Clinical outcomes and patient-matched molecular composition of relapsed medulloblastoma

© 2021 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.info:eu-repo/semantics/publishedVersio

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Delayed Union and Nonunion: Current Concepts, Prevention, and Correction: A Review

Surgical management of fractures has advanced with the incorporation of advanced technology, surgical techniques, and regenerative therapies, but delayed bone healing remains a clinical challenge and the prevalence of long bone nonunion ranges from 10 to 15% of surgically managed fractures. Delayed bone healing arises from a combination of mechanical, biological, and systemic factors acting on the site of tissue remodeling, and careful consideration of each case’s injury-related, patient-dependent, surgical, and mechanical risk factors is key to successful bone union. In this review, we describe the biology and biomechanics of delayed bone healing, outline the known risk factors for nonunion development, and introduce modern preventative and corrective therapies targeting fracture nonunion

A dynamic threshold model for terminal investment

Although reproductive strategies can be influenced by a variety of intrinsic and extrinsic factors, life history theory provides a rigorous framework for explaining variation in reproductive effort. The terminal investment hypothesis proposes that a decreased expectation of future reproduction (as might arise from a mortality threat) should precipitate increased investment in current reproduction. Terminal investment has been widely studied, and a variety of intrinsic and extrinsic cues that elicit such a response have been identified across an array of taxa. Although terminal investment is often treated as a static strategy, the level at which a cue of decreased future reproduction is sufficient to trigger increased current reproductive effort (i.e., the terminal investment threshold) may depend on the context, including the internal state of the organism or its current external environment, independent of the cue that triggers a shift in reproductive investment. Here, we review empirical studies that address the terminal investment hypothesis, exploring both the intrinsic and extrinsic factors that mediate its expression. Based on these studies, we propose a novel framework within which to view the strategy of terminal investment, incorporating factors that influence an individual’s residual reproductive value beyond a terminal investment trigger—the dynamic terminal investment threshold

Assessment of Gait Following Locking Plate Fixation of a Tibial Segmental Defect and Cast Immobilization in Goats

The purpose of this study was to analyze the effects of locking plate fixation used for bridging of tibial segmental ostectomy and of cast immobilization on gait biomechanics in goats. We hypothesized that stable fixation of a segmental bone defect, using a locking plate construct, would result in minimal changes in biomechanical variables of gait in goats, but full-limb immobilization would result in lasting alterations in the immobilized limb’s gait kinetics. A pressure-sensing walkway was used to measure biomechanical characteristics for stride, gait, and walking vertical force. Thirteen, non-lame adult Boer-cross goats were trained to walk over a pressure-sensing walkway prior to instrumentation. Segmental ostectomy was performed on the right hind tibia of each goat and the defect was stabilized using bridging plate fixation with a locking compression plate. Per the protocol of an ongoing orthopedic study, the same goats underwent right hindlimb cast immobilization between one and four months postoperatively. Data was collected preoperatively and then over twelve months postoperatively in goats with unrestricted mobility. Statistical analysis revealed no significant alterations in hindlimb kinematics or maximum force when comparing the period after surgery with that after cast immobilization; significant decreases in forelimb stride length and velocity were noted postoperatively but normalized prior to cast placement, suggesting the overall functional stability of fixation. Cast immobilization had a profound and sustained effect on gait with significant alterations in both forelimb kinetics and hindlimb kinetics and kinematics for the remainder of the trial period; increased hindlimb asymmetry characterized by greater weight distribution and impulse to the left hindlimb was observed, suggesting the potential for long-term and/or permanent detrimental effects of prolonged limb immobilization

A Case-Based, Brief, Intensive Interprofessional Education Experience for School Practitioners

Professionals from healthcare and education frequently work together to serve clients in public schools. We devised an interprofessional activity including students in occupational therapy, physical therapy, speech-language pathology, social work, and education in which students designed an interprofessional intervention program for a school child with complex needs. Allied health students who expressed interest in pediatric practice were recruited to participate. Students filled out the Interdisciplinary Education Perception Scale (IEPS), a Likert-scale measure of perceptions about related disciplines, before and after the experience. Quantitative analysis of responses on the IEPS showed a significant improvement in interdisciplinary perceptions after the experience as evidenced by higher IEPS scores. Qualitative analysis using a narrative thematic description of reflections on the experience confirmed this finding. These findings suggest a brief, intensive preservice interprofessional experience can have a positive effect on students\u27 interprofessional attitudes, and points toward aspects of these experiences, including student-led discussions and small group conversations, that students find especially appealing

Changes in tibial cortical dimensions and density associated with long‐term locking plate fixation in goats

