Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy.

The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.

Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma.

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

Impact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes.

Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes.

Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

Outcomes of Patients with Brain Metastases from Renal Cell Carcinoma Receiving First-line Therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Patients with brain metastases (BrM) from renal cell carcinoma and their outcomes are not well characterized owing to frequent exclusion of this population from clinical trials. We analyzed data for patients with or without BrM using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). A total of 389/4799 patients (8.1%) had BrM on initiation of systemic therapy. First-line immuno-oncology (IO)-based combination therapy was associated with longer median overall survival (OS; 32.7 mo, 95% confidence interval [CI] 22.3-not reached) versus tyrosine kinase inhibitor monotherapy (20.6 mo, 95% CI 15.7-24.5; p = 0.019), as were intensive focal therapies with stereotactic radiotherapy or neurosurgery (31.4 mo, 95% CI 22.3-37.5) versus whole-brain radiotherapy alone or no focal therapy (16.5 mo, 95% CI 10.2-21.1; p = 0.028). On multivariable analysis, IO-based regimens (HR 0.49, 95% CI 0.25-0.97; p = 0.040) and stereotactic radiotherapy or neurosurgery (HR 0.48, 95% CI 0.29-0.78; p = 0.003) were independently associated with longer OS, as was IMDC favorable or intermediate risk (HR 0.40, 95% CI 0.24-0.66; p < 0.001). Intensive systemic and focal therapies were associated with better prognosis in this population. Further studies should explore the clinical effectiveness of multimodal strategies. PATIENT SUMMARY: In a large group of patients with advanced kidney cancer, we found that 8.1% had brain metastases when starting systemic therapy. Patients with brain metastases had significantly poorer prognosis than those without brain metastases. Receipt of combination immunotherapy, stereotactic radiotherapy, or neurosurgery was associated with longer overall survival.

Liquid biopsy epigenomic profiling for cancer subtyping.

Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1 ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling.

Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19.

Importance: Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking. Objective: To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer. Design, Setting, and Participants: This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022. Exposure: Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19. Main Outcomes and Measures: Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up. Results: Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13). Conclusions and Relevance: In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer.

Emerging Biomarkers of Response to Systemic Therapies in Metastatic Clear Cell Renal Cell Carcinoma.

Patients with metastatic clear cell renal cell carcinoma (mccRCC) experience highly heterogeneous outcomes when treated with standard-of-care systemic regimens. Therefore, valid biomarkers are needed to predict the clinical response to these therapies and help guide management. In this review, the authors outline relevant and promising biomarkers for patients with mccRCC receiving systemic therapies, with a focus on immunotherapy-based regimens.

Novel Immune Therapies for Renal Cell Carcinoma: Looking Beyond the Programmed Cell Death Protein 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Axes.

Immunotherapy has revolutionized treatment for patients with advanced and metastatic renal cell carcinoma. Nevertheless, many patients do not benefit or eventually relapse, highlighting the need for novel immune targets to overcome primary and acquired resistance. This review discusses 2 strategies currently being investigated: disabling inhibitory stimuli that maintain immunosuppression ("brakes") and priming the immune system to target tumoral cells ("gas pedals"). We explore each class of novel immunotherapy, including the rationale behind it, supporting preclinical and clinical evidence, and limitations.

Novel Targeted Therapies for Renal Cell Carcinoma: Building on the Successes of Vascular Endothelial Growth Factor and mTOR Inhibition.

Targeted therapies have revolutionized the treatment of renal cell carcinoma (RCC). The VHL/HIF pathway is responsible for the regulation of oxygen homeostasis and is frequently altered in RCC. Targeting this pathway as well as the mTOR pathway have yielded remarkable advances in the treatment of RCC. Here, we review the most promising novel targeted therapies for the treatment of RCC, including HIF2α, MET, metabolic targeting, and epigenomic reprogramming.

Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma.

Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.

Functional assessment using 3D movement analysis can better predict health-related quality of life outcomes in patients with adult spinal deformity: a machine learning approach.

Introduction: Adult spinal deformity (ASD) is classically evaluated by health-related quality of life (HRQoL) questionnaires and static radiographic spino-pelvic and global alignment parameters. Recently, 3D movement analysis (3DMA) was used for functional assessment of ASD to objectively quantify patient's independence during daily life activities. The aim of this study was to determine the role of both static and functional assessments in the prediction of HRQoL outcomes using machine learning methods. Methods: ASD patients and controls underwent full-body biplanar low-dose x-rays with 3D reconstruction of skeletal segment as well as 3DMA of gait and filled HRQoL questionnaires: SF-36 physical and mental components (PCS&MCS), Oswestry Disability Index (ODI), Beck's Depression Inventory (BDI), and visual analog scale (VAS) for pain. A random forest machine learning (ML) model was used to predict HRQoL outcomes based on three simulations: (1) radiographic, (2) kinematic, (3) both radiographic and kinematic parameters. Accuracy of prediction and RMSE of the model were evaluated using 10-fold cross validation in each simulation and compared between simulations. The model was also used to investigate the possibility of predicting HRQoL outcomes in ASD after treatment. Results: In total, 173 primary ASD and 57 controls were enrolled; 30 ASD were followed-up after surgical or medical treatment. The first ML simulation had a median accuracy of 83.4%. The second simulation had a median accuracy of 84.7%. The third simulation had a median accuracy of 87%. Simulations 2 and 3 had comparable accuracies of prediction for all HRQoL outcomes and higher predictions compared to Simulation 1 (i.e., accuracy for PCS = 85 ± 5 vs. 88.4 ± 4 and 89.7% ± 4%, for MCS = 83.7 ± 8.3 vs. 86.3 ± 5.6 and 87.7% ± 6.8% for simulations 1, 2 and 3 resp., p < 0.05). Similar results were reported when the 3 simulations were tested on ASD after treatment. Discussion: This study showed that kinematic parameters can better predict HRQoL outcomes than stand-alone classical radiographic parameters, not only for physical but also for mental scores. Moreover, 3DMA was shown to be a good predictive of HRQoL outcomes for ASD follow-up after medical or surgical treatment. Thus, the assessment of ASD patients should no longer rely on radiographs alone but on movement analysis as well.

Impact of COVID-19 in patients on active melanoma therapy and with history of melanoma.

INTRODUCTION: COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors. RESULTS: Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35). CONCLUSIONS: Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors.

Germline variants associated with toxicity to immune checkpoint blockade.

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10-11; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10-8; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10-8, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.

Demographics, Outcomes, and Risk Factors for Patients with Sarcoma and COVID-19: A CCC19-Registry Based Retrospective Cohort Study.

BACKGROUND: Patients with sarcoma often require individualized treatment strategies and are likely to receive aggressive immunosuppressive therapies, which may place them at higher risk for severe COVID-19. We aimed to describe demographics, risk factors, and outcomes for patients with sarcoma and COVID-19. METHODS: We performed a retrospective cohort study of patients with sarcoma and COVID-19 reported to the COVID-19 and Cancer Consortium (CCC19) registry (NCT04354701) from 17 March 2020 to 30 September 2021. Demographics, sarcoma histologic type, treatments, and COVID-19 outcomes were analyzed. RESULTS: of 281 patients, 49% (n = 139) were hospitalized, 33% (n = 93) received supplemental oxygen, 11% (n = 31) were admitted to the ICU, and 6% (n = 16) received mechanical ventilation. A total of 23 (8%) died within 30 days of COVID-19 diagnosis and 44 (16%) died overall at the time of analysis. When evaluated by sarcoma subtype, patients with bone sarcoma and COVID-19 had a higher mortality rate than patients from a matched SEER cohort (13.5% vs 4.4%). Older age, poor performance status, recent systemic anti-cancer therapy, and lung metastases all contributed to higher COVID-19 severity. CONCLUSIONS: Patients with sarcoma have high rates of severe COVID-19 and those with bone sarcoma may have the greatest risk of death.

Alterations of gait kinematics depend on the deformity type in the setting of adult spinal deformity.

PURPOSE: To evaluate 3D kinematic alterations during gait in Adult Spinal Deformity (ASD) subjects with different deformity presentations. METHODS: One hundred nineteen primary ASD (51 ± 19y, 90F), age and sex-matched to 60 controls, underwent 3D gait analysis with subsequent calculation of 3D lower limb, trunk and segmental spine kinematics as well as the gait deviation index (GDI). ASD were classified into three groups: 51 with sagittal malalignment (ASD-Sag: SVA > 50 mm, PT > 25°, and/or PI-LL > 10°), 28 with only frontal deformity (ASD-Front: Cobb > 20°) and 40 with only hyperkyphosis (ASD-HyperTK: TK > 60°). Kinematics were compared between groups. RESULTS: ASD-Sag had a decreased pelvic mobility compared to controls with a decreased ROM of hips (38 vs. 45°) and knees (51 vs. 61°). Furthermore, ASD-Sag exhibited a decreased walking speed (0.8 vs. 1.2 m/s) and GDI (80 vs. 95, all p < 0.05) making them more prone to falls. ASD-HyperTK showed similar patterns but in a less pronounced way. ASD-Front had normal walking patterns. GDI, knee flex/extension and walking speed were significantly associated with SVA and PT (r = 0.30-0.65). CONCLUSION: Sagittal spinal malalignment seems to be the driver of gait alterations in ASD. Patients with higher GT, SVA, PT or PI-LL tended to walk slower, with shorter steps in order to maintain stability with a limited flexibility in the pelvis, hips and knees. These changes were found to a lesser extent in ASD with only hyperkyphosis but not in those with only frontal deformity. 3D gait analysis is an objective tool to evaluate functionality in ASD patients depending on their type of spinal deformity. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.

Reliability assessment of cervical spine parameters measured on full-body radiographs in asymptomatic subjects and patients with spinal deformity.

BACKGROUND: Cervical spinal alignment is usually assessed on full-body radiographs allowing for the concomitant evaluation of possible compensatory mechanisms that may occur at any level in the setting of postural malalignment. HYPOTHESIS: Cervical parameters measured on full-body radiographs are reliable. PATIENTS AND METHODS: A total of 70 subjects were included and divided in 3 groups: asymptomatic adults (n=21), adolescents with idiopathic scoliosis (n=20), and adults with spinal deformity (n=29), for whom full-body low-dose biplanar radiographs were obtained. Eighteen cervical parameters including gaze and cervical curvature, upper cervical spine, global cervical alignment, thoraco-cervical and cervico-pelvic parameters were measured by 4 operators, three times each. The intraclass correlation coefficient (ICC) and the 95% confidence interval (95% CI) where calculated for each parameter and compared between the 3 groups. RESULTS: ICC and the 95% CI were similar between the 3 groups. The measured parameters showed a very high repeatability (ICC>0.8) except for C0-C2, which presented an average repeatability (ICC=0.57). The cSVA, CTPA, C2-SPi, cranial offset, T1-SPi, CBVA and cranial tilt had a 95% CI<2 (° or cm). The TIA, T1-CL and C0-C2 had a 95% CI>6°. DISCUSSION: The poor visibility of the foramen magnum, hard palate, C7, T1, and the sternum on radiographs could explain why certain parameters showed a higher measurement error. The assessment of these error margins is essential for an accurate evaluation of cervical spinal deformities and a proper therapeutic approach. LEVEL OF EVIDENCE: III; retrospective analysis of prospectively collected data.

Gait kinematic alterations in subjects with adult spinal deformity and their radiological determinants.

BACKGROUND: Adults with spinal deformity (ASD) are known to have postural malalignment affecting their quality of life. Classical evaluation and follow-up are usually based on full-body static radiographs and health related quality of life questionnaires. Despite being an essential daily life activity, formal gait assessment lacks in clinical practice. RESEARCH QUESTION: What are the main alterations in gait kinematics of ASD and their radiological determinants? METHODS: 52 ASD and 63 control subjects underwent full-body 3D gait analysis with calculation of joint kinematics and full-body biplanar X-rays with calculation of 3D postural parameters. Kinematics and postural parameters were compared between groups. Determinants of gait alterations among postural radiographic parameters were explored. RESULTS: ASD had increased sagittal vertical axis (SVA:34 ±â€¯59 vs -5 ±â€¯20 mm), pelvic tilt (PT:19 ±â€¯13 vs 11 ±â€¯6°) and frontal Cobb (25 ±â€¯21 vs 4 ±â€¯6°) compared to controls (all p < 0.001). ASD displayed decrease walking speed (0.9 ±â€¯0.3 vs 1.2 ±â€¯0.2 m/s), step length (0.58 ±â€¯0.11 vs 0.64 ±â€¯0.07 m) and increased single support (0.45 ±â€¯0.05 vs 0.42 ±â€¯0.04 s). ASD walked with decreased hip extension in stance (-3 ±â€¯10 vs -7 ±â€¯8°), increased knee flexion at initial contact and in stance (10 ±â€¯11 vs 5 ±â€¯10° and 19 ±â€¯7 vs 16 ±â€¯8° respectively), and decreased knee flexion/extension ROM (55 ±â€¯9 vs 59 ±â€¯7°). ASD had increased trunk flexion (12 ±â€¯12 vs 6 ±â€¯11°) and reduced dynamic lumbar lordosis (-11 ±â€¯12 vs -15 ±â€¯7°, all p < 0.001). Sagittal knee ROM, walking speed and step length were negatively determined by SVA; lack of lumbar lordosis during gait was negatively determined by radiological lumbar lordosis. SIGNIFICANCE: Static compensations in ASD persist during gait, where they exhibit a flexed attitude at the trunk, hips and knees, reduced hip and knee mobility and loss of dynamic lordosis. ASD walked at a slower pace with increased single and double support times that might contribute to their gait stability. These dynamic discrepancies were strongly related to static sagittal malalignment.

Toward understanding the underlying mechanisms of pelvic tilt reserve in adult spinal deformity: the role of the 3D hip orientation.

PURPOSE: To explore 3D hip orientation in standing position in subjects with adult spinal deformity (ASD) presenting with different levels of compensatory mechanisms. METHODS: Subjects with ASD (n = 159) and controls (n = 68) underwent full-body biplanar X-rays with the calculation of 3D spinopelvic, postural and hip parameters. ASD subjects were grouped as ASD with knee flexion (ASD-KF) if they compensated by flexing their knees (knee flexion ≥ 5°), and ASD with knee extension (ASD-KE) otherwise (knee flexion < 5°). Spinopelvic, postural and hip parameters were compared between the three groups. Univariate and multivariate analyses were then computed between spinopelvic and hip parameters. RESULTS: ASD-KF had higher SVA (67 ± 66 mm vs. 2 ± 33 mm and 11 ± 21 mm), PT (27 ± 14° vs. 18 ± 9° and 11 ± 7°) and PI-LL mismatch (20 ± 26° vs - 1 ± 18° and - 13 ± 10°) when compared to ASD-KE and controls (all p < 0.05). ASD-KF also had a more tilted (34 ± 11° vs. 28 ± 9° and 26 ± 7°), anteverted (24 ± 6° vs. 20 ± 5° and 18 ± 4°) and abducted (59 ± 6° vs. 57 ± 4° and 56 ± 4°) acetabulum, with a higher posterior coverage (100 ± 6° vs. 97 ± 7° for ASD-KE) when compared to ASD-KE and controls (all p < 0.05). The main determinants of acetabular tilt, acetabular abduction and anterior acetabular coverage were PT, SVA and LL (adjusted R2 [0.12; 0.5]). CONCLUSIONS: ASD subjects compensating with knee flexion have altered hip orientation, characterized by increased posterior coverage (acetabular anteversion, tilt and posterior coverage) and decreased anterior coverage which can together lead to posterior femoro-acetabular impingement, thus limiting pelvic retroversion. This underlying mechanism could be potentially involved in the hip-spine syndrome.