Citations

AbstractPrimary care physicians (PCPs) are commonly approached with concerns involving patient genetics. This is a challenge because most PCPs lack expertise in genetic testing compared to their genetic counselor counterparts. Currently, the recommended best practice is to refer patients for genetic testing based on cancer‐related family history questionnaires with a genetic counseling referral to discuss their results and any implications. However, the extent to which PCPs are using these questionnaires for this purpose remains poorly understood. In this cross‐sectional study, PCPs were presented with the American Cancer Society's seven recommended family history questions to determine the percentage who consider each to be an indicator for referral to a genetics specialist. Questionnaires were completed by 88 of 260 attending PCPs at a national primary care review conference. The main outcome was the percentage of PCPs who identified each question as a trigger for genetic testing. Secondary outcomes included correlations with years of practice, genetics training, and methods used to obtain patient family history. Only two of the seven questions were considered triggers by most PCPs (range, 76–83%). The remaining five had lower percentages (range, 22–55%). Years of practice did not influence the number of triggers identified (Spearman correlation coefficient test: r = 0.05, p = 0.68). Few PCPs (3.4%) felt they had good to excellent genetics training during residency. Only 44.3% had genetics specialists available for referral. Overall, low percentages of PCPs consider the American Cancer Society questions to be triggers for genetic testing referrals. Furthermore, many do not have a genetics specialist or counselor available for referral. Addressing these concerns may help PCPs understand the basics of genetic testing and use standardized questionnaires to make appropriate referrals to genetic specialists, thereby reducing inappropriate referrals and improving appointment access to this precious resource for those who truly need it.

Study Design: Systematic review and meta-analysis. Objective: To perform a systematic review of the clinical symptoms, radiographic findings, and outcomes after spinal decompression in B-cell lymphoma. Summary of Background Data: B-cell lymphoma is a potential cause of spinal cord compression that presents ambiguously with nonspecific symptoms and variable imaging findings. Surgical decompression is a mainstay for both diagnosis and management, especially in patients with acute neurological deficits; however, the efficacy of surgical intervention compared with nonoperative management is still unclear. Methods: The databases of Medline, PubMed, and the Cochrane Database of Systemic Reviews were queried for all articles reporting spinal B-cell lymphoma. Data on presenting symptoms, treatments, survival outcomes, and histologic markers were extracted. Using the R software “survival” package, we generated bivariate and multivariate Cox survival regression models and Kaplan-Meier curves. Results: In total, 65 studies were included with 72 patients diagnosed with spinal B-cell lymphoma. The mean age was 56.22 (interquartile range: 45.00–70.25) with 68% of patients being males and 4.2% of patients being immunocompromised. Back pain was the most common symptom (74%), whereas B symptoms and cauda equina symptoms were present in 6% and 29%, respectively. The average duration of symptoms before presentation was 3.81 months (interquartile range: 0.45–3.25). The most common location was the thoracic spine (53%), with most lesions being hyperintense (28%) on T2 magnetic resonance imaging. Surgical resection was performed in 83% of patients. Symptoms improved in 91% of patients after surgery and in 80% of patients treated nonoperatively. For all 72 patients, the overall survival at 1 and 5 years was 85% (95% CI: 0.749–0.953; n = 72) and 66% (95% CI: 0.512–0.847; n = 72), respectively. Conclusion: Although surgery is usually offered in patients with acute spinal cord compression from B-cell lymphoma, chemotherapy and radiation alone offer a hopeful alternative to achieve symptomatic relief, particularly in patients who are unable to undergo surgery.

Context: Many clinicians, trainers, and athletes do not have a true understanding of the effects of commonly used performance-enhancing drugs (PEDs) on performance and health. Objective: To provide an evidence-based review of 7 commonly used pharmacological interventions for performance enhancement in athletes. Data Sources: PubMed and Scopus databases were searched on April 8, 2022. Study Selection: Systematic reviews (SRs) and meta-analyses (MAs) assessing the performance-enhancing effects of the following interventions were included: androgenic anabolic steroids (AAS), growth hormone (GH), selective androgen receptor modulators (SARMs), creatine, angiotensin-converting enzyme (ACE)-inhibitors, recombinant human erythropoietin (rHuEPO), and cannabis. Study Design: Umbrella review of SRs and MAs. Level of Evidence: Level 4. Data Extraction: Primary outcomes collected were (1) body mass, (2) muscle strength, (3) performance, and (4) recovery. Adverse effects were also noted. Results: A total of 27 papers evaluating 5 pharmacological interventions met inclusion criteria. No studies evaluating SARMs or ACE-inhibitors were included. AAS lead to a 5% to 52% increase in strength and a 0.62 standard mean difference in lean body mass with subsequent lipid derangements. GH alters body composition, without providing a strength or performance benefit, but potential risks include soft tissue edema, fatigue, arthralgias, and carpel tunnel syndrome. Creatine use during resistance training can safely increase total and lean body mass, strength, and performance in high-intensity, short-duration, repetitive tasks. Limited evidence supports rHuEPO benefit on performance despite increases in both VO 2 max and maximal power output, and severe cardiovascular risks are documented. Cannabis provides no performance benefit and may even impair athletic performance. Conclusion: In young healthy persons and athletes, creatine can safely provide a performance-enhancing benefit when taken in controlled doses. AAS, GH, and rHuEPO are associated with severe adverse events and do not support a performance benefit, despite showing the ability to change bodily composition, strength, and/or physiologic measures. Cannabis may have an ergolytic, instead of ergogenic, effect.

