An Investigation of Subaxial Cervical Spine Trauma and Surgical Treatment through Biomechanical Simulation and Kinematic Analysis

In vitro biomechanical investigations can help to identify changes in subaxial cervical spine (C3-C7) stability following injury, and determine the efficacy of surgical treatments through controlled joint simulation experiments and kinematic analyses. However, with the large spectrum of cervical spine trauma, a large fraction of the potential injuries have not been examined biomechanically. This includes a lack of studies investigating prevalent flexion-distraction injuries. Therefore, the overall objective of this thesis was to investigate the changes in subaxial cervical spine kinematic stability with simulated flexion-distraction injuries and current surgical instrumentation approaches using both established and novel biomechanical techniques. Three in vitro experiments were performed with a custom-designed spinal loading simulator. The first evaluated sequential disruption of the posterior ligaments with and without a simulated facet fracture (n=7). In these specimens, posterior lateral mass screw fixation provided more stability than anterior cervical discectomy and fusion with plating (ACDFP). A second study examined a unilateral facet perch injury by reproducing a flexion-distraction injury mechanism with the simulator (n=9). The resulting soft tissue damage was quantified through meticulous dissection of each specimen, which identified the most commonly injured structures across all specimens as both facet capsules, ¾ of the annulus, and ½ of the ligamentum flavum. This information was used to develop and validate a standardized injury model (SIM) in new specimens (n=10). A final study examined the ACDFP surgical factor of graft size height (bony spacer replacing the intervertebral disc to promote fusion) for the SIM and two other injuries (n=7). Results were motion and injury dependent, which suggests that both these factors must be considered in the surgical decision. Two additional investigations were completed. The first examined mathematical techniques to generate a large number of accurate finite helical axes from six-DOF rigid body tracker output to describe changes in cervical spine kinematic stability. The second explored the effect of boundary conditions and PID control settings on the ability of the current simulator design to reproduce desired loading techniques. Ultimately, it is hoped that these results, and the protocols developed for future investigations, will provide valuable biomechanical evidence for standardized treatment algorithms

DESIGN AND DEVELOPMENT OF IN VITRO TOOLS TO ASSESS FIXATION AND MOTION IN THE SPINE

In vitro biomechanical testing of the spine is an important method for evaluating new surgical methods and components, prior to in vivo implementation. This relies upon special laboratory tools and techniques to create spinal motion and loading similar to those experienced in the body. In this thesis, two different studies were performed to evaluate the effects of spinal fixation and motion. The first study compared the fixation of a novel hollow screw and a conventional solid screw in an in vitro sacral model. Screws were tested in seven cadaveric sacra and subjected to stair-cased cyclic flexion- extension loading to simulate the clinical loading scenario. The hollow screw was less resistant to loosening compared to the solid screw in this model. In the second part of this thesis, a spinal loading simulator was developed as a modification to an existing Instron® materials testing machine to produce motion in a multi-segment spine using applied pure bending moments (i.e. flexibility protocol). A custom-designed 2D optical tracking system was used to record the planar motion achieved. An experimental validation study was performed using the developed apparatus, and showed the device was capable of independently producing repeatable and reproducible spine motions (i.e. flexion-extension, lateral bending, and axial rotation) in a single cadaveric specimen. Future work will focus on the continued development of the simulator for use in the assessment of spinal orthopaedic interventions

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial

Background: The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. // Methods: In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I–III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0–2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. // Findings: Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9–85·6), 5-year overall survival was 81·4% (95% CI 77·2–85·8) with chemoradiotherapy versus 76·1% (71·6–80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51–0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5–80·7) versus 69·1% (63·8–73·8; HR 0·70 [0·52–0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3–26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4–34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55–0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0–2·1) in both groups (HR 0·99 [95% CI 0·06–15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3–2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3–2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17–3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported. // Interpretation: This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival

Influence of graft size on spinal instability with anterior cervical plate fixation following in vitro flexion-distraction injuries

© 2015 Elsevier Inc. Background Context Anterior cervical discectomy and fusion with plating (ACDFP) is commonly used for the treatment of distractive-flexion cervical spine injuries. Despite the prevalence of ACDFP, there is little biomechanical evidence for graft height selection in the unstable trauma scenario. Purpose This study aimed to investigate whether changes in graft height affect the kinematics of instrumented ACDFP C5–C6 motion segments in the context of varying degrees of simulated facet injuries. Study Design In vitro cadaveric biomechanical study was used as study design. Methods Seven C5–C6 motion segments were mounted in a custom spine simulator and taken through flexibility testing in axial rotation, lateral flexion, and flexion-extension. Specimens were first tested intact, followed by a standardized injury model (SIM) for a unilateral facet perch at C5–C6. The stability of the ACDFP approach was then examined with three graft heights (computed tomography-measured disc space height, disc space height undersized by 2.5 mm, and disc space height oversized by 2.5 mm) within three increasing unstable injuries (SIM, an added unilateral facet fracture, and a simulated bilateral facet dislocation injury). Results In all motions, regardless of graft size, ACDFP reduced range of motion (ROM) from the SIM state. For flexion-extension, the oversized graft had a larger decrease in ROM compared with the other graft sizes (p\u3c.05). Between graft sizes and injury states, there were a number of interactions in axial rotation and lateral flexion, where specifically in the most severe injury, the undersized graft had a larger decrease in ROM than the other two sizes (p\u3c.05). Conclusions This study found that graft size did affect the kinematic stability of ACDFP in a series of distractive-flexion injuries; the undersized graft resulted in both facet overlap and locking of the uncovertebral joints leading to decreased ROM in lateral bending and axial rotation, whereas an oversized graft provided larger ROM decreases in flexion-extension. As such, a graft that engages the uncovertebral joint may be more advantageous in providing a rigid environment for fusion with ACDFP