomes included ≥30% Oswestry Disability Index (ODI) improvement and Patient Global Impression of Chance (PGIC) ≥6 points, among others. Data were analyzed using contingency tables and mixed-effects logistic regression models. RESULTS: Of 1128 patients screened, 32 met eligibility criteria, were randomized, and received their allocated study treatment. In total, 20 (62.5%) and 12 (37.5%) participants received C-LRFA and FIJ, respectively. In the C-LRFA group, 70% (95% CI 48-85), 55% (95% CI 34-74), and 45% (95% CI 26-66) of participants met the NPRS responder definition, compared to 25% (95%CI 9-53), 25% (95% CI 9-53), and 17% (95% CI 5-45) in the FJI group at 3, 6, and 12 months, respectively (P = .014 at 3 months). The PGIC responder proportion was higher in the C-LRFA compared to FJI group at 3 and 6 months (P < .05). CONCLUSIONS: C-LRFA demonstrated superior success rates compared to FJI across pain and functional outcome domains. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov (NCT03614793); August 3, 2018.

Changes in Interventional Pain Physician Decision-Making, Practice Patterns, and Mental Health During the Early Phase of the SARS-CoV-2 Global Pandemic.

BACKGROUND AND OBJECTIVES: The novel coronavirus outbreak (SARS-CoV-2) began in late 2019 and dramatically impacted health care systems. This study aimed to describe the impact of the early phase of the pandemic on physician decision-making, practice patterns, and mental health. METHODS: An anonymous survey was distributed to physician members of the Spine Intervention Society (SIS) on March 24 and April 7, 2020. Respondents provided information regarding changes in clinical volume, treatment, and mental health (Patient Health Questionnaire [PHQ-4]) before April 10, 2020. RESULTS: Of the 1,430 individuals who opened the survey, 260 completed it (18.2%). Overall clinical and procedural volume decreased to 69.6% and 13.0% of prepandemic volume, respectively. Mean in-person clinic visits were reduced to 17.7% of total prepandemic clinic volume. Ongoing clinical visits were predominantly completed via telemedicine (video) or telephone (74.5%), rather than in-person (25.5%). Telemedicine and telephone visits represented 24.6% and 27.3% of prepandemic clinical volume, respectively. Respondents decreased in-person visits of select groups of high-risk patients by 85.8-94.6%. Significantly more providers reported increasing rather than decreasing prescriptions of the following medications: opioids (28.8% vs 6.2% of providers, P < 0.001), muscle relaxants (22.3% vs 5.4%, P < 0.001), neuropathic pain medications (29.6% vs 3.8%, P < 0.001), and acetaminophen (26.2% vs 4.2%, P < 0.001). Respondents' mean PHQ-4 score was 3.1, with 19% reporting moderate or severe psychological distress. Several demographic factors were significantly associated with practice changes. CONCLUSIONS: The novel coronavirus pandemic dramatically altered the practice and prescribing patterns of interventional pain physicians.

The Effectiveness of Cervical Medial Branch Radiofrequency Ablation for Chronic Facet Joint Syndrome in Patients Selected by a Practical Medial Branch Block Paradigm.

BACKGROUND: Cervical medial branch radiofrequency ablation (CMBRFA) is an effective treatment for facetogenic pain in patients selected by Spine Intervention Society (SIS) guidelines of 100% symptom improvement with dual medial branch blocks (MBBs) ± placebo block. Patient selection for CMBRFA using ≥80% symptom improvement after dual concordant MBBs is common; however, this has not been studied. OBJECTIVE: To evaluate the effectiveness of CMBRFA and compare outcomes in individuals selected by 80-99% vs 100% symptom improvement with dual concordant MBBs. DESIGN: Cross-sectional cohort study. METHODS: Medical records of 87 consecutive patients were reviewed; 50 met inclusion criteria. A standardized telephone survey was performed at six or more months post-CMBRFA to query numerical rating scale (NRS) pain and patient global impression of change (PGIC) scores. The primary outcomes were the proportion of patients reporting ≥50% reduction of index pain. RESULTS: At a mean follow-up time of 16.9 ± 12.7 months, 54% (95% confidence interval [CI] = 35-73%) and 54% (95% CI = 32-74%) of the 80-99% and 100% MBBs groups, respectively, reported ≥50% pain reduction. Between-group comparison showed a relative risk of 0.99 (95% CI = 0.59-1.66) for meeting the primary outcome. Seventy percent (95% CI = 56-81%) of patients reported a PGIC score consistent with "improved or very much improved" at follow-up. CONCLUSIONS: CMBRFA is an effective treatment in patients who report ≥80% symptom relief with dual concordant MBBs. The present study demonstrated an overall ≥50% pain reduction rate of 54% and no significant difference between those selected by 80-99% vs 100% symptom relief with dual concordant MBBs.

The Effectiveness of Radiofrequency Ablation of Medial Branch Nerves for Chronic Lumbar Facet Joint Syndrome in Patients Selected by Guideline-Concordant Dual Comparative Medial Branch Blocks.

OBJECTIVES: Although the effectiveness of lumbar medial branch radiofrequency ablation (RFA) for the treatment of zygapophyseal joint (z-joint)-mediated low back pain has been characterized, few studies have described outcomes in patients selected using a guideline-concordant paradigm of ≥80% pain relief with dual comparative medial branch blocks (MBBs). We investigated long-term treatment outcomes of patients selected according to this paradigm. DESIGN: Cross-sectional cohort study. METHODS: The medical records of 111 consecutive patients were reviewed; 85 met inclusion criteria. A standardized telephone survey was used to capture current numerical rating scale (NRS) and Patient Global Impression of Change (PGIC) scores. The primary outcome was the proportion of patients reporting ≥50% reduction of index pain. Binary logistic regression analysis was performed to explore associations between the primary outcome and covariates, including age, duration of pain, presence of scoliosis, degenerative spondylolisthesis, and >75% disc height loss. RESULTS: At six to 12, 12-24, and >24 months, 63.2% (95% confidence interval [CI] = 41-85%), 65.6% (95% CI = 49-82%), and 44.1% (95% CI = 27-61%) of patients reported a ≥50% pain reduction (P = 0.170), respectively. At a minimum of six months, 70.6% of patients reported a pain reduction of two or more points (minimally clinically important change), and 54.1% reported a PGIC score consistent with "much improved" or better. Older age and a smaller Cobb angle were associated with a ≥50% pain reduction (P < 0.05). CONCLUSION: Lumbar medial branch RFA is an effective, durable treatment for a significant proportion of patients with recalcitrant lumbar z-joint pain when candidacy is determined by the guideline-concordant paradigm of ≥80% pain relief with dual comparative MBBs.

Does the Contrast Dispersion Pattern During Fluoroscopically Guided Cervical Transforaminal Epidural Steroid Injection Predict Short-Term Pain and Functional Outcomes? An Exploratory Analysis of Prospective Cohort Data.

SUMMARY OF BACKGROUND DATA: No study has evaluated the relationship between contrast dispersion patterns and outcomes after fluoroscopically guided cervical transforaminal epidural steroid injection (CTFESI). OBJECTIVES: Determine whether contrast dispersion patterns predict pain and functional outcomes after CTFESI. METHODS: Secondary analysis of data collected during two prospective studies of CTFESI for the treatment of refractory radicular pain. Contrast dispersion patterns visualized by true anteroposterior (AP) projections during CTFESIs were categorized by flow: 1) completely external to the lateral border of the neuroforamen (zone 1); 2) within the neuroforamen but without entry into the lateral epidural space (zone 2); and 3) with extension into the lateral epidural space (zone 3). At baseline and at 1 month post-CTFESI, neck pain, arm pain, and "dominant index pain" (the greater of arm or neck pain) were evaluated using a numeric rating scale (NRS); physical function was assessed using the Five-Item Version of the Neck Disability Index (NDI-5). RESULTS: One-month post-CTFESI, neck pain, arm pain, and "dominant index pain" reductions of ≥50% were observed in 39.4% (95% confidence interval [CI], 28.2-51.8), 55.6% (95% CI, 43.0-67.5), and 44.1% (95% CI, 32.7-56.2) of participants, respectively. Regarding "dominant index pain," 72.7% (95% CI, 40.8-91.2), 39.4% (95% CI, 24.2-57.0), and 37.5% (95% CI, 20.5-58.2) of participants reported ≥50% pain reduction when zone 1, zone 2, and zone 3 contrast flow patterns were observed. Contrast dispersion zone was not significantly associated with subgroup differences in neck pain, arm pain, or NDI-5 scores (P>0.05). CONCLUSION: Improvements in pain and function 1 month after treatment with CTFESI did not differ significantly based on the contrast dispersion pattern. Future study is needed to confirm or refute these findings in other procedural settings, in broader patient populations, and with longer-term outcome assessment.