Abstract Purpose Cortical porosis, secondary to either vascular injury or stress‐shielding, is a comorbidity of fracture fixation using compression bone plating. Locking plate constructs have unique mechanics of load transmission and lack of reliance on contact pressures for fixation stability, so secondary cortical porosis adjacent to the plate has not been widely investigated. Therefore, this study aimed to assess the effects of long‐term locking plate fixation on cortical dimensions and density in a caprine tibial segmental ostectomy model. Methods Data was acquired from a population of goats enrolled in ongoing orthopedic research which utilized locking plate fixation of 2 cm tibial diaphyseal segmental defects to evaluate bone healing over periods of 3, 6, 9, and 12 months. Quantitative data included tibial cortical width measurements and three‐dimensionally reconstructed slab density measurements, both assessed using computed tomographic examinations performed at the time of plate removal. Additional surgical and demographic variables were analyzed for effect on cortical widths and density, and all cis‐cortex measurements were compared to both the trans‐cortex and to the contralateral limbs. Results The tibial cis‐cortex was significantly wider and more irregular than the trans‐cortex at the same level. This width asymmetry differed in both magnitude and direction from the contralateral limb. The bone underlying the plate was significantly less dense than the trans‐cortex, and this cortical density difference was significantly greater than that of the contralateral limb. These cortical changes were independent of both duration of fixation and degree of ostectomy bone healing. Conclusions This study provides evidence that cortical bone loss consistent with cortical porosity is a comorbidity of locking plate fixation in a caprine tibial ostectomy model. Further research is necessary to identify risk factors for locking‐plate‐associated bone loss and to inform clinical decisions in cases necessitating long‐term locking plate fixation

Replacement of tibialis cranialis tendon with polyester, silicone-coated artificial tendon preserves biomechanical function in rabbits compared to tendon excision only

Abstract Background Artificial tendons may be an effective alternative to autologous and allogenic tendon grafts for repairing critically sized tendon defects. The goal of this study was to quantify the in vivo hindlimb biomechanics (ground contact pressure and sagittal-plane motion) during hopping gait of rabbits having a critically sized tendon defect of the tibialis cranialis and either with or without repair using an artificial tendon. Methods In five rabbits, the tibialis cranialis tendon of the left hindlimb was surgically replaced with a polyester, silicone-coated artificial tendon (PET-SI); five operated control rabbits underwent complete surgical excision of the biological tibialis cranialis tendon in the left hindlimb with no replacement (TE). Results At 8 weeks post-surgery, peak vertical ground contact force in the left hindlimb was statistically significantly less compared to baseline for the TE group (p = 0.0215). Statistical parametric mapping (SPM) analysis showed that, compared to baseline, the knee was significantly more extended during stance at 2 weeks post-surgery and during the swing phase of stride at 2 and 8 weeks post-surgery for the TE group (p < 0.05). Also, the ankle was significantly more plantarflexed during swing at 2 and 8 weeks postoperative for the TE group (p < 0.05). In contrast, there were no significant differences in the SPM analysis among timepoints in the PET-SI group for the knee or ankle. Conclusions Our findings suggest that the artificial tibialis cranialis tendon effectively replaced the biomechanical function of the native tendon. Future studies should investigate (1) effects of artificial tendons on other (e.g., neuromuscular) tissues and systems and (2) biomechanical outcomes when there is a delay between tendon injury and artificial tendon implantation

In vitro analysis and in vivo assessment of fracture complications associated with use of locking plate constructs for stabilization of caprine tibial segmental defects

Abstract Purpose Locking plate fixation of caprine tibial segmental defects is widely utilized for translational modeling of human osteopathology, and it is a useful research model in tissue engineering and orthopedic biomaterials research due to its inherent stability while maintaining unobstructed visualization of the gap defect and associated healing. However, research regarding surgical technique and long-term complications associated with this fixation method are lacking. The goal of this study was to assess the effects of surgeon-selected factors including locking plate length, plate positioning, and relative extent of tibial coverage on fixation failure, in the form of postoperative fracture. Methods In vitro, the effect of plate length was evaluated using single cycle compressive load to failure mechanical testing of locking plate fixations of caprine tibial gap defects. In vivo, effects of plate length, positioning, and relative tibial coverage were evaluated using data from a population of goats enrolled in ongoing orthopedic research which utilized locking plate fixation of 2 cm tibial diaphyseal segmental defects to evaluate bone healing over 3, 6, 9, and 12 months. Results In vitro, no significant differences in maximum compressive load or total strain were noted between fixations using 14 cm locking plates and 18 cm locking plates. In vivo, both plate length and tibial coverage ratio were significantly associated with postoperative fixation failure. The incidence of any cortical fracture in goats stabilized with a 14 cm plate was 57%, as compared with 3% in goats stabilized with an 18 cm plate. Craniocaudal and mediolateral angular positioning variables were not significantly associated with fixation failure. Decreasing distance between the gap defect and the proximal screw of the distal bone segment was associated with increased incidence of fracture, suggesting an effect on proximodistal positioning on overall fixation stability. Conclusions This study emphasizes the differences between in vitro modeling and in vivo application of surgical fixation methods, and, based on the in vivo results, maximization of plate-to-tibia coverage is recommended when using locking plate fixation of the goat tibial segmental defect as a model in orthopedic research