Citations

Abstract Purpose: The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations. Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1–89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites; all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs. 23%; P < 0.001) and improved OS (HR, 0.38; P < 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS (P < 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1–positive tumors were independently associated with higher ORR and longer OS. Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma. Clin Cancer Res; 24(20); 4960–7. ©2018 AACR. See related commentary by Warner and Postow, p. 4915

OBJECTIVEThe long-term effects of surgical fusion on the growing subaxial cervical spine are largely unknown. Recent cross-sectional studies have demonstrated that there is continued growth of the cervical spine through the teenage years. The purpose of this multicenter study was to determine the effects of rigid instrumentation and fusion on the growing subaxial cervical spine by investigating vertical growth, cervical alignment, cervical curvature, and adjacent-segment instability over time.METHODSA total of 15 centers participated in this multi-institutional retrospective study. Cases involving children less than 16 years of age who underwent rigid instrumentation and fusion of the subaxial cervical spine (C-2 and T-1 inclusive) with at least 1 year of clinical and radiographic follow-up were investigated. Charts were reviewed for clinical data. Postoperative and most recent radiographs, CT, and MR images were used to measure vertical growth and assess alignment and stability.RESULTSEighty-one patients were included in the study, with a mean follow-up of 33 months. Ninety-five percent of patients had complete clinical resolution or significant improvement in symptoms. Postoperative cervical kyphosis was seen in only 4 patients (5%), and none developed a swan-neck deformity, unintended adjacent-level fusion, or instability. Of patients with at least 2 years of follow-up, 62% demonstrated growth across the fusion construct. On average, vertical growth was 79% (4-level constructs), 83% (3-level constructs), or 100% (2-level constructs) of expected growth. When comparing the group with continued vertical growth to the one without growth, there were no statistically significant differences in terms of age, sex, underlying etiology, surgical approach, or number of levels fused.CONCLUSIONSContinued vertical growth of the subaxial spine occurs in nearly two-thirds of children after rigid instrumentation and fusion of the subaxial spine. Failure of continued vertical growth is not associated with the patient’s age, sex, underlying etiology, number of levels fused, or surgical approach. Further studies are needed to understand this dichotomy and determine the long-term biomechanical effects of surgery on the growing pediatric cervical spine.

It is unknown whether the greater total work of breathing (WOB) with aging is due to greater elastic and/or resistive WOB. We hypothesized that older compared with younger adults would exhibit a greater total WOB at matched ventilations (V̇e) during graded exercise, secondary to greater inspiratory resistive and elastic as well as expiratory resistive WOB. Older (OA: 60 ± 8 yr; n = 9) and younger (YA: 38 ± 7 yr; n = 9) adults performed an incremental cycling test to volitional fatigue. Esophageal pressure, inspiratory (IRV) and expiratory reserve volumes (ERV), expiratory flow limitation (EFL), and ventilatory variables were measured at matched V̇e (i.e., 25, 50, and 75 l/min) during exercise. The inspiratory resistive and elastic as well as expiratory resistive WOB were quantified using the Otis method. At V̇e of 75 l/min, older adults had greater %EFL and larger tidal volumes to inspiratory capacity but smaller relative IRV ( P ≤ 0.03) than younger adults. Older compared with younger adults had greater total WOB at V̇Eof 50 and 75 l/min (OA: 90 ± 43 vs. YA: 49 ± 21 J/min; P < 0.04 for both). At V̇e of 75 l/min, older adults had greater inspiratory elastic and resistive WOB (OA: 44 ± 27 vs. YA: 24 ± 22 and OA: 23 ± 15 vs. YA: 11 ± 3 J/min, respectively, P < 0.03 for both) and expiratory resistive WOB (OA: 23 ± 19 vs. YA: 14 ± 9 J/min, P = 0.02) than younger adults. These data demonstrate that aging-induced pulmonary alterations result in greater inspiratory elastic and resistive as well as expiratory resistive WOB, which may have implications for the integrated response during exercise.NEW & NOTEWORTHY Aging-induced changes to the pulmonary system result in increased work of breathing (WOB) during exercise. However, it is not known whether this higher WOB with aging is due to differences in elastic and/or resistive WOB. Herein, we demonstrate that older adults exhibited greater inspiratory elastic and resistive as well as expiratory resistive WOB during exercise.

