Outcomes for International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Groups in Contemporary First-line Combination Therapies for Metastatic Renal Cell Carcinoma

Immunotherapy; Prognostication; Metastatic renal cell carcinomaImmunoteràpia; Pronòstic; Carcinoma de cèl·lules renals metastàticInmunoterapia; Pronóstico; Carcinoma de células renales metastásicoBackground The combination of immuno-oncology (IO) agents ipilimumab and nivolumab (IPI-NIVO) and vascular endothelial growth factor targeted therapies (VEGF-TT) combined with IO (IO-VEGF) are current standard of care first-line treatments for metastatic renal cell carcinoma (mRCC). Objective To establish real-world clinical benchmarks for IO combination therapies based on the International mRCC Database Consortium (IMDC) criteria. Design, setting, and participants Patients with mRCC who received first-line IPI-NIVO, IO-VEGF, or VEGF-TT from 2002 to 2021 were identified using the IMDC database and stratified according to IMDC risk groups. Outcome measurements and statistical analysis Overall survival (OS), time to next treatment (TTNT), and treatment duration (TD) were calculated using the Kaplan-Meier method and compared between IMDC risk groups within each treatment cohort by the log-rank test. The overall response rate (ORR) was calculated by physician assessment of the best overall response. The primary outcome was OS at 18 mo. Results and limitations In total, 728 patients received IPI-NIVO, 282 IO-VEGF, and 7163 VEGF-TT. The median follow-up times for patients remaining alive were 14.3 mo for IPI-NIVO, 14.9 mo IO-VEGF, and 34.4 mo for VEGF-TT. OS at 18 mo for favorable, intermediate, and poor risk was, respectively, 90%, 78%, and 50% for those receiving IPI-NIVO; 93%, 83%, and 74% for IO-VEGF; and 84%, 64%, and 28% for VEGF-TT. ORRs in favorable-, intermediate-, and poor-risk groups were 41.3%, 40.6%, and 33.0% for those receiving IPI-NIVO; 60.3%, 56.8%, and 40.9% for IO-VEGF; and 39.3%, 33.5%, and 20.9% for VEGF-TT, respectively. The IMDC model stratified patients into statistically distinct risk groups for the three endpoints of OS, TTNT, and TD within each treatment cohort. Limitations of this study were the retrospective design and short follow-up. Conclusions This study demonstrated that the IMDC model continues to risk stratify patients with mRCC treated with contemporary first-line IO combination therapies and provided real-world survival benchmarks

Assessing population diversity in phase III trials of cancer drugs supporting Food and Drug Administration approval in solid tumors

Our study aimed to assess inequities in the clinical trial participation for the selected patient groups. We searched the Food and Drug Administration (FDA) database and extracted phase-III clinical trial data from MEDLINE for each approved drug by the FDA between January 1, 2006, and June 30, 2020. We analyzed the inclusion/exclusion criteria, participation according to gender, ethnic group, performance score, the positivity of HBV and HCV, and HIV, having comorbidities and brain metastasis. We compared the findings with that of the general population by retrieving data from the Surveillance, Epidemiology and End Results (SEER) database. We identified 142 phase III pivotal oncology trials that enrolled 105 397 patients. The proportion of female patients in trials was lower than their relative prevalence in the general population from SEER region (36% vs 49.6%, P < .001). The rates of black patients included were lower than their relative prevalence from SEER region (2.1% vs 9.8%, P < .001). 1.3% and 0.8% of patients had HBV and HCV infections, respectively. The patients' numbers with organ dysfunction were not established due to insufficient data from clinical trials. 1.6% of all patients had controlled brain metastasis. Black patients, women and patients with brain metastasis or with HBV and HCV were underrepresented. Our study underscores the importance of expanding the inclusion/exclusion criteria of pivotal oncology trials to be more representative of patients seen in clinical practice

How do 3D skeletal parameters and demographics determine kinematic adaptation from normal to fast speed gait?

The occurrence of falls during gait in elderly people is an important source of morbidity [1]. One of the useful screening tests for falls is the kinematic analysis of fast walking, that identifies subjects with risk of multiple falls [2]. Although the kinematic adaptations from normal to fast speed gait have been studied in asymptomatic adults [3], the demographic and skeletal determinants of these adaptations are still unknown

How do 3D skeletal parameters influence kinetics?

Lower limb joints are subject to mechanical load during daily activities, such as gait, which is an important risk factor of osteoarthritis. Moreover, kinetics are known to be influenced by gait alterations in patients with osteoarthritis [1]. While skeletal parameters are known to determine gait kinematics [2], it is still unknown how skeletal parameters influence kinetic parameters

The variation of lateral and posterior coverage of the femoral head by the acetabulum during walking influences stability during gait

1. Introduction Gait balance, assessed by the angle formed between the line joining the center-of-mass (COM) to the center-of-pressure (COP) and the vertical during gait, has been shown to be related to skeletal-postural and anthro- pometric parameters [1]. Although skeletal-postural parameters are mea- sured on standing radiographs, they are known to vary during gait. There are currently no studies evaluating how the variations of skeletal-postural parameters during gait influence subject’s balance during walking. 2. Research question How does the variation of skeletal-postural parameters during gait influence subject’s balance during walking? 3. Methods 72 asymptomatic subjects (age: 28.6 ± 11 years [18–59], 29F) underwent 3D gait analysis [2] with additional markers on the thighs and shanks. The COM-COP angle with the vertical was calculated in both the frontal and sagittal planes during the gait cycle [3] (Fig. 1). Subjects then underwent low-dose full-body biplanar X-rays with the markers still in place. 3D reconstructions were obtained for the spine, pelvis and lower limbs. 3D bones were registered at each frame of the gait cycle [4]. A new technique developed for this study, utilizing finite element modelling, was used to reduce soft tissue artefacts. Skeletal- postural parameters were then computed during the gait cycle, using the 3D registered bones, at each time frame (Fig. 2); mean, minimum, maximum and ROM were calculated on the waveforms during the gait cycle. In order to determine which varying skeletal-postural parameter during gait determined the variation of the COM-COP angles, univariate analysis (Pearson’s correlation) followed by a multivariate analysis (stepwise-multiple-linear-regression models) were computed; COM- COP parameters were the dependant variables and varying skeletal- postural parameters during gait were the independent variables. 4. Results Minimum (−14.2 ± 3.4°) and average (3.1 ± 1.6°) of the sagittal COM-COP angle were found to be determined by the minimum of the posterior coverage (post_cov) of the femoral head by the acetabulum during gait (β = 0.40; R2 = 0.16; p = 0.003 and β = 0.32; R2 = 0.1; p = 0.001,respectively).ROM(33.9 ± 5.1°)andmaximum (19.7 ± 2.8°) of the sagittal COM-COP angle were found to be related to the ROM (β = 0.29; R2 = 0.09; p = 0.03) and maximum (β = 0.34; R2 = 0.11; p = 0.006) of the acetabular abduction during gait, re- spectively. ROM of the frontal COM-COP angle (8.8 ± 2.51°) was found to be determined by the average of the post_cov (β = 0.51; R2 = 0.26; p = 0.004) during gait. 5. Discussion This is the first study to evaluate how the variation of skeletal- postural parameters during walking influences the stability during gait (Fig. 3). A less pronounced posterior coverage of the acetabulum during gait predisposes to more instability by decreasing the minimum COM- COP angle; a more pronounced acetabular abduction (decreased lateral coverage) during gait predisposes to more instability by increasing the ROM and the maximum of the COM-COP angle. Therefore, gait in- stability in the sagittal plane seems to be influenced by the variation of the posterior and lateral coverage of the femoral head by the acet- abulum during walking

How does the variation of the 3D orientation of the acetabulum during walking influence hip kinematics?

Acetabular cup orientation is crucial for total hip arthroplasty (THA), and its malpositioning could lead to impingement and dislocation [1]. Acetabular cup orientation currently relies on static 3D hip parameters [2] and was shown to be related to changes in pelvic positioning [3]. While pelvic position varies during walking, it is still unknown how dynamic variation of hip orientation during gait could influence hip kinematics

How do skeletal and postural parameters contribute to maintain balance during walking?

Introduction: Maintaining balance during gait allows subjects to minimize energy expenditure and avoid falls. Gait balance can be measured by assessing the relationship between the center of mass (COM) and center of pressure (COP) during gait. Demographics, skeletal and postural parameters are known to influence gait balance. Purpose: What are the determinants of dynamic balance during gait in asymptomatic adults among skeletal and demographic parameters? Methods: 115 adults underwent 3D gait analysis and full-body biplanar X-rays. Angles between the COM-COP line and the vertical were calculated in frontal and sagittal planes during gait: maxima, minima, and ROM were evaluated. Full-body 3D reconstructions were obtained; skeletal and postural parameters of the spine (lumbar lordosis, thoracic kyphosis, sagittal vertical axis SVA), pelvis (pelvic tilt and incidence, acetabular orientation in the 3 planes) and lower limbs (neck shaft angle femoral and tibial torsions) were calculated. A univariate followed by a multivariate analysis were computed between the COM-COP parameters and skeletal and demographic parameters. Results: The univariate analysis showed that in the frontal plane, maximum (4.6°) of the COMCOP angle was significantly correlated with weight (r =0.53), age (r =0.28), height (r = 0.35), SVA (r = 0.23), T1T12 (r = 0.24) and pelvic width (r = 0.25).In the sagittal plane, maximum COM-COP (19.7 ± 2.8°) angle was significantly correlated to acetabular tilt (r = 0.25) and acetabular anteversion (r =0.21). The multivariate analysis showed that, in the frontal plane, an increase in the maximum of the COM-COP angle was determined by a decreasing height (β = −0.28), an increasing weight (β = 0.48), being a male (β = −0.42), and an increasing posterior acetabular coverage (β = 0.22). In the sagittal plane, an increasing maximum COMCOP angle was determined by a decreasing height (β = −0.38) and an increasing SVA (β = 0.19). Conclusion: Frontal imbalance appeared to be mainly correlated to demographic parameters. Sagittal imbalance was found to be correlated with weight, height, acetabular parameters and SVA. These results suggest that in addition to demographic parameters, acetabular parameters and SVA are important determinants of balance during gait.This research was funded by the University of Saint-Joseph (grant FM183). The funding source did not intervene in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication

Influence of Spino-Pelvic and Postural Alignment Parameters on Gait Kinematics

Introduction: Postural alignment is altered with spine deformities that might occur with age. Alteration of spino-pelvic and postural alignment parameters are known to affect daily life activities such as gait. It is still unknown how spino-pelvic and postural alignment parameters are related to gait kinematics. Research question: To assess the relationships between spino-pelvic/postural alignment parameters and gait kinematics in asymptomatic adults. Methods: 134 asymptomatic subjects (aged 18-59 years) underwent 3D gait analysis, from which kinematics of the pelvis and lower limbs were extracted in the 3 planes. Subjects then underwent full-body biplanar X-rays, from which skeletal 3D reconstructions and spino-pelvic and postural alignment parameters were obtained such as sagittal vertical axis (SVA), center of auditory meatus to hip axis plumbline (CAM-HA), thoracic kyphosis (TK) and radiologic pelvic tilt (rPT). In order to assess the influence of spino-pelvic and postural alignment parameters on gait kinematics a univariate followed by a multivariate analysis were performed. Results: SVA was related to knee flexion during loading response (β = 0.268); CAM-HA to ROM pelvic obliquity (β = -0.19); rPT to mean pelvic tilt (β = -0.185) and ROM pelvic obliquity (β = -0.297); TK to ROM hip flexion/extension in stance (β = -0.17), mean foot progression in stance (β = -0.329), walking speed (β = -0.19), foot off (β = 0.223) and step length (β = -0.181). Significance: This study showed that increasing SVA, CAM-HA, TK and rPT, which is known to occur in adults with spinal deformities, could alter gait kinematics. Increases in these parameters, even in asymptomatic subjects, were related to a retroverted pelvis during gait, a reduced pelvic obliquity and hip flexion/extension mobility, an increased knee flexion during loading response as well as an increase in external foot progression angle. This was associated with a decrease in the walking pace: reduced speed, step length and longer stance phase

Is the apical vertebra the most rotated vertebra in the scoliotic curve ?

OBJECTIVE The aim of this study was to determine if the apical vertebra (AV) in patients with adolescent idiopathic scoliosis (AIS) is the most rotated vertebra in the scoliotic segment. METHODS A total of 158 patients with AIS (Cobb angle range 20°–101°) underwent biplanar radiography with 3D reconstructions of the spine and calculation of vertebral axial rotations. The type of major curvature was recorded (thoracic, thoracolumbar, or lumbar), and both major and minor curvatures were included. The difference of levels (DL) between the level of maximal vertebral rotation (LMVR) and the AV was calculated as follows: DL = 0 if LMVR and AV were the same, DL = 1 if LMVR was directly above or below the AV, and DL = 2 if LMVR was separated by 1 vertebra or more from the AV. To investigate which factors explained the divergence of the LMVR from the AV, multinomial models were computed. RESULTS The distribution of the DL was as follows: for major curvatures, 143 were DL = 0, 11 were DL = 1, and 4 were DL = 2; and for minor curvatures, 53 were DL = 0, 9 were DL = 1, and 31 were DL = 2. The determinants of a DL = 2 (compared with DL = 0) were lumbar curvature (compared with thoracic; adjusted OR 0.094, p = 0.001), major curvature (compared with minor; adjusted OR 0.116, p = 0.001), and curvatures with increasing apical vertebral rotation (adjusted OR 0.788, p < 0.001). CONCLUSIONS This study showed that the AV is the most rotated vertebra in the majority of major curvatures, while in minor curvatures, the most rotated vertebra appears to be the junctional vertebra between major and minor curvatures in a significant proportion of cases

Alterations of 3D acetabular and lower limb parameters in adolescent idiopathic scoliosis

Purpose: To evaluate the 3D deformity of the acetabula and lower limbs in subjects with adolescent idiopathic scoliosis (AIS) and their relationship with spino-pelvic alignment. Methods: Two hundred and seventy-four subjects with AIS (frontal Cobb: 33.5° ± 18° [10°-110°]) and 84 controls were enrolled. All subjects underwent full-body biplanar X-rays with subsequent 3D reconstructions. Classic spino-pelvic and lower limb parameters were collected as well as acetabular parameters: acetabular orientation in the 3 planes (tilt, anteversion and abduction), center-edge angle (CEA) and anterior and posterior sector angles. Subjects with AIS were represented by both lower limb sides and classified by elevated (ES) or lowered (LS), depending on the frontal pelvic obliquity. Parameters were then compared between groups. Determinants of acetabular and lower limb alterations were investigated among spino-pelvic parameters. Results: Acetabular abduction was higher on the ES in AIS (59.2° ± 6°) when compared to both LS (55.6° ± 6°) and controls (57.5° ± 3.9°, p < 0.001). CEA and acetabular anteversion were higher on the LS in AIS (32° ± 6.1°, 20.5° ± 5.7°) when compared to both ES (28.7° ± 5.1°, 19.8° ± 5.1°) and controls (29.8° ± 4.8°, 19.1° ± 4°, respectively, p < 0.001). Anterior sector angle was lower on both ES and LS in AIS when compared to controls. CEA, acetabular abduction and acetabular anteversion were found to be mostly determined (adjusted R2: 0.08-0.32) by pelvic tilt and less by frontal pelvic obliquity, frontal Cobb and T1T12. Conclusions: Subjects with AIS had a more abducted acetabulum at the lowered side, more anteverted acetabulum and a lack of anterior coverage of both acetabula. These alterations were strongly related to pelvic tilt.This study was funded by the University of Saint-Joseph (Grant No. FM300)