A Randomized Comparative Trial of Targeted Steroid Injection via Epidural Catheter vs Standard Transforaminal Epidural Injection for the Treatment of Unilateral Cervical Radicular Pain: Six-Month Results.

OBJECTIVES: Compare the effectiveness of catheter-directed cervical interlaminar epidural steroid injection (C-CIESI) with triamcinolone to cervical transforaminal steroid injection (CTFESI) with dexamethasone for the treatment of refractory unilateral radicular pain. DESIGN: Prospective, randomized, comparative trial. METHODS: Primary outcome: proportion of participants with ≥50% numeric rating scale pain score reduction from baseline "dominant pain" (the greater of arm vs neck) at one month postinjection. Secondary outcomes: ≥30% Neck Disability Index (NDI-5) reduction and Patient Global Impression of Change (PGIC) response indicating "much improved" or "very much improved." RESULTS: One hundred twenty participants (55.6% females, 52.3 ± 12.5 years of age, BMI 28.2 ± 6.5 kg/m2), were enrolled. The proportions of participants who experienced ≥50% pain reduction at one, three, and six months were 68.5% (95% CI = 54.9-79.5%), 59.3% (95% CI = 45.7-71.6%), and 60.8% (95% CI = 46.7-73.2%), respectively, in the C-CIESI group compared with 49.1% (95% CI = 36.4-62.0%), 46.4% (95% CI = 33.8-59.6%), and 51.9% (95% CI = 38.4-65.2%), respectively, in the CTFESI group. The between-group difference at one month was significant (P = 0.038). The proportions of participants who experienced a ≥30% NDI-5 score improvement were 64.0% (95% CI = 49.8-76.1%) and 54.9% (95% CI = 41.1-68.0%) in the C-CIESI and CTFESI groups (P = 0.352). Participants reported similar PGIC improvement in both groups: At six months, 53.2% (95% CI 38.9-67.1%) and 54.5% (95% CI = 39.7-68.7%) of the C-CIESI and CTFESI groups reported being "much improved" or "very much improved," respectively (P = 0.897). CONCLUSIONS: Both C-CIESI with triamcinolone and CTFESI with dexamethasone are effective in reducing pain and disability associated with refractory unilateral cervical radiculopathy in a substantial proportion of participants for at least six months.

A Novel Technical Protocol for Improved Capture of the Genicular Nerves by Radiofrequency Ablation.

BACKGROUND: Fluoroscopically guided cooled genicular nerve radiofrequency ablation (RFA) is an increasingly performed procedure for chronic, refractory knee pain due to osteoarthritis. Traditionally, partial sensory denervation has been accomplished through ablation of the superomedial, superolateral, and inferomedial genicular nerves. However, recent cadaveric studies have demonstrated additional sensory nerves and significant anatomic variation that impact current protocols. OBJECTIVE: We describe an updated cooled genicular nerve radiofrequency ablation protocol that accounts for varied nerve location of the superomedial, superolateral, and inferomedial genicular nerves, as well as capture of the terminal articular branches of the nerves to the vastus intermedius, vastus lateralis, and vastus medialis. Furthermore, we describe an adjusted technique for inferomedial genicular nerve capture that mitigates the risk of pes anserine tendon injury. DESIGN: Technical report and brief literature review. METHODS: Cadaveric studies relating to the sensory innervation of the anterior knee joint were reviewed, and a more accurate and comprehensive cooled genicular nerve radiofrequency ablation (CRFA) protocol is proposed. CONCLUSIONS: Based on recent, rigorous anatomic dissections of the knee, the proposed genicular nerve CRFA protocol will provide more complete sensory denervation and potentially improve clinical outcomes. Prospective studies will be needed to confirm the hypothesis that this protocol will result in improved effectiveness and safety of genicular nerve RFA.

The Relationship of PROMIS Pain Interference and Physical Function Scales.

Objectives: To examine the relationship between the Patient Reported Outcome Measurement Information System (PROMIS) Pain Interference (PI) and PROMIS Physical Function (PF) scales in patients with spinal pain at a university spine center. Design: Retrospective analysis of prospectively collected patient-reported outcome data at a university spine clinic. Pearson correlation was done to examine the relationship of the PROMIS PF and PROMIS PI scores. Age, gender, and race were analyzed by subgroups on the PROMIS Physical Function and Pain Interference score. Linear regression analyzed predictive relationships. Statistical significance was set at P < 0.05. Results: A total of 1,992 participants completed an assessment, with 1,923 completing the PF CAT and 1,927 the PI CAT. Participants' mean age was 52.8 years (range = 18-94 years, SD = 6.5 years). Correlation analysis of the PROMIS PF with the PROMIS PI showed a Pearson correlation value of -0.717 (P < 0.05). There was a strong linear relationship with a high negative correlation between PF CAT and PI CAT. The PI CAT predicted PF CAT scores (ß = -0.707, P < 0.001). Conclusions: For patients with pain from spinal origin, there is a strong negative correlation between self-reported physical function and pain interference related to physical, social, and mental health. The predictive relationship of function from pain scores supports the PROMIS PI being used as an important adjunct measure of physical function in patients with spinal pain.

What Are the MCIDs for PROMIS, NDI, and ODI Instruments Among Patients With Spinal Conditions?

BACKGROUND: As new Patient-Reported Outcomes Measurement Information System (PROMIS) instruments are incorporated into clinical practice, determining how large a change on these instruments represents a clinically relevant difference is important; the metric that describes this is the minimum clinically important difference (MCID). Prior research on MCIDs of the Neck Disability Index (NDI) and Oswestry Disability Index (ODI) has produced values ranging from 5 to 10 points, but these measures have not been presented in relation to MCID values of PROMIS instruments. QUESTIONS/PURPOSES: To establish a comprehensive repository of MCID values calculated both with distribution-based and anchor-based methods for four outcomes instruments in spine care, we asked: (1) What are the MCIDs of the PROMIS Physical Function (PF); (2) the PROMIS Pain Interference (PI); (3) the NDI; and (4) the ODI among spine patients? METHODS: We conducted a prospective study of previously tested diagnostic measures on 1945 consecutive patients with a reference standard applied. All patients aged 18 years and older visiting an orthopaedic spine clinic between October 2013 and January 2017 completed the PROMIS PF and PI, NDI, and ODI on tablet computers before their clinic visits. Patients were grouped by change level (self-report of meaningful change versus slight or no change) using an anchor question in comparison to baseline. Descriptive statistics, two anchor-based MCID values (mean change and receiver operating characteristic curve), and five distribution-based values (SD at 1/2 and 1/3 values and minimum detectable change [MDC] at 90%, 95%, and 99%) were analyzed four different times between 3 months and > 6 months of followup. A total of 1945 included patients with a wide range of spine conditions and varying treatments had a mean age of 58 years (SD = 15.5), were 51% (988 of 1945) male, 90% (1754 of 1945) self-identified as white, and 5% (94 of 1945) as Hispanic with 1% to 2% of patients refusing participation. RESULTS: The PROMIS PF mean change scores in the changed group (much worse, worse, improved, or much improved) ranged between 7 and 8 points. MCID values ranged from 3 to 23 points depending on the method of calculation with a median of 8. For the PROMIS PI, mean change scores ranged from 8 to 9 points and MCID values from 1 to 24 points with a median of 8. For the NDI, mean change scores ranged from 13 to 18 points and MCID values ranged from 6 to 43 points with a median of 18. For the ODI, mean change ranged from 17 to 19 points and MCID values ranged from 7 to 51 points with a median of 24. For each instrument, distribution-based SD yielded the smallest values, followed by anchor-based methods, with MDC yielding the largest MCID values. CONCLUSIONS: This study uses a range of methods for determining MCIDs of the PROMIS PF and PI, NDI, and ODI from anchor-based to distribution-based methods. MCIDs do not have a static value for a given outcome measure, but have a range of values and are dependent on the method calculated. The lowest MCIDs identified for the NDI and ODI are consistent with prior studies, but those at the upper range are much higher. Anchor-based methods are thought to be most relevant in the clinical setting and are more easily understood by clinicians, whereas the distribution-based MCIDs are useful in understanding population breadth. Lower MCID values may be most appropriate for screening purposes or low-risk effects, and the median or higher MCID values should be used for high-risk effects or outcomes. LEVEL OF EVIDENCE: Level I, diagnostic study.

Association between wrist ratio and carpal tunnel syndrome: Effect modification by body mass index.

INTRODUCTION: Previous studies have reported higher wrist ratios (WR) related to carpal tunnel syndrome (CTS) but have not assessed effect modification by obesity and may have inadequately controlled for confounders. METHODS: Baseline data of a multicenter prospective cohort study were analyzed. CTS was defined by nerve conduction study (NCS) criteria and symptoms. RESULTS: Among the 1,206 participants, a square-shaped wrist was associated with CTS after controlling for confounders (prevalence ratio = 2.27; 95% confidence interval [95% CI], 1.33-3.86). Body mass index (BMI) was a strong effect modifier on the relationship between WR and both CTS and abnormal NCS results, with normal weight strata of rectangular versus square wrists = 8.18 (95% CI, 1.63-49.96) and 7.12 (95% CI, 2.19-23.16), respectively. DISCUSSION: A square wrist is significantly associated with CTS after controlling for confounders. Effect modification by high BMI masked the eightfold magnitude adjusted relationship seen between WR and CTS among normal weight participants. Muscle Nerve 56: 1047-1053, 2017.

Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.

PURPOSE: Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. CONCLUSION: These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.

Association between Epicondylitis and Cardiovascular Risk Factors in Pooled Occupational Cohorts.

BACKGROUND: The pathophysiology of lateral epicondylitis (LE) is unclear. Recent evidence suggests some common musculoskeletal disorders may have a basis in cardiovascular disease (CVD) risk factors. Thus, we examined CVD risks as potential LE risks. METHODS: Workers (n = 1824) were enrolled in two large prospective studies and underwent structured interviews and physical examinations at baseline. Analysis of pooled baseline data assessed the relationships separately between a modified Framingham Heart Study CVD risk score and three prevalence outcomes of: 1) lateral elbow pain, 2) positive resisted wrist or middle finger extension, and 3) a combination of both symptoms and at least one resisted maneuver. Quantified job exposures, personal and psychosocial confounders were statistically controlled. Odds ratios (ORs) and 95% Confidence Intervals (CIs) were calculated. RESULTS: There was a strong relationship between CVD risk score and lateral elbow symptoms, resisted wrist or middle finger extension and LE after adjustment for confounders. The adjusted ORs for symptoms were as high as 3.81 (95% CI 2.11, 6.85), for positive examination with adjusted odds ratios as high as 2.85 (95% CI 1.59, 5.12) and for combined symptoms and physical examination 6.20 (95% CI 2.04, 18.82). Relationships trended higher with higher CVD risk scores. CONCLUSIONS: These data suggest a potentially modifiable disease mechanism for LE.

Antagonism of Ang-Tie2 and Dll4-Notch signaling has opposing effects on tumor endothelial cell proliferation, evidenced by a new flow cytometry method.

Sustained angiogenesis is essential for tumor growth as it provides the tumor with a network of blood vessels that supply both oxygen and essential nutrients. Limiting tumor-associated angiogenesis is a proven strategy for the treatment of human cancer. To date, the rapid detection and quantitation of tumor-associated endothelial cell (TAEC) proliferation has been challenging, largely due to the low frequency of endothelial cells (ECs) within the tumor microenvironment. In this report, we address this problem using a new multiparametric flow cytometry method capable of rapid and precise quantitation of proliferation by measuring bromodeoxyuridine (BrdUrd) uptake in mouse TAECs from established human tumor xenografts. We determined the basal proliferation labeling index of TAECs in two human tumor xenografts representing two distinct histologies, COLO 205 (colorectal cancer) and U-87 (glioblastoma). We then investigated the effects of two large-molecule antiangiogenic agents targeting different biochemical pathways. Blocking angiopoietin-Tie2 signaling with the peptide-Fc fusion protein, trebananib (AMG 386), inhibited proliferation of TAECs, whereas blocking Dll4-Notch signaling with an anti-Dll4-specific antibody induced hyperproliferation of TAECs. These pharmacodynamic studies highlight the sensitivity and utility of this flow cytometry-based method and demonstrate the value of this assay to rapidly assess the in vivo proliferative effects of angiogenesis-targeted agents on both the tumor and the associated vasculature.

AMG 900, a potent inhibitor of aurora kinases causes pharmacodynamic changes in p-Histone H3 immunoreactivity in human tumor xenografts and proliferating mouse tissues.

BACKGROUND: The Aurora family of serine-threonine kinases are essential regulators of cell division in mammalian cells. Aurora-A and -B expression and kinase activity is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis. AMG 900 is a highly potent and selective pan-aurora kinase inhibitor that has entered clinical evaluation in adult patients with advanced cancers. In mice, oral administration of AMG 900 blocks the phosphorylation of histone H3 on serine-10 (p-Histone H3), a proximal substrate of aurora-B and inhibits the growth of multiple human tumor xenografts, including multidrug-resistant models. METHODS: In order to establish a preclinical pharmacokinetic-pharmacodynamic (PK-PD) relationship for AMG 900 that could be translated to the clinic, we used flow cytometry and laser scanning cytometry detection platforms to assess the effects on p-Histone H3 inhibition in terms of sensitivity, precision, and specificity, in human tumor xenografts in conjunction with mouse skin and bone marrow tissues. Mice with established COLO 205 tumors were administered AMG 900 at 3.75, 7.5, and 15 mg/kg and assessed after 3 hours. RESULTS: Significant suppression of p-Histone H3 in mouse skin was only observed at 15 mg/kg (p <0.0001), whereas in mouse bone marrow and in tumor a dose-dependent inhibition was achieved at all three doses (p ≤ 0.00015). These studies demonstrate that AMG 900 inhibits p-Histone H3 in tumors and surrogate tissues (although tissues such as skin may be less sensitive for assessing PD effects). To further extend our work, we evaluated the feasibility of measuring p-Histone H3 using fine-needle aspirate (FNA) tumor xenograft biopsies. Treatment with AMG 900 significantly inhibited p-Histone H3 (>99% inhibition, p <0.0001) in COLO 205 tumors. Lastly, we illustrate this LSC-based approach can detect p-Histone H3 positive cells using mock FNAs from primary human breast tumor tissues. CONCLUSION: Phosphorylation of histone H3 is a useful biomarker to determine the pharmacodynamics (PD) activity of AMG 900. FNA biopsies may be a viable approach for assessing AMG 900 PD effects in the clinic.

Comparison of HRQL between unicompartmental knee arthroplasty and total knee arthroplasty for the treatment of osteoarthritis.

This retrospective study evaluates the health related quality of life (HRQL) of patients following unicompartmental knee arthroplasty (UKA) compared to total knee arthroplasty (TKA) for osteoarthritis treatment. The Western Ontario and McMaster Osteoarthritis index (WOMAC) and the Oxford Knee score (OKS) were recorded at baseline, 3 and 6 months. Analysis of 317 UKAs and 425 TKAs showed no significant differences in HRQL between the two groups at baseline, but the TKA group was significantly older and more likely to be male. Both groups showed an overall improvement in the total WOMAC and OKS over time, with males showing significant improvement over females. Adjusting for age and gender, there was no significant difference between UKA and TKA in HRQL over the first 6 months following surgery.

Cardiovascular Disease Risk Factors Predict the Development and Numbers of Common Musculoskeletal Disorders in a Prospective Cohort.

OBJECTIVE: The aim of the study is to assess risk of common musculoskeletal disorders (MSDs) based on cardiovascular disease (CVD) risk scores. METHODS: Data from a 9-year prospective cohort of 1224 workers in three states were analyzed. Baseline data included questionnaires, structured interviews, physical examinations, anthropometric measurements, nerve conduction studies, and individualized measurement of job physical factors. Monthly follow-ups were conducted. Framingham risk scores were calculated. A priori case definitions were constructed for carpal tunnel syndrome, lateral epicondylopathy, medial epicondylopathy, and rotator cuff tendinopathy. RESULTS: Adjusted RRs for one or more MSDs increased to 3.90 (95% confidence interval, 2.20-6.90) among those with 10-year cardiovascular disease risk scores greater than 15% and 17.4 (95% confidence interval, 3.85-78.62) among those with more than 4 disorders. CONCLUSIONS: Cardiovascular disease factors are strongly associated with the subsequent development of common MSDs. Risks among those with multiple MSDs are considerably stronger.

HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity.

BACKGROUND: One of the major challenges in chimeric antigen receptor (CAR)-T cell therapy for solid tumors is the potential for on-target off-tumor toxicity due to the expression of CAR tumor antigens in essential tissues and organs. Here, we describe a dual CAR NOT gate incorporating an inhibitory CAR (iCAR) recognizing HLA-A*02 ("A2") that enables effective treatment with a potent HER2 activating CAR (aCAR) in the context of A2 loss of heterozygosity (LOH). METHODS: A CAR-T cell screen was conducted to identify inhibitory domains derived from natural immune receptors (iDomains) to be used in a NOT gate, to kill A2- HER2+ lung cancer cell lines but spare A2+ HER2+ lung cancer cell-lines with high specificity. The extensive analysis of lead candidates included T-cell activation and killing, assays of reversibility and durability in sequential challenges, target cell specificity in mixed 3D spheroids and 2D cultures, and the characterization of CAR expression level and cell-trafficking. RESULTS: A leukocyte immunoglobulin-like receptor B1 (LIR1) iDomain iCAR was identified as most effective in regulating the cytotoxicity of a second generation HER2 aCAR. Target transfer experiments demonstrated that the 'on' and 'off' cell state of the LIR1 NOT gate CAR-T cell is both durable and reversible. Protection required iCAR signaling and was associated with reduced aCAR and iCAR surface expression. iCAR regulation was sufficient to generate high target specificity in a 3D adjacent spheroid assay designed to model the interface between clonal A2 LOH foci and normal tissue. However, we observed significant bystander killing of A2+ cells in admix culture through aCAR dependent and independent mechanisms. LIR1 NOT gate CAR-T cells conferred protection against H1703-A2+ tumors and high efficacy against H1703-A2- tumors in-vivo. We observed that the iCAR is inactive in A2+ donors due to cis-binding, but Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout of HLA-A fully restored iCAR activity. CONCLUSIONS: We have preclinically validated an iCAR NOT gate technology broadly applicable for targeting HER2 expression in the context of A2 LOH. This approach is designed to prevent off tumor toxicity while allowing highly potent antitumor activity.