Background: Recent epidemiologic reports have demonstrated rising injury rates in Major League Baseball (MLB) and Minor League Baseball (MiLB). Although several studies have recently been published on specific injuries, the majority of injuries have not yet been formally studied. Purpose: The purpose of this study is to (1) generate a summative analysis of all injuries that occur in MLB and MiLB, (2) identify the 50 most common injuries, and (3) generate focused reports and fact sheets on the characteristics of each of those diagnoses. Study Design: Case series; Level of evidence, 4. Methods: The MLB Health and Injury Tracking System was used to identify injuries occurring in MLB and MiLB players from 2011 to 2016. Injuries were defined as those that occurred during normal baseball activity and resulted in at least 1 day out of play. A multitude of player and injury characteristics were analyzed, and detailed reports of the 50 most commonly occurring injuries were generated. Results: A total of 49,955 injuries occurred during the study period; 45,123 were non–season ending, and they resulted in 722,176 days out of play. The mean (median) days missed per injury was 16 (6) days. Overall, 39.1% of all injuries occurred in pitchers. The upper extremity was involved in 39% of injuries, while 35% occurred in the hip/groin/lower extremity. Surgery was required in 6.5% of cases, and 9.7% of injuries were season ending. Hamstring strains were the most common injury (n = 3337), followed by rotator cuff strain/tear (n = 1874), paralumbar muscle strain (n = 1313), biceps tendinitis (n = 1264), oblique strain (n = 1249), and elbow ulnar collateral ligament injury (n = 1191). The diagnoses that were most likely to end a player’s season were elbow ulnar collateral ligament injury (60% season ending) and superior labrum anterior and posterior tear (50.9% season ending). Conclusion: Contrary to prior reports relying on disabled list data, the annual number of injuries in professional baseball remained steady from 2011 to 2016. Similar trends were noted for the annual number of days missed and mean days missed per injury. Although the mean days missed per injury was high (16), the median was much lower at 6 days.

Background: Although vascularity plays a critical role in healing after ulnar collateral ligament (UCL) reconstruction, intraosseous blood flow to the medial epicondyle (ME) and sublime tubercle remains undefined. Purpose: To quantify vascular disruption caused by tunnel drilling with the modified Jobe and docking techniques for UCL reconstruction. Study Design: Controlled laboratory study. Methods: Eight matched pairs (16 specimens) of fresh-frozen cadaveric upper extremities were randomized to 1 of 2 study groups: docking technique or modified Jobe technique. One elbow in each pair underwent tunnel drilling by the assigned technique, while the contralateral elbow served as a control. Pregadolinium and postgadolinium magnetic resonance imaging were performed to quantify intraosseous vascularity within the ME, trochlea, and proximal ulna. Three-dimensional computed tomography (CT) and gross dissection were performed to assess terminal vessel integrity. Results: Ulnar tunnel drilling had minimal impact on vascularity of the proximal ulna, with maintenance of >95% blood flow for each technique. Perfusion in the ME was reduced 14% (to 86% of baseline) for the docking technique and 60% (to 40% of baseline) for the modified Jobe technique (mean difference, 46%; P = .029). Three-dimensional CT and gross dissection revealed increased disruption of small perforating vessels of the posterior aspect of the ME for the modified Jobe technique. Conclusion: Although tunnel drilling in the sublime tubercle appears to have a minimal effect on intraosseous vascularity of the proximal ulna, both the docking and modified Jobe techniques reduce flow in the ME. This reduction was 4 times greater for the modified Jobe technique, and these findings have important implications for UCL reconstruction surgery. Clinical Relevance: As the rate of revision UCL reconstructions continues to rise, investigation into causes for failure of primary surgery is needed. One potential cause is poor tendon-to-bone healing due to inadequate vascularity. This study quantifies the amount of vascular insult that is incurred in the ME during UCL reconstruction. While vascular insult is only one of many factors that affects the surgical success rate, surgeons performing this procedure should be mindful of this potential for vascular disruption.

AbstractAtopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high‐level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for “the Agency's current thinking on a particular subject.” Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices).

Background: A more detailed assessment of the anatomy of the entire medial ulnar collateral ligament complex (MUCLC) is desired as the rate of medial elbow reconstruction surgery continues to rise. Purpose: To quantify the anatomy of the MUCLC, including the anterior bundle (AB), posterior bundle (PB), and transverse ligament (TL). Study Design: Descriptive laboratory study. Methods: Ten unpaired, fresh-frozen cadaveric elbows underwent 3-dimensional (3D) digitization and computed tomography with 3D reconstruction. Ligament footprint areas and geometries, distances to key bony landmarks, and isometry were determined. A surgeon digitized the visual center of each footprint, and this location was compared with the geometric centroid calculated from the outline of the digitized footprint. Results: The mean surface area of the AB was 324.2 mm 2 , with an origin footprint of 32.3 mm 2 and an elongated insertional footprint of 187.6 mm 2 (length, 29.7 mm). The mean area of the PB was 116.6 mm 2 (origin, 25.9 mm 2 ; insertion, 15.8 mm 2 ), and the mean surface area of the TL was 134.5 mm 2 (origin, 21.2 mm 2 ; insertion, 16.7 mm 2 ). The geometric centroids of all footprints could be predicted within 0.8 to 1.3 mm, with the exception of the AB insertion centroid, which was 7.6 mm distal to the perceived center at the apex of the sublime tubercle. While the PB remained relatively isometric from 0° to 90° of flexion ( P = .606), the AB lengthened by 2.2 mm ( P < .001). Conclusion: Contrary to several historical reports, the insertional footprint of the AB was larger, elongated, and tapered. The TL demonstrated a previously unrecognized expansive soft tissue insertion directly onto the AB, and additional analysis of the biomechanical contribution of this structure is needed. Clinical Relevance: These findings may serve as a foundation for future study of the MUCLC and help refine current surgical reconstruction techniques.

AbstractAimIn contrast to knowledge that heart failure (HF) patients demonstrate peak exercise uncoupling across ventilation, gas exchange and cardiac haemodynamics, whether this dyssynchrony follows that at the exercise on‐transition is unclear. This study tested whether exercise on‐transition temporal lag for ventilation relative to gas exchange and oxygen pulse (O2pulse) couples with effects from abnormal pulmonary gaseous oxygen store (O2store) contributions to O2 to interdependently precipitate persistently elevated ventilatory demand and low oxidative metabolic capacity in HF.MethodsBeat‐to‐beat HR and breath‐to‐breath ventilation and gas exchange were continuously acquired in HF (N = 9, ejection fraction = 30 ± 9%) and matched controls (N = 10) during square‐wave ergometry at 60% O2peak (46 ± 14 vs 125 ± 54‐W, P < .001). Temporal responses across E, O2 and O2pulse were assessed for the exercise on‐transition using single exponential model Phase II on‐kinetic time constants (τ = time to reach 63% steady‐state rise). Breath‐to‐breath gas fractions and respiratory flows were used to determine O2stores.ResultsHF vs controls: τ for E (137 ± 93 vs 74 ± 40‐seconds, P = .03), O2 (60 ± 40 vs 23 ± 5‐seconds, P = .03) and O2pulse (28 ± 18 vs 23 ± 15‐seconds, P = .59). Within HF, τ for E differed from O2pulse (P < .02), but not O2. Exercise E rise (workload indexed) differed in HF vs controls (545 ± 139 vs 309 ± 88‐mL min−1 W−1, P < .001). Exercise on‐transition O2store depletion in HF exceeded controls, generally persisting to end‐exercise.ConclusionThese data suggest HF demonstrated exercise on‐transition O2store depletion (high O2store contribution to O2) coupled with dyssynchronous E, O2 and O2pulse kinetics—not attributable to prolonged cardiac haemodynamics. Persistent high ventilatory demand and low oxidative metabolic capacity in HF may be precipitated by physiological uncoupling occurring within the exercise on‐transition.

PurposeTo build and evaluate a small‐footprint, lightweight, high‐performance 3T MRI scanner for advanced brain imaging with image quality that is equal to or better than conventional whole‐body clinical 3T MRI scanners, while achieving substantial reductions in installation costs.MethodsA conduction‐cooled magnet was developed that uses less than 12 liters of liquid helium in a gas‐charged sealed system, and standard NbTi wire, and weighs approximately 2000 kg. A 42‐cm inner‐diameter gradient coil with asymmetric transverse axes was developed to provide patient access for head and extremity exams, while minimizing magnet‐gradient interactions that adversely affect image quality. The gradient coil was designed to achieve simultaneous operation of 80‐mT/m peak gradient amplitude at a slew rate of 700 T/m/s on each gradient axis using readily available 1‐MVA gradient drivers.ResultsIn a comparison of anatomical imaging in 16 patients using T2‐weighted 3D fluid‐attenuated inversion recovery (FLAIR) between the compact 3T and whole‐body 3T, image quality was assessed as equivalent to or better across several metrics. The ability to fully use a high slew rate of 700 T/m/s simultaneously with 80‐mT/m maximum gradient amplitude resulted in improvements in image quality across EPI, DWI, and anatomical imaging of the brain.ConclusionsThe compact 3T MRI system has been in continuous operation at the Mayo Clinic since March 2016. To date, over 200 patient studies have been completed, including 96 comparison studies with a clinical 3T whole‐body MRI. The increased gradient performance has reliably resulted in consistently improved image quality.