Additional consensus recommendations for conducting complex innovative trials of oncology agents: a post-pandemic perspective.

In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.

Is Sacral Dysmorphism Protective Against Spinopelvic Dissociation? Multicenter Case Series.

OBJECTIVES: Investigate the incidence of sacral dysmorphism (SD) in patients with spinopelvic dissociation (SPD). DESIGN: Retrospective case series. SETTING: Two academic level 1 trauma centers. PATIENTS/PARTICIPANTS: One thousand eight hundred fifty adult patients with sacral and pelvic fractures (OTA/AO 61-A, B, C). INTERVENTION: Plain pelvic radiographs and CT scans. MAIN OUTCOME MEASUREMENTS: Incidence of SD in patients with SPD. Secondary radiographic evaluation of fracture classification and deformity on sagittal imaging. RESULTS: Eighty-two patients with SPD were identified, and 12.2% displayed features of SD, significantly less than reported in the literature. The S2 sacral body was the most common horizontal fracture location in patients with SD and nondysmorphic sacra (ND). Roy-Camille type I patterns were more common in ND (35%), versus type II in SD patients (40%). SD patients had lower body mass indexes (19.7 vs. 25.2, P = 0.001). Segmental kyphosis (22.5 degrees ND vs. 23.8 degrees SD, P = 0.838) and sacral kyphosis (26 degrees ND vs. 31 degrees SD, P = 0.605) were similar between groups. Percutaneous fixation was the most common surgical technique. CONCLUSIONS: We report a significantly lower prevalence of SD in patients with SPD than previously reported in the literature. This suggests that variations in sacral osseous anatomy alter force transmission across the sacrum during traumatic loading, which may be protective against certain high-energy fracture patterns. Preoperative evaluation of sacral anatomy is critical, not only in determining the size and orientation of sacral segment safe zones for screw placement, but also to better understand the pathomechanics involved in sacral trauma. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Complications After Pelvic Arteriography in Patients With Pelvic Ring Disruptions.

INTRODUCTION: Pelvic angiography with transcatheter arterial embolization (TAE) is an established intervention for management of pelvic arterial hemorrhage. This study analyzes complication rates after angiography among patients with pelvic trauma treated in the context of a multidisciplinary institutional pelvic fracture protocol. METHODS: Retrospective analysis of prospectively collected data was conducted. Demographics, fracture type, embolization (ie, unilateral versus bilateral and selective versus nonselective), and complications (ie, pseudoaneurysm, renal failure, soft-tissue necrosis/infection, and anaphylactic reactions) were noted. RESULTS: Eighty-one patients with pelvic ring injuries underwent angiography from 2009 to 2013. Complications among 41 patients who underwent angiography with TAE were compared with a control group of 40 patients who underwent angiography without TAE. Eight of 41 patients with TAE had complications (19.5%) compared with 3 of 40 (7.5%) in the control group (P = 0.19). The overall complication rate was 13.6%. CONCLUSION: The use of angiography with TAE as part of an institutional pelvic fracture protocol involves an acceptable rate of complications. LEVEL OF EVIDENCE: III.

Age-Dependent Schwann Cell Phenotype Regulation Following Peripheral Nerve Injury.

BACKGROUND: Schwann cells are integral to the regenerative capacity of the peripheral nervous system, which declines after adolescence. The mechanisms underlying this decline are poorly understood. This study sought to compare the protein expression of Notch, c-Jun, and Krox-20 after nerve crush injury in adolescent and young adult rats. We hypothesized that these Schwann cell myelinating regulatory factors are down-regulated after nerve injury in an age-dependent fashion. METHODS: Adolescent (2 months old) and young adult (12 months old) rats (n = 48) underwent sciatic nerve crush injury. Protein expression of Notch, c-Jun, and Krox-20 was quantified by Western blot analysis at 1, 3, and 7 days post-injury. Functional recovery was assessed in a separate group of animals (n = 8) by gait analysis (sciatic functional index) and electromyography (compound motor action potential) over an 8-week post-injury period. RESULTS: Young adult rats demonstrated a trend of delayed onset of the dedifferentiating regulatory factors, Notch and c-Jun, corresponding to the delayed functional recovery observed in young adult rats compared to adolescent rats. Compound motor action potential area was significantly greater in adolescent rats relative to young adult rats, while amplitude and velocity trended toward statistical significance. CONCLUSIONS: The process of Schwann cell dedifferentiation following peripheral nerve injury shows different trends with age. These trends of delayed onset of key regulatory factors responsible for Schwann cell myelination may be one of many possible factors mediating the significant differences in functional recovery between adolescent and young adult rats following peripheral nerve injury.

Reliable Method for Avoiding Malrotation Deformity After Intramedullary Nailing of Comminuted Femur Fractures: Clinical Validation of a Previously Described Technique.

OBJECTIVES: To evaluate a previously described technique using the inherent anteversion of intramedullary nail (IMN) to avoid malrotation in comminuted femur fractures and describe the use of magnetic resonance imaging (MRI) as an alternative method for assessing postoperative femoral version. DESIGN: Prospective consecutive cohort study. SETTING: Level I trauma center. PATIENT/PARTICIPANTS: Twenty-five consecutive patients with comminuted femur fractures (Winquist III/IV, OTA/AO 32-B/32-C) treated by a single surgeon with IMN between September 1, 2011, and February 28, 2015. INTERVENTION: IMN on a fracture table with intraoperative femoral version set by the inherent version of the implant. All patients received a postoperative computed tomography (CT) or MRI to assess femoral version. MAIN OUTCOME MEASUREMENTS: Mean difference in postoperative femoral anteversion (DFA) between injured limb and uninjured limb as measured by CT or MRI. Mean difference in postoperative femoral version of the injured femur from the inherent version of the implant (12 degrees) was measured with CT or MRI. RESULTS: The mean postoperative DFA was 9.1 ± 5.6 degrees. Postoperative DFA greater than 15 degrees was found in 2 (8.0%) patients. Mean difference in postoperative version of the injured femur from the inherent 12 degrees of the implant was 7.1 ± 5.4 degrees. Patients tolerated MRI studies well. CONCLUSIONS: Our previously described technique using the inherent anteversion of an IMN is effective and leads to a very low rate of malrotation, even in highly comminuted fractures. The technique is particularly useful in treating bilateral femur fractures. MRI can be used safely and effectively to assess anteversion after fixation of femur fractures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Finding Value in Surgical Didactics: Longitudinal Resident Feedback From Case-Based and Traditional Lectures in an Orthopaedic Residency.

OBJECTIVE: To evaluate orthopedic resident perceptions of a didactic curriculum presented in traditional and case-based formats. DESIGN: Prospective cohort study using anonymous web-based survey after each conference evaluating resident perceptions of faculty participation, didactic delivery, content, and overall conference value. Conferences were structured as primarily case-based or traditional lecture. Logistic analysis was performed to determine factors predictive of rating a conference as valuable time spent. SETTING: Orthopedic residency training program at single institution over an academic year. PARTICIPANTS: Orthopedic residents in postgraduate training year 1 to 5 attending mandatory didactic conference. RESULTS: Cased-based conferences received higher Likert ratings on residents' perception of faculty participation, instructor delivery, and improvement in topic understanding when compared to traditional lecture-based conferences (p < 0.0001 for each factor). Residents also were more likely to rate case-based conferences as valuable time spent (p < 0.0001). In our logistic model, factors associated with a negative likelihood of rating a conference as valuable were lecture format (odds ratio [OR] = 0.155, 95% CI: 0.115-0.208), PGY-2 level presenter (OR = 0.288, 95% CI: 0.169-0.490), and PGY-3 level presenter (OR = 0.433, 95% CI: 0.269-0.696). Timing in the year, surgical subspeciality, and conference identity were not significant predictors of conference value rating. CONCLUSIONS: Longitudinal resident feedback demonstrates highly favorable resident perceptions toward case-based formats in didactic sessions. Junior levels residents are not perceived as effective as senior residents and faculty in presenting material in either format. These methods allow for a dynamic approach to identifying strengths and weaknesses in a resident curriculum as a well as a means for more focused and real-time improvements.

Effects of age and insulin-like growth factor-1 on rat neurotrophin receptor expression after nerve injury.

INTRODUCTION: Neurotrophin receptors, such as p75(NTR) , direct neuronal response to injury. Insulin-like growth factor-1 receptor (IGF-1R) mediates the increase in p75(NTR) during aging. The aim of this study was to examine the effect of aging and insulin-like growth factor-1 (IGF-1) treatment on recovery after peripheral nerve injury. METHODS: Young and aged rats underwent tibial nerve transection with either local saline or IGF-1 treatment. Neurotrophin receptor mRNA and protein expression were quantified. RESULTS: Aged rats expressed elevated baseline IGF-1R (34% higher, P = 0.01) and p75(NTR) (68% higher, P < 0.01) compared with young rats. Post-injury, aged animals expressed significantly higher p75(NTR) levels (68.5% above baseline at 4 weeks). IGF-1 treatment suppressed p75(NTR) gene expression at 4 weeks (17.2% above baseline, P = 0.002) post-injury. CONCLUSIONS: Local IGF-1 treatment reverses age-related declines in recovery after peripheral nerve injuries by suppressing p75(NTR) upregulation and pro-apoptotic complexes. IGF-1 may be considered a viable adjuvant therapy to current treatment modalities. Muscle Nerve 54: 769-775, 2016.

Spinopelvic dissociation: multidetector computed tomographic evaluation of fracture patterns and associated injuries at a single level 1 trauma center.

The objective of the present study is to evaluate multidetector computed tomographic (MDCT) fracture patterns and associated injuries in patients with spinopelvic dissociation (SPD). Our institutional trauma registry database was reviewed from Jan. 1, 2006, to Sept. 30, 2012, specifically evaluating patients with sacral fractures. MDCT scans of patients with sacral fractures were reviewed to determine the presence of SPD. SPD cases were characterized into the following fracture patterns: U-shaped, Y-shaped, T-shaped, H-shaped, and burst. The following MDCT features were recorded: level of the horizontal fracture, location of vertical fracture, kyphosis between major fracture fragments, displacement of fracture fragment, narrowing of central spinal canal, narrowing of neural foramina, and extension into sacroiliac joints. Quantitative evaluation of the sacral fractures was performed in accordance with the consensus statement by the Spine Trauma Study Group. Medical records were reviewed to determine associated pelvic and non-pelvic fractures, bladder and bowel injuries, nerve injuries, and type of surgical intervention. Twenty-one patients had SPD, of whom 13 were men and eight were women. Mean age was 41.8 years (range 18.8 to 87.7). Five fractures (24 %) were U-shaped, six (29 %) H-shaped, four (19 %) Y-shaped, and six (29 %) burst. Nine patients (43 %) had central canal narrowing, and 19 (90 %) had neural foramina narrowing. Eleven patients (52 %) had kyphotic angulation between major fracture fragments, and seven patients (33 %) had either anterior (24 %) or posterior (10 %) displacement of the proximal fracture fragment. Fourteen patients (67 %) had associated pelvic fractures, and 20 (95 %) had associated non-pelvic fractures. Two patients (10 %) had associated urethral injuries, and one (5 %) had an associated colon injury. Seven patients (33 %) had associated nerve injuries. Six patients (29 %) had surgical fixation while 15 (71 %) were managed non-operatively. On trauma MDCT examinations, patients with SPD have characteristic fracture patterns. It is important to differentiate SPD from other pelvic ring injuries due to high rate of associated injuries. Although all SPD injuries are unstable and need fixation, the decision for operative management in an individual patient depends on the systemic injury pattern, specific fracture pattern, and the ability to attain stable screw fixation.

A chronically-denervated versus a freshly-harvested autograft for nerve repair in rats.

OBJECTIVES: Autologous nerve grafting remains the gold standard for repair of peripheral nerve injuries. Its use, however, is limited by donor nerve availability and donor site morbidity. This is especially problematic after failure of an initial autograft that requires a repeat nerve graft, resulting in a second surgical site with associated morbidity. Based on the molecular differences in nerve degeneration in the proximal and distal segments after transection, we hypothesized that a chronically-denervated proximal stump may be viable for autologous nerve repair. METHODS: 20 Sprague-Dawley rats underwent right sciatic nerve excision and sural nerve transection. After 8 weeks, nerve repair was performed by harvesting the proximal segment of the sural nerve (n=10) or a fresh sural nerve (n=10) from the contralateral hind limb. Electrophysiological changes were analyzed to compare the fresh and denervated grafts. RESULTS: Electrophysiological testing demonstrated higher compound motor action potential in the denervated group compared to the fresh autograft group, however this difference was not statistically significant (p=0.117). CONCLUSION: The proximal segment of a chronically-denervated sural nerve can be as effective as a fresh sural nerve for autologous repair of peripheral nerve injuries in a rodent model.

A human hair keratin hydrogel scaffold enhances median nerve regeneration in nonhuman primates: an electrophysiological and histological study.

A human hair keratin biomaterial hydrogel scaffold was evaluated as a nerve conduit luminal filler following median nerve transection injury in 10 Macaca fascicularis nonhuman primates (NHP). A 1 cm nerve gap was grafted with a NeuraGen® collagen conduit filled with either saline or keratin hydrogel and nerve regeneration was evaluated by electrophysiology for a period of 12 months. The keratin hydrogel-grafted nerves showed significant improvement in return of compound motor action potential (CMAP) latency and recovery of baseline nerve conduction velocity (NCV) compared with the saline-treated nerves. Histological evaluation was performed on retrieved median nerves and abductor pollicis brevis (APB) muscles at 12 months. Nerve histomorphometry showed a significantly larger nerve area in the keratin group compared with the saline group and the keratin APB muscles had a significantly higher myofiber density than the saline group. This is the first published study to show that an acellular biomaterial hydrogel conduit filler can be used to enhance peripheral nerve regeneration and motor recovery in an NHP model.

Metaphyseal ulnar shortening osteotomy for the treatment of ulnocarpal abutment syndrome using distal ulna hook plate: case series.

PURPOSE: To determine the efficacy of a transverse ulnar-shortening osteotomy at the metaphysis in combination with osteosynthesis using a low-profile, 2.0-mm, locking compression distal ulna plate for the treatment of ulnocarpal abutment syndrome. METHODS: We enrolled into this prospective case series 6 patients with symptomatic ulnocarpal abutment syndrome without distal radioulnar joint ligamentous instability, who had previously failed conservative treatment. We recorded Quick Disability of Arm, Shoulder, and Hand score; wrist range of motion; and visual analog scale score for pain before and after surgery for statistical comparisons. RESULTS: All parameters improved after the surgery. The Quick Disabilities of the Arm, Shoulder, and Hand improved from a mean of 65 to 17, and the visual analog score improved from a mean of 7 to 2. No hardware removal was required and no complications were reported. CONCLUSIONS: Metaphyseal ulnar-shortening osteotomy provided the functional advantages of a midshaft ulnar-shortening osteotomy with the potential for improved bone healing and the reduced risk for complications. This technique was a useful alternative for treatment of ulnocarpal abutment syndrome, especially in patients with more than 2 mm ulnar positive variance. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Computer simulation of nerve transfer strategies for restoring shoulder function after adult C5 and C6 root avulsion injuries.

PURPOSE: Functional ability after nerve transfer for upper brachial plexus injuries relies on both the function and magnitude of force recovery of targeted muscles. Following nerve transfers targeting either the axillary nerve, suprascapular nerve, or both, it is unclear whether functional ability is restored in the face of limited muscle force recovery. METHODS: We used a computer model to simulate flexing the elbow while maintaining a functional shoulder posture for 3 nerve transfer scenarios. We assessed the minimum restored force capacity necessary to perform the task, the associated compensations by neighboring muscles, and the effect of altered muscle coordination on movement effort. RESULTS: The minimum force restored by the axillary, suprascapular, and combined nerve transfers that was required for the model to simulate the desired movement was 25%, 40%, and 15% of the unimpaired muscle force capacity, respectively. When the deltoid was paralyzed, the infraspinatus and subscapularis muscles generated higher shoulder abduction moments to compensate for deltoid weakness. For all scenarios, movement effort increased as restored force capacity decreased. CONCLUSIONS: Combined axillary and suprascapular nerve transfer required the least restored force capacity to perform the desired elbow flexion task, whereas single suprascapular nerve transfer required the most restored force capacity to perform the same task. Although compensation mechanisms allowed all scenarios to perform the desired movement despite weakened shoulder muscles, compensation increased movement effort. Dynamic simulations allowed independent evaluation of the effect of restored force capacity on functional outcome in a way that is not possible experimentally. CLINICAL RELEVANCE: Simultaneous nerve transfer to suprascapular and axillary nerves yields the best simulated biomechanical outcome for lower magnitudes of muscle force recovery in this computer model. Axillary nerve transfer performs nearly as well as the combined transfer, whereas suprascapular nerve transfer is more sensitive to the magnitude of reinnervation and is therefore avoided.

Repair of peripheral nerve defects in rabbits using keratin hydrogel scaffolds.

Entubulation of transected nerves using bioabsorbable conduits is a promising alternative to sural nerve autografting, but full functional recovery is rarely achieved. Numerous studies have suggested that scaffold-based conduit fillers may promote axon regeneration, but no neuroinductive biomaterial filler has been identified. We previously showed that a nerve guide filled with keratin hydrogel actively stimulates regeneration in a mouse model, and results in functional outcomes superior to empty conduits at early time points. The goal of the present study was to develop a peripheral nerve defect model in a rabbit and assess the effectiveness of a keratin hydrogel filler. Although repairs with keratin-filled conduits were not as consistently successful as autograft overall, the use of keratin resulted in a significant improvement in conduction delay compared to both empty conduits and autograft, as well as a significant improvement in amplitude recovery compared to empty conduits when measurable regeneration did occur. Taking into account all study animals (i.e., regenerated and nonregenerated), histological assessment showed that keratin-treated nerves had significantly greater myelin thickness than empty conduits. These data support the findings of our earlier study and suggest that keratin hydrogel fillers have the potential to be used clinically to improve conduit repair.

Soft-tissue coverage of complex dorsal hand and finger defects using the turnover adipofascial flap.

Complex hand wounds with exposed tendon or bone often require free tissue transfer. We report results in 13 patients with complex dorsal hand or digital wounds who underwent soft-tissue reconstruction using a turnover adipofascial flap and skin grafting over a 35-month period. The mean patient age was 44 years. Mechanism of injury included the following: three gunshot, four degloving, one table saw, three chain saw, one thumb avulsion, and one crush. Flap sizes varied from 2 × 4 to 10 × 18 cm, involving the dorsum of the hand in four patients, thumb in two patients, index finger in one patient, long finger in three patients, long and ring fingers in one patient, and web space in two patients. Skin graft survival was 100% in 12 patients. One patient died of sepsis from unrelated medical conditions. All fractures were healed at follow-up, and there were no donor site complications. The adipofascial flap is a good alternative to free tissue transfer for the coverage of complex dorsal hand and finger soft-tissue defects and is associated with technical ease, good cosmetic results, and minimal donor site morbidity.

An ulnar intraneural ganglion arising from the pisotriquetral joint: case report.

Intraneural ganglions of the hand are rare and remain poorly understood. We report a case of an intraneural ganglion arising from the pisotriquetral joint that penetrated the ulnar nerve at Guyon's canal. Although rare, these ganglions should be considered in the differential diagnosis of any neoplasms causing compression neuropathy.

Microcomputed tomography characterization of shoulder osseous deformity after brachial plexus birth palsy: a rat model study.

BACKGROUND: Shoulder deformities are common secondary sequelae associated with brachial plexus birth palsy. The aim of the present study was to characterize three-dimensional glenohumeral deformity associated with brachial plexus birth palsy with use of microcomputed tomography scanning in a recently developed animal model. METHODS: Brachial plexus birth palsy was produced by a right-sided neurotomy of the C5 and C6 nerve roots in seven five-day-old Sprague-Dawley rats. Microcomputed tomography scanning was performed when the rats were four months of age. Glenoid size, version, and inclination; humeral head size; and acromion-glenoid distance were measured. Normal shoulders of age-matched rats (n = 9) served as controls. Statistical analysis was performed with use of the unpaired two-tailed Student t test. RESULTS: There were significant increases in glenoid retroversion (-7.6° ± 4.9° compared with 3.6° ± 2.1°; p = 0.038) and glenoid inclination (38.7° ± 7.3° compared with 11.2° ± 1.9°; p = 0.015) in the shoulders with simulated brachial plexus birth palsy in comparison with the normal, control shoulders. The glenohumeral joints were more medialized in the joints with simulated brachial plexus birth palsy as reflected by the acromion-glenoid distance measurement; however, the difference was not significant (3.20 ± 0.51 compared with 2.40 ± 0.18 mm; p = 0.12). Although the mean humeral head height and width measurements, on the average, were smaller in the brachial plexus birth palsy shoulders as compared with the normal, control shoulders, only the measurement of humeral head height was significantly different between the two groups (4.25 ± 2.02 compared with 4.97 ± 0.11 mm [p = 0.008] and 3.56 ± 0.27 compared with 4.19 ± 0.17 mm [p = 0.056], respectively). CONCLUSIONS: In this animal model, rats with simulated brachial plexus birth palsy developed gross architectural joint distortion characterized by increased glenoid retroversion and inclination. In addition, humeral heads tended to be smaller four months after simulated brachial plexus birth palsy.

Open versus closed treatment of the fibula in Maissoneuve injuries.

BACKGROUND: Masissoneuve fractures of the proximal half of the fibula are infrequently reported with only a few reports existing recommending closed reduction of the syndesmosis and percutaneous syndesmotic fixation. The purpose of this study was to compare the reduction obtained with open and closed reduction techniques of the fibular fracture with screw fixation of the syndesmosis. MATERIALS AND METHODS: Twelve patients with acute displaced fibula fractures in the proximal one-half with syndesmotic disruption were enrolled in the study. One orthopedic traumatology team at the time of the study routinely treated these injuries with open reduction of the fibular fracture site with screw fixation of the syndesmosis. The other orthopedic traumatology service routinely treated these patients with a closed reduction of the syndesmosis and percutaneous syndesmotic screw fixation. All syndesmotic injuries were treated with two stainless steel screws. Postoperative reduction was analyzed with a CT scan and plain radiographs to assess rotation, AP translation of the distal fibula, medial and lateral joint space (talofibular space), talocrural angle and superior ankle joint space. Control data from 20 normal ankle CT scans collected in a previous study were used for comparison. RESULTS: There were eight patients in the closed group and four in the open treatment group. A statistically significant difference in the reduction of the syndesmosis was found with the open group showing anatomic or near anatomic reductions in all patients while the closed fibular reduction group showed variable reductions. The talocrural angle was 12.8 degrees in the open group and 9.9 degrees in the closed group. CONCLUSION: Proximal fibular fractures with syndesmotic disruption can be difficult to treat, especially with closed reduction and percutaneous fixation of the syndesmosis. In this limited series of patients, we found an unacceptable rate of malreduction with closed reduction and percutaneouso fixation and have now abandoned this technique.