Abstract One of the main components of articular cartilage is the chondrocyte's pericellular matrix (PCM), which is critical for regulating mechanotransduction, biochemical cues, and healthy cartilage development. Here, individual primary human chondrocytes (PHC) are encapsulated and cultured in 50 µm diameter alginate microgels using drop‐based microfluidics. This unique culturing method enables PCM formation and manipulation of individual cells. Over ten days, matrix formation is observed using autofluorescence imaging, and the elastic moduli of isolated cells are measured using AFM. Matrix production and elastic modulus increase are observed for the chondrons cultured in microgels. Furthermore, the elastic modulus of cells grown in microgels increases ≈ten‐fold over ten days, nearly reaching the elastic modulus of in vivo PCM. The AFM data is further analyzed using a Gaussian mixture model and shows that the population of PHCs grown in microgels exhibit two distinct populations with elastic moduli averaging 9.0 and 38.0 kPa. Overall, this work shows that microgels provide an excellent culture platform for the growth and isolation of PHCs, enabling PCM formation that is mechanically similar to native PCM. The microgel culture platform presented here has the potential to revolutionize cartilage regeneration procedures through the inclusion of in vitro developed PCM.

Posterior spinal fusion has long been established as an effective treatment for the surgical management of spine deformity. However, interest in nonfusion options continues to grow. Vertebral body tethering is a nonfusion alternative that allows for the preservation of growth and flexibility of the spine. The purpose of this investigation is to provide a practical and relevant review of the literature on the current evidence-based indications for vertebral body tethering. Early results and short-term outcomes show promise for the first generation of this technology. At this time, patients should expect less predictable deformity correction and higher revision rates. Long-term studies are necessary to establish the durability of early results. In addition, further studies should aim to refine preoperative evaluation and patient selection as well as defining the benefits of motion preservation and its long-term effects on spine health to ensure optimal patient outcomes.

Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are large-vessel vasculitides affecting the aorta and its branches. Arterial damage from these diseases may result in ischemic complications, aneurysms, and dissections. Despite their similarities, the management of GCA and TAK differs. Glucocorticoids are used frequently but relapses are common, and glucocorticoid toxicity contributes to significant morbidity. Conventional immunosuppressive therapies can be beneficial in TAK, though their role in the management of GCA remains unclear. Tumor necrosis factor inhibitors improve remission rates and appear to limit vascular damage in TAK; these agents are not beneficial in GCA. Tocilizumab is the first biologic glucocorticoid-sparing agent approved for use in GCA and also appears to be effective in TAK. A better understanding of the pathogenesis of both conditions and the availability of targeted therapies hold much promise for future management.

Abstract BACKGROUND Cerebrospinal fluid (CSF) is emerging as an abundant source of candidate biomarkers, including proteins, for gliomas. Longitudinal CSF access may enable insights into treatment response and resistance. To that end, we have established a growing biobank of CSF samples, many of which have been obtained longitudinally via CSF access devices, such as Ommaya reservoirs, through our ongoing biomarker discovery clinical trials (NCT04692337, 04692324). We have previously presented our initial data demonstrating a conserved proteomic signature of HGG that decreased with resection and increased with recurrence. Since then, samples have been acquired throughout individual patients’ treatments toward our goal of identifying CSF-derived biomarkers of treatment response. MATERIAL AND METHODS CSF samples obtained prior to, during, and throughout treatment underwent global proteomics analysis via the SomaScan® assay by Somalogic, which uses slow off-rate modified aptamers to sensitively detect over 7,000 proteins. Fold-changes for each protein were calculated between different timepoints for each patient and ranked based on the comparison of interest. Comparisons included prior to versus after resection, chemoradiation or adjuvant temozolomide (each with or without pembrolizumab), bevacizumab, and low versus high blood contamination. RESULTS Treatment with pembrolizumab alone resulted in increased IL-23 (5.01x), IL-12 (4.25x), lymphocyte activation gene 3 protein (LAG3) (3.26x), and granzyme A (2.93x). Chemoradiation, with or without pembrolizumab, consistently downregulated NAD kinase, acetyl CoA transferase, and Bcl-2 and upregulated proteins related to neuronal signaling, such as neurexins and cerebellins, in addition to LAG-3, suggesting potential for synergy between chemoradiation and anti-LAG-3 antibodies currently in clinical trials. Interestingly, pembrolizumab and chemoradiation decreased MMP-12 and MMP-9 abundance as compared to chemoradiation alone (0.25x vs. 18.5x; 0.54x vs. 4.99x). Finally, bevacizumab treatment consistently increased VEGF (7.32x), GFAP (3.38x), and MMP-3 (2.99x) abundance, while decreasing the presence of our previously reported plasma-associated protein signature in CSF, suggesting decreased blood-brain barrier disruption. CONCