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Importance There have been numerous publications involving the use of biologics in sports medicine injuries. However, a lack of clarity exists with reporting industry affiliations and sources of funding. Objective The purposes of this study were (1) to determine the frequency of reporting of funding sources in randomised clinical trials evaluating the clinical effects of biological treatments in sports medicine and (2) to evaluate potential relationships between reported clinical results and affiliated funding sources. We hypothesised that funding sources would be under-reported and the favourability of the results would be associated with the specific type of funding received. Evidence review A systematic search of MEDLINE and Embase databases was performed to identify funding sources and favourability of conclusions reported for all randomised clinical trials that compared a biological treatment to a standard treatment for sports medicine-related injuries. Industry affiliation was defined as a funding source or author affiliation with the company that provided the biological product being studied. Extracted data included the reported purpose, conclusion, funding sources, researcher industry affiliations, sample size, minimum follow-up (FU) and the outcome metrics used. Two-tailed t-tests and logistic regression analyses were performed for analysis. Findings Ninety-eight studies met our inclusion criteria and included a total of 5898 subjects with a minimum FU of 6 weeks–24 months. These studies investigated shoulder, knee, foot and ankle, and elbow issues. Forty-eight of the 98 studies (49%) did not report the source of study funding. In total, 47 of the 98 studies (48%) reported favourable results, and 5 of these studies (10.6%) reported industry affiliations. Published studies with unknown funding sources reported conclusions in favour of the biological treatment significantly more often than those with reported funding sources (p=0.015). Conclusions and relevance Nearly half of the included studies did not disclose funding sources, and studies with unknown funding sources more frequently reported results in favour of the biological treatment. Clinical reports of randomised trials should emphasise reporting of funding sources to ensure data transparency and interpretability of results. Future initiatives should focus on developing standard international criteria for reporting research funding in scientific publications. Level of evidence II

Background: The timing of return to play after anterior cruciate ligament (ACL) reconstruction is still controversial due to uncertainty of true ACL graft state at the time of RTP. Recent work utilizing ultra-short echo T2* (UTE-T2*) magnetic resonance imaging (MRI) as a scanner-independent method to objectively and non-invasively assess the status of in vivo ACL graft remodeling has produced promising results. Purpose/Hypothesis: The purpose of this study was to prospectively and noninvasively investigate longitudinal changes in T2* within ACL autografts at incremental time points up to 12 months after primary ACL reconstruction in human patients. We hypothesized that (1) T2* would increase from baseline and initially exceed that of the intact contralateral ACL, followed by a gradual decline as the graft undergoes remodeling, and (2) remodeling would occur in a region-dependent manner. Study Design: Case series; Level of evidence, 4. Methods: Twelve patients (age range, 14-45 years) who underwent primary ACL reconstruction with semitendinosus tendon or bone–patellar tendon–bone autograft (with or without meniscal repair) were enrolled. Patients with a history of previous injury or surgery to either knee were excluded. Patients returned for UTE MRI at 1, 3, 6, 9, and 12 months after ACL reconstruction. Imaging at 1 month included the contralateral knee. MRI pulse sequences included high-resolution 3-dimensional gradient echo sequence and a 4-echo T2-UTE sequence (slice thickness, 1 mm; repetition time, 20 ms; echo time, 0.3, 3.3, 6.3, and 9.3 ms). All slices containing the intra-articular ACL were segmented from high-resolution sequences to generate volumetric regions of interest (ROIs). ROIs were divided into proximal/distal and core/peripheral sub-ROIs using standardized methods, followed by voxel-to-voxel registration to generate T2* maps at each time point. This process was repeated by a second reviewer for interobserver reliability. Statistical differences in mean T2* values and mean ratios of T2*inj/T2*intact (ie, injured knee to intact knee) among the ROIs and sub-ROIs were assessed using repeated measures and one-way analyses of variance. P < .05 represented statistical significance. Results: Twelve patients enrolled in this prospective study, 2 withdrew, and ultimately 10 patients were included in the analysis (n = 7, semitendinosus tendon; n = 3, bone–patellar tendon–bone). Interobserver reliability for T2* values was good to excellent (intraclass correlation coefficient, 0.84; 95% CI, 0.59-0.94; P < .001). T2* values increased from 5.5 ± 2.1 ms (mean ± SD) at 1 month to 10.0 ± 2.9 ms at 6 months ( P = .001), followed by a decline to 8.1 ± 2.0 ms at 12 months ( P = .129, vs 1 month; P = .094, vs 6 months). Similarly, mean T2*inj/T2*intact ratios increased from 62.8% ± 22.9% at 1 month to 111.1% ± 23.9% at 6 months ( P = .001), followed by a decline to 92.8% ± 29.8% at 12 months ( P = .110, vs 1 month; P = .086, vs 6 months). Sub-ROIs exhibited similar increases in T2* until reaching a peak at 6 months, followed by a gradual decline until the 12-month time point. There were no statistically significant differences among the sub-ROIs ( P > .05). Conclusion: In this preliminary study, T2* values for ACL autografts exhibited a statistically significant increase of 82% between 1 and 6 months, followed by an approximate 19% decline in T2* values between 6 and 12 months. In the future, UTE-T2* MRI may provide unique insights into the condition of remodeling ACL grafts and may improve our ability to noninvasively assess graft maturity before return to play.

We report a case of a patient with newly diagnosed, locally extensive and cystic, suprasellar papillary craniopharyngioma successfully treated with single-agent Dabrafenib. The patient was symptomatic with gait imbalance with falls, lethargic episodes, fatigue and incontinence. Diagnostic imaging demonstrated a cystic suprasellar tumor extending into the third ventricle causing obstructive hydrocephalus. The tumor was partially debulked, and bilateral shunts were placed. NGS sequencing demonstrated BRAF V600E mutation, and the patient was prescribed dual agent Dabrafenib and Trametinib. However, due to insurance denial for Trametinib, he only received single-agent Dabrafenib (150mg BID). The treatment resulted in a major response (over two years), including reduction of the tumor cyst, and improvement of the clinical symptoms. No adverse events have been reported. The patient continues on Dabrafenib (150 mg BID) with a steady reduction in tumor size, and improvement in cognitive function leading to independent living.

Background Prior retrospective and prospective studies suggest improved survival with the use of stereotactic radiosurgery (SRS) and bevacizumab in the treatment of limited-volume glioblastoma (GBM) recurrences. Methods We retrospectively reviewed our experience with gamma knife SRS in combination with bevacizumab for the treatment of focal GBM recurrence during 2009–2015. Outcomes include overall survival, progression free survival (PFS), and radiation-related adverse events. Kaplan–Meier methods and multivariable Cox proportional hazards models were performed for survival analysis. Results Within a median of 13.7 months after diagnosis, a total of 45 patients with GBM underwent gamma knife SRS and bevacizumab treatment. Median age was 57 years (range: 20–78 years) and 63.3% were women. The median Karnofsky Performance Score (KPS) at recurrence was 80 (range: 40–100). Sixty-four percent of patients had single radiosurgery target (range: 1–4) and median target volume and margin dose were 2.2 cm3 (range: 0.1–25.2 cm3) and 17.0 gray (Gy) (range: 13–24 Gy), respectively. Median PFS and overall survival were 9.3, 31.0 months following diagnosis, and 5.2, 13.3 months after SRS, respectively. Factors associated with poor outcomes were KPS ≤70, SRS dose Conclusions SRS in combination with bevacizumab can be safely used to treat focal GBM recurrence. KPS, radiation dose, and multi-agent chemotherapy usage prior to SRS demonstrated significant impact on PFS. Bevacizumab may provide clinically relevant radioprotection.

Combined chemotherapy with temozolomide (TMZ), bevacizumab (BEV) and irinotecan (IRI) [TBI] has been used in patients with recurrent or progressive high-grade gliomas. Patients tolerated the regimen well with increased frequency of reversible clinical myelosuppression (CM), hypertension and proteinuria. However, organ-specific toxicities have never been evaluated by post-mortem examination. From 2009 to 2019, post-mortem examinations were performed in seventy-six decedents, including gliomas (N=68, 44/M and 24/F, median age: 59, ranging 23–80 years old) and brain metastases (N=8, 5/M and 3/F, ranging 39–75 years old). Twenty-four glioma subjects were treated with 1–25 cycles TBI (median 5.5) at glioma recurrence. All subjects’ clinical information, treatment histories and adverse events were collected. Five (7.7%, 5/65) glioma decedents (excluding three glioma patients who never received TMZ) permanently discontinued TMZ due to severe CM during concurrent chemoradiation therapy. There is no significantly elevated severity of CM from TBI when compared to standard of care therapies, nor when comparing extended TMZ treatment to the standard 12 cycles of TMZ. However, exposure to IRI significantly increased the CM occurrence (p< 0.05). Among glioma decedents, the most common cause of death was tumor progression (63.2 %, N=43), followed by aspiration pneumonia (48.5%, N=33). No deaths were attributed to acute toxicity from TBI. An electromicroscopic (EM) examination was performed in addition to routine autopsy procedures to investigate the cause of hypertension and proteinuria frequently developing in patients received BEV therapy. Ultrastructural evidence of thrombotic microangiopathy was observed in the kidneys among BEV users; however, it is difficult to conclude such changes were related to BEV due to rapid autolytic changes and artifacts. CONCLUSION: IRI, not the extended use of TMZ, significantly increased the frequency of reversible CM in recurrent glioma patients. There are no unexpected adverse events or organ-specific toxicities detected among glioma decedents who received the TBI regimen.

Objectives: Post-reconstruction imaging of the anterior cruciate ligament (ACL) is needed to non-invasively assess in vivo graft maturity before release to play. The purpose of this study was to evaluate autograft remodeling up to 12 months after ACL reconstruction using 3D ultra-short time to echo (UTE) T2* MRI. We hypothesized that the T2* values of ACL autografts would progressively change over time, initially resembling the values for the native contralateral graft source and gradually approaching that of the intact contralateral ACL. Methods: After IRB approval, 12 patients (ages 14-45 years) who underwent primary ACL reconstruction (ACLR) with semitendinosus (SemiT) or bone-patellar tendon-bone (BTB) autograft were enrolled. Patients with a history of prior injury or surgery to either knee were excluded. Subjects returned for UTE MRIs at 1, 3, 6, 9, and 12 months after ACLR. Imaging at 1-month included the contralateral knee. All scans were performed on a Philips Ingenia 3T system. MRI pulse sequences included high-resolution 3D T2 (slice thickness: 0.6mm, TR: 18.7ms; TE: 11.5ms) and a four-echo T2 UTE (slice thickness: 1mm, TR: 20ms; TE: 0.3, 3.3, 6.3, and 9.3ms). Using high-resolution 3D T2 sequences at 1 month, all slices containing the intra-articular ACL were segmented semi-automatically to generate volumetric regions of interest (ROIs) (Materialise, Inc.; Leuven, Belgium). ROIs were divided into proximal/distal and core/peripheral sub-ROIs using standardized methods. Each ROI was co-registered voxel-by-voxel to T2* maps also obtained at 1 month. These T2* maps were then co-registered with those of subsequent time points. The segmentation process was repeated for the 1-, 3-, and 6-month time points by a second reviewer for inter-observer reliability (κ). Statistical differences among the ROIs and sub-ROIs of ACL autografts were assessed with repeated-measures ANOVA and two-tailed non-parametric t-tests. PResults: Twelve subjects were enrolled in this prospective study, and after 2 subjects withdrew, 10 subjects were included in the analysis (n=7 SemiT; n=3 BTB). Nine of 10 subjects attended all postoperative imaging sessions at the time of this writing. Inter-observer reliability for T2* values was found to be excellent (κ=0.832; 95% CI [0.70-0.91]; pConclusions: ACL autografts exhibited progressively increasing T2* values and T2*[inj]/T2*[intact] ratios up to 12 months after ACLR, and these changes appear to be region-dependent. UTE T2* MR imaging can provide unique insights into the condition of remodeling ACL grafts, and may improve our ability to non-invasively assess graft maturity before allowing patients to resume high-intensity activities.

Author(s): Pogorzelski, David; Nguyen, Uyen; McKay, Paula; Thabane, Lehana; Camara, Megan; Ramsey, Lolita; Seymour, Rachel; Goodman, J Brett; McGee, Sheketha; Fraifogl, Joanne; Hudgins, Andrea; Tanner, Stephanie L; Bhandari, Mohit; Slobogean, Gerard P; Sprague, Sheila; PREP-IT Investigators Executive Committee:; Steering Committee; Adjudication Committee; Data and Safety Monitoring Committee; Research Methodology Core; Patient Centred Outcomes Core; Orthopaedic Surgery Core; Operating Room Core; Infectious Disease Core; Military Core; McMaster University Methods Center; University of Maryland School of Medicine Administrative Center; University of Maryland School of Pharmacy, The PATIENTS Program; PREP-IT Clinical Sites: Lead Clinical Site (Aqueous-PREP and PREPARE); Aqueous-PREP and PREPARE; Aqueous-PREP; PREPARE; PREP-IT Investigators Executive Committee | Abstract: IntroductionPragmatic trials in comparative effectiveness research assess the effects of different treatment, therapeutic, or healthcare options in clinical practice. They are characterized by broad eligibility criteria and large sample sizes, which can lead to an unmanageable number of participants, increasing the risk of bias and affecting the integrity of the trial. We describe the development of a sampling strategy tool and its use in the PREPARE trial to circumvent the challenge of unmanageable work flow.MethodsGiven the broad eligibility criteria and high fracture volume at participating clinical sites in the PREPARE trial, a pragmatic sampling strategy was needed. Using data from PREPARE, descriptive statistics were used to describe the use of the sampling strategy across clinical sites. A Chi-square test was performed to explore whether use of the sampling strategy was associated with a reduction in the number of missed eligible patients.Results7 of 20 clinical sites (35%) elected to adopt a sampling strategy. There were 1539 patients excluded due to the use of the sampling strategy, which represents 30% of all excluded patients and 20% of all patients screened for participation. Use of the sampling strategy was associated with lower odds of missed eligible patients (297/4545 (6.5%) versus 341/3200 (10.7%) p l 0.001).ConclusionsImplementing a sampling strategy in the PREPARE trial has helped to limit the number of missed eligible patients. This sampling strategy represents a simple, easy to use tool for managing work flow at clinical sites and maintaining the integrity of a large trial.

Central nervous system (CNS) malignancies can be difficult to diagnose and many do not respond satisfactorily to existing therapies. Monitoring patients with CNS malignancies for treatment response and tumour recurrence can be challenging because of the difficulty and risks of brain biopsies, and the low specificity and sensitivity of the less invasive methodologies that are currently available. Uncertainty about tumour diagnosis or whether a tumour has responded to treatment or has recurred can cause delays in therapeutic decisions that can impact patient outcome. Therefore, there is an urgent need to develop and validate reliable and minimally invasive biomarkers for CNS tumours that can be used alone or in combination with current clinical practices. Blood-based biomarkers can be informative in the diagnosis and monitoring of various types of cancer. However, blood-based biomarkers have proven suboptimal for analysis of CNS tumours. In contrast, circulating biomarkers in cerebrospinal fluid (CSF), including circulating tumour DNA, microRNAs and metabolites, hold promise for accurate and minimally invasive assessment of CNS tumours. This review summarises the current understanding of these three types of CSF biomarkers and their potential use in neuro-oncologic clinical practice.

Objectives: Recent emphasis has been placed on concussion safety in American football and has driven the development of new anti-concussive helmet designs which are becoming more popular in the National Football League (NFL). However, their larger diameter may inadvertently complicate on-field stabilization procedures for players with suspected cervical spine injuries. The purpose of this study was to compare the total arc of extension in the supine position before and after removal of a traditional helmet and a larger-diameter anti-concussive helmet. We hypothesized that removal of the larger helmet would result in a significantly increased total arc of extension when compared to removal of a traditional helmet. Methods: IRB approval was obtained prior to initiation of this study. Following the guidance of a priori power analysis, 27 adult male volunteers between 20 and 30 years of age were enrolled. Head circumference, height, and weight measurements were obtained before being fitted with NFL-style shoulder pads, a traditional helmet (TH), and a newly-introduced, larger anti-concussive helmet (LH). With the shoulder pads in place, each subject was asked to lay supine on the x-ray table which was equipped with standardized visible landmarks to facilitate consistent positioning between patients. Lateral radiographs were then obtained while wearing the TH, the LH, and while wearing no helmet (NH). With assistance, subjects were immobilized to the extent possible while removing/exchanging headgear between radiographs. Three cobb angle measurements were obtained for each helmet condition beginning from the most caudal aspect of C1 to the most cranial aspects of the C3, C4, and C5 vertebral bodies, respectively. Maintenance of atlanto-dens intervals were confirmed between helmet conditions in each subject. All Cobb angles were measured in duplicate by two independent observers on two occasions separated by at least 2 weeks for calculation of inter- and intra-rater reliability (κ). Statistical comparisons between helmet conditions were performed using repeated measures analysis of variance (ANOVA). Statistical significance was declared when pResults: Twenty-seven male subjects with a mean age of 24.0 years (range, 22.0-36.0 years; standard deviation [SD], 3.0 years), mean body mass index (BMI) of 25.1 kg/m2 (range, 21.0-31.9 kg/m2; SD, 2.7 kg/m2), and mean head circumference of 58.2 cm (range, 53.0-62.0 cm; SD, 1.6 cm). Cobb angle measurements were found to have good-to-excellent intra-class correlation (κ). Relative to NH, the average total extension arc after removal LH removal was significantly greater than after SH removal between the C1-C3 (-2.6°; p=0.024), C1-C4 (-2.6°; p=0.036), and C1-C5 intervals (-2.9°; p=0.023), amounting to a 50-60% increased arc of cervical extension after removal of the LH relative to the TH (Table 1 and Figure 1). Conclusion: The degree of passive cervical lordosis that occurs after removal of new larger-diameter anti-concussive football helmets in the supine position is significantly greater than after removal of traditional helmets, thus potentially increasing the risk of iatrogenic cervical spine injury while attempting on-field helmet removal. Current guidelines and procedures for management of on-field cervical spine trauma in American football should be modified to account for larger helmet designs that are becoming more popular in American football. [Table: see text]

2021 Background: Microtubule inhibitors, including taxanes, are active in preclinical models of glioblastoma (GBM), however, clinical benefit is hampered by poor blood-brain barrier (BBB) accumulation. TPI 287, a third-generation taxane designed to evade P-glycoprotein mediated efflux, readily penetrates the BBB and overcomes this limitation. CB-017 is a multi-center phase 1/2 trial designed to determine the optimal dose of TPI 287 and potential efficacy in patients treated with this drug plus bevacizumab (BEV) for treatment of recurrent GBM. Final results of the dose escalation Phase 1 stage of this trial are reported. Methods: GBM patients at first or second relapse after standard therapy and without prior exposure to anti-angiogenic agents were eligible for enrollment. BEV was administered at 10 mg/kg every 2 weeks and TPI 287 every 3 weeks via IV infusion. MRIs were obtained every six weeks with response assessed via RANO criteria. TPI 287 dose escalation was based on a traditional 3+3 design. Results: Twenty-four patients were enrolled in 7 TPI 287 dose-escalation cohorts (140-220 mg/m2) from 6 U.S. centers. Twenty and 23 patients were evaluable for response and survival, respectively. Median follow-up was 28 months. Results are shown in the table below. Of the 9 patients from which biomarker data was available, tumors from 8 patients (89%) harbored an unmethylated MGMT promoter, an established negative prognostic indicator for survival. No DLTs were reported and myelosuppression (n=3) was the only drug-related grade 3/4 adverse event. Conclusions: TPI 287 in combination with BEV is safe and well tolerated at doses up to 220 mg/m2. Final survival results from the Phase 1 portion of this study compare favorably with historical controls and support further investigation of TPI 287 plus BEV for treatment of recurrent GBM. Clinical trial information: NCT01933815. [Table: see text]

Chemotherapies [temozolomide (TMZ), bevacizumab (BEV), irinotecan (IRI)] are commonly used drugs treating glioblastoma multiforme (GBM). The side effects from individual drug are well-known clinically and are manageable. Most of side effects are reversible after discounting the suspected drug(s). Combination chemotherapies either concurrently or in sequence are common in oncology practice. Most GBM patients received TMZ first followed by BEV with or without IRI. However, the side effects or permanent end-organs injuries of cumulative toxicity profiles are not well established. Whether these chemotherapies will lead to permanent end-organ damage by post-mortem pathological examination after long term use of either single drug or combination of two or three of the above listed chemotherapy drugs has never been studied in detail. In this study, 45 post-mortem pathological examination and some with electronic microscopic examinations are performed to study possible end-organ toxicity attributed to chemotherapies. Consent for autopsy were obtained from next of kin from each of the subjects. Postmortem organ specific studies including gross exam, H&E, immunohistochemistry study, electron microscopy (EM) (n=8) and immunofluorescence (IF). Autopsy cases include 35 GBMs, 6 brain metastatic cancers, 1 grade II and 2 grade III gliomas, 1 spinal glioma from UTHealth and Tufts medical center since 2007 to 2016. Twenty eight male and 17 female subjects were included with ages ranging from 20 to 79 years old (median 62 years old). Clinical toxicities and laboratory abnormalities were collected and correlated with autopsy results. At autopsy, there was no significant morphologic evidence of TMZ/BEV or TMZ/BEV/IRI-related injury in heart, lung, liver, adrenal glands, thyroid, pancreas, spleen, bladder or bone marrow which we did not know clinically. The cause of death in most patients was bronchopneumonia. Pulmonary embolism was confirmed in 4 cases with 2 case showing additional alveolar hemorrhage. One case had peritonitis with diverticular perforation diagnosed pre-mortem during BEV therapy. EM evaluation of renal glomerular ultrastructure reveal extensive postmortem autolytic change; however there was sufficient preservation to determine that podocyte foot processes were mostly preserved, but glomeruli had segmental to global subendothelial expansion by edematous, flocculent, matrix indicative of endothelial injury. IF examination showed no immune complex deposition. With exception of kidney, there is no significant end-organ damage found by standard postmortem pathological examinations including subjects with long term use of combination of TMZ, BEV and IRI therapies. In the kidney, the toxicity is mild to moderate endothelial injury which is consistent with thrombotic microangiopathy which may be the cause of proteinuria and hypertension seen clinically.