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Open Access Publications from the University of California

Open Access Policy Deposits

This series is automatically populated with publications deposited by UCSF Department of Orthopaedic Surgery researchers in accordance with the University of California’s open access policies. For more information see Open Access Policy Deposits and the UC Publication Management System.

Cover page of Validation of Anticorrelated TGFβ Signaling and Alternative End-Joining DNA Repair Signatures that Predict Response to Genotoxic Cancer Therapy.

Validation of Anticorrelated TGFβ Signaling and Alternative End-Joining DNA Repair Signatures that Predict Response to Genotoxic Cancer Therapy.

(2022)

Purpose

Loss of TGFβ signaling increases error-prone alternative end-joining (alt-EJ) DNA repair. We previously translated this mechanistic relationship as TGFβ and alt-EJ gene expression signatures, which we showed are anticorrelated across cancer types. A score representing anticorrelation, βAlt, predicts patient outcome in response to genotoxic therapy. Here we sought to verify this biology in live specimens and additional datasets.

Experimental design

Human head and neck squamous carcinoma (HNSC) explants were treated in vitro to test whether the signatures report TGFβ signaling, indicated by SMAD2 phosphorylation, and unrepaired DNA damage, indicated by persistent 53BP1 foci after irradiation or olaparib. A custom NanoString assay was implemented to analyze the signatures' expression in explants. Each signature gene was then weighted by its association with functional responses to define a modified score, βAltw, that was retested for association with response to genotoxic therapies in independent datasets.

Results

Most genes in each signature were positively correlated with the expected biological response in tumor explants. Anticorrelation of TGFβ and alt-EJ signatures measured by NanoString was confirmed in explants. βAltw was significantly (P < 0.001) better than βAlt in predicting overall survival in response to genotoxic therapy in The Cancer Genome Atlas (TCGA) pancancer patients and in independent HNSC and ovarian cancer patient datasets.

Conclusions

Association of the TGFβ and alt-EJ signatures with their biological response validates TGFβ competency as a key mediator of DNA repair that can be readily assayed by gene expression. The predictive value of βAltw supports its development to assist in clinical decision making.

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Cover page of Clinical outcomes one year after a digital musculoskeletal (MSK) program: an observational, longitudinal study with nonparticipant comparison group.

Clinical outcomes one year after a digital musculoskeletal (MSK) program: an observational, longitudinal study with nonparticipant comparison group.

(2022)

Background

The evidence base for the impact of digital health on musculoskeletal (MSK) outcomes is growing, but it is unclear how much digital MSK programs address pain and function in the intermediate and long term.

Methods

This observational study of digital MSK program participants versus nonparticipants (n = 2570) examined pain, function, depression, and anxiety at 3, 6, and 12 months, and health care use at 12 months. The intervention group engaged in a digital MSK program that included exercise, education, and coaching for at least 3 months. The nonparticipant group registered, but never started the program. We collected data in app or by emailed survey at 3, 6, and 12 months after registering for the program. We conducted descriptive analyses and unadjusted and adjusted regression modeling.

Results

The odds ratio of achieving a minimally clinically important difference (MCID) in pain improvement for the intervention versus the nonparticipant group was 1.97 (95% CI: 1.28, 3.02; p = .002) at 3 months, 1.44 (95% CI: 0.91, 2.25; p = .11) at 6 months, and 2.06 (95% CI: 1.38, 3.08; p = .004) at 12 months in adjusted models. The odds ratio of achieving a MCID in functional improvement for the intervention versus the nonparticipant group was 1.56 (95% CI: 1.03, 2.38; p = .01) at 3 months, 1.55 (95% CI: 1.02, 2.37; p = .04) at 6 months, and 1.35 (95% CI: 0.89, 2.06, p = 0.16) at 12 months in adjusted models. For those with moderate to severe depression or anxiety at baseline, we observed statistically significant lower odds of moderate to severe depression or anxiety at 3 months, 6 months, and 12 months for the intervention versus the nonparticipant group in adjusted models (p < .05). At 12 months, the percentage with invasive, imaging, and conservative services was higher for the nonparticipant versus intervention group by 5.7, 8.1, and 16.7 percentage points, respectively (p < 0.05).

Conclusions

A digital MSK program may offer participants sustained improvement in pain, depression, and anxiety with concomitant decreases in health care use.

Arthroscopic Single-Portal Suprapectoral Biceps Tenodesis With All-Suture Anchor.

(2022)

Tenodesis of the long head of the biceps tendon can be performed through arthroscopic and open techniques with various fixation methods and at different locations on the humerus. Many techniques have been described, with controversy surrounding the advantages and disadvantages of each. In this Technical Note, we describe an all-arthroscopic, intra-articular, single-portal, suprapectoral biceps tenodesis with an all-suture anchor. This technique also allows for suture passage through the biceps tendon before tenotomy to ensure proper maintenance of the length-tension relationship of the biceps musculotendinous unit.

Upper instrumented vertebra-femoral angle and correlation with proximal junctional kyphosis in adult spinal deformity.

(2022)

Introduction

Although matching lumbar lordosis (LL) with pelvic incidence (PI) is an important surgical goal for adult spinal deformity (ASD), there is concern that overcorrection may lead to proximal junctional kyphosis (PJK). We introduce the upper instrumented vertebra-femoral angle (UIVFA) as a measure of appropriate postoperative position in the setting of lower thoracic to pelvis surgical correction for patients with sagittal imbalance. We hypothesize that a more posterior UIV position in relation to the center of the femoral head is associated with an increased risk of PJK given compensatory hyperkyphosis above the UIV.

Methods

In this retrospective cohort study, adult patients undergoing lower thoracic (T9-T12) to pelvis correction of ASD with a minimum of 2-year follow-up were included. UIVFA was measured as the angle subtended by a line from the UIV centroid to the femoral head center to the vertical axis. Patients who developed PJK and those who did not were compared with preoperative and postoperative UIVFA as well as change between postoperative and preoperative UIVFA (deltaUIVFA).

Results

Of 119 patients included with an average 3.6-year follow-up, 51 (42.9%) had PJK and 24 (20.2%) had PJF. Patients with PJK had significantly higher postoperative UIVFA (12.6 ± 4.8° vs. 9.4 ± 6.6°, p = 0.04), deltaUIVFA (6.1 ± 7.6° vs. 2.1 ± 5.6°, p < 0.01), postoperative pelvic tilt (27.3 ± 9.2 vs. 23.3 ± 11, p = 0.04), postoperative lumbar lordosis (47.7 ± 13.9° vs. 42.4 ± 13.1, p = 0.04) and postoperative thoracic kyphosis (44.9 ± 13.2 vs. 31.6 ± 18.8) than patients without PJK. With multivariate logistic regression, postoperative UIVFA and deltaUIVFA were found to be independent risk factors for PJK (p < 0.05). DeltaUIVFA was found to be an independent risk factor for PJF (p < 0.05). A receiver operating characteristic (ROC) curve for UIVFA as a predictor for PJK was established with an area under the curve of 0.67 (95% CI 0.59-0.76). Per the Youden index, the optimal UIVFA cut-off value is 11.5 degrees.

Conclusion

The more posterior the UIV is from the femoral head center after lower thoracic to pelvis surgical correction for ASD, the more patients are at risk for PJK. The greater the magnitude of posterior translation of the UIV from the femoral head center from preop to postop, the greater the likelihood for PJF.

Gender Influences on Shoulder Arthroplasty.

(2022)

Purpose of review

As the incidence of shoulder arthroplasty continues to increase, there is growing interest in patient-based factors that may predict outcomes. Based on existing literature demonstrating gender-based disparities following total hip and knee arthroplasty, gender may also influence shoulder arthroplasty. The purpose of this review is to discuss the recent literature on the influence of gender on shoulder arthroplasty, focusing on differences in preoperative parameters, perioperative complications, and postoperative outcomes.

Recent findings

While both female and male patients generally benefit from shoulder arthroplasty, several differences may exist in preoperative factors, acute perioperative complications, and postoperative outcomes. Preoperatively, female patients undergo shoulder arthroplasty at an older age compared to their male counterparts. They may also have greater levels of preoperative disability and different preoperative expectations. Perioperatively, female patients may be at increased risk of extended length of stay, postoperative thromboembolic events, and blood transfusion. Postoperatively, female patients may achieve lower postoperative functional scores and decreased range of motion compared to male patients. Differences in postoperative functional scores may be influenced by gender-based differences in activities of daily living. Finally, female patients may be at greater risk for periprosthetic fracture and aseptic loosening while male patients appear to be at greater risk for periprosthetic infection and revision surgery. Current literature on the influence of gender on shoulder arthroplasty is limited and conflicting. Further research is necessary to delineate how gender affects patients at the pre- and postoperative levels to better inform decision-making and outcomes.

Cover page of Mammary Tumor-Derived Transplants as Breast Cancer Models to Evaluate Tumor-Immune Interactions and Therapeutic Responses.

Mammary Tumor-Derived Transplants as Breast Cancer Models to Evaluate Tumor-Immune Interactions and Therapeutic Responses.

(2022)

In breast cancer, the type and distribution of infiltrating immune cells are associated with clinical outcome. Moreover, cancers with abundant tumor-infiltrating lymphocytes (TIL) are more likely to respond to immunotherapy, whereas those in which CD8+ T cells are completely absent (deserts) or excluded are less likely to respond. Detailed understanding of this biology is limited by a lack of preclinical breast cancer models that recapitulate TIL distributions and their associated biology. Here we established mammary tumor-derived transplants (mTDT) from 12 Trp53-null mammary tumors in syngeneic BALB/cJ mice and examined the stability of their growth rate, TIL distribution, and transcriptomic profiles. All mTDTs were estrogen receptor negative. Half of the parental tumors were classified as infiltrated, and the rest were divided between excluded and desert phenotypes. After two orthotopic passages, most (70%) mTDT from infiltrated parents recapitulated this pattern, whereas the desert or excluded parental patterns were maintained in about half of daughter mTDT. Approximately 30% of mTDT gave rise to lung or liver metastases, although metastasis was not associated with a TIL phenotype. Unsupervised transcriptomic analysis clustered mTDT according to their TIL spatial patterns. Infiltrated mTDT transplanted subcutaneously or orthotopically were resistant to anti-PD-L1. Profiling implicated prolonged antigen stimulation and loss of effector function of lymphocytes rather than T-cell exhaustion in the lack of response of infiltrated mTDT to checkpoint blockade. In summary, the molecular diversity and immune complexity of mTDT should facilitate the dissection of mechanisms of breast cancer response to immunotherapies. SIGNIFICANCE: A set of diverse preclinical models of breast cancer is characterized to enable mechanistic dissection of tumor-immune interactions and to improve the efficacy of immunotherapies.

Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy.

(2022)

The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies.

MOntelukast as a potential CHondroprotective treatment following Anterior cruciate ligament reconstruction (MOCHA Trial): study protocol for a double-blind, randomized, placebo-controlled clinical trial.

(2022)

Background

After anterior cruciate ligament (ACL) reconstruction, patient-reported outcomes are improved 10 years post-surgery; however, cytokine concentrations remain elevated years after surgery with over 80% of those with combined ACL and meniscus injuries having posttraumatic osteoarthritis (PTOA) within 10-15 years. The purpose of this multicenter, randomized, placebo-controlled trial is to assess whether a 6-month course of oral montelukast after ACL reconstruction reduces systemic markers of inflammation and biochemical and imaging biomarkers of cartilage degradation.

Methods

We will enroll 30 individuals undergoing primary ACL reconstruction to participate in this IRB-approved multicenter clinical trial. This trial will target those at greatest risk of a more rapid PTOA onset (age range 25-50 with concomitant meniscus injury). Patients will be randomly assigned to a group instructed to take 10 mg of montelukast daily for 6 months following ACL reconstruction or placebo. Patients will be assessed prior to surgery and 1, 6, and 12 months following surgery. To determine if montelukast alters systemic inflammation following surgery, we will compare systemic concentrations of prostaglandin E2, monocyte chemoattractant protein-1, and pro-inflammatory cytokines between groups. We will also compare degradative changes on magnetic resonance imaging (MRI) collected 1 and 12 months following surgery between groups with reductions in early biomarkers of cartilage degradation assessed with urinary biomarkers of type II collagen breakdown and bony remodeling.

Discussion

There is a complex interplay between the pro-inflammatory intra-articular environment, underlying bone remodeling, and progressive cartilage degradation. PTOA affects multiple tissues and appears to be more similar to rheumatoid arthritis than osteoarthritis with respect to inflammation. There is currently no treatment to delay or prevent PTOA after ACL injury. Since there is a larger and more persistent inflammatory response after ACL reconstruction than the initial insult of injury, treatment may need to be initiated after surgery, sustained over a period of time, and target multiple mechanisms in order to successfully alter the disease process. This study will assess whether a 6-month postoperative course of oral montelukast affects multiple PTOA mechanisms. Because montelukast administration can be safely sustained for long durations and offers a low-cost treatment option, should it be proven effective in the current trial, these results can be immediately incorporated into clinical practice.

Trial registration

ClinicalTrials.gov NCT04572256 . Registered on October 1, 2020.

Evaluating Utilization Trends in Adhesive Capsulitis of the Shoulder: A Retrospective Cohort Analysis of a Large Database.

(2022)

Background

Nonoperative and operative treatment modalities have been used for symptom management of adhesive capsulitis, but neither has been shown to significantly alter the long-term natural history.

Purpose/hypothesis

The purpose was to evaluate the current trends in resource and treatment strategy utilization for patients with adhesive capsulitis. It was hypothesized that (1) patients with idiopathic adhesive capsulitis will primarily undergo nonoperative treatment and (2) patients with systemic medical comorbidities will demonstrate relatively higher utilization of nonoperative therapies.

Study design

Cross-sectional study; Level of evidence, 3.

Methods

We searched the Mariner/PearlDiver database for Current Procedural Terminology and International Classification of Diseases codes to identify patients with adhesive capsulitis from 2010 to 2020 and to track their usage of diagnostic and therapeutic modalities, including radiography, magnetic resonance imaging (MRI), physical therapy, surgery, opioids, and injection. Patients with active records 1 year before and 2 years after initial diagnosis of adhesive capsulitis were eligible. Excluded were patients with secondary causes of adhesive capsulitis, such as fracture, infection, prior surgery, or other intra-articular pathology.

Results

The median age of this 165,937-patient cohort was 58 years, with 67% being women. There was a high prevalence of comorbid diabetes (44.2%), thyroid disorder (29.6%), and Dupuytren contracture (1.3%). Within 2 years of diagnosis of adhesive capsulitis, diagnostic and therapeutic modality utilization included radiography (47.2%), opioids (46.7%), physical therapy (43.1%), injection (39.0%), MRI (15.8%), arthroscopic surgery (2.7%), and manipulation under anesthesia (2.5%). Over 68% of the diagnostic and therapeutic modalities were rendered from 3 months before to 3 months after diagnosis. Patients with diabetes, thyroid disorders, tobacco use, and obesity had greater odds for treatment with physical therapy, opioids, radiography, and injection when compared with patients without these comorbidities (odds ratio [OR] range, 1.05-2.21; P < .0001). Patients with diabetes and thyroid disorders had decreased odds for surgery (OR range, 0.88-0.91; P ≤ .003). Patients with Dupuytren contracture had increased odds for all therapeutic modalities (OR range, 1.20-1.68; P < .0001).

Conclusion

Patients with adhesive capsulitis underwent primarily nonoperative treatment, with a high percentage utilizing opioids. The most active periods for treatment were from 3 months before diagnosis to 3 months after, and patients with medical comorbidities were more likely to undergo nonoperative treatment.

Cover page of Best Practice Guidelines for Assessment and Management of Osteoporosis in Adult Patients Undergoing Elective Spinal Reconstruction.

Best Practice Guidelines for Assessment and Management of Osteoporosis in Adult Patients Undergoing Elective Spinal Reconstruction.

(2022)

Study design

Expert consensus study.

Objective

This expert panel was created to establish best practice guidelines to identify and treat patients with poor bone health prior to elective spinal reconstruction.

Summary of background data

Currently, no guidelines exist for the management of osteoporosis and osteopenia in patients undergoing spinal reconstructive surgery. Untreated osteoporosis in spine reconstruction surgery is associated with higher complications and worse outcomes.

Methods

A multidisciplinary panel with 18 experts was assembled including orthopedic and neurological surgeons, endocrinologists, and rheumatologists. Surveys and discussions regarding the current literature were held according to Delphi method until a final set of guidelines was created with over 70% consensus.

Results

Panelists agreed that bone health should be considered in every patient prior to elective spinal reconstruction. All patients above 65 and those under 65 with particular risk factors (chronic glucocorticoid use, high fracture risk or previous fracture, limited mobility, and eight other key factors) should have a formal bone health evaluation prior to undergoing surgery. DXA scans of the hip are preferable due to their wide availability. Opportunistic CT Hounsfield Units of the vertebrae can be useful in identifying poor bone health. In the absence of contraindications, anabolic agents are considered first line therapy due to their bone building properties as compared with antiresorptive medications. Medications should be administered preoperatively for at least 2 months and postoperatively for minimum 8 months.

Conclusion

Based on the consensus of a multidisciplinary panel of experts, we propose best practice guidelines for assessment and treatment of poor bone health prior to elective spinal reconstructive surgery. Patients above age 65 and those with particular risk factors under 65 should undergo formal bone health evaluation. We also established guidelines on perioperative optimization, utility of various diagnostic modalities, and the optimal medical management of bone health in this population.Level of Evidence: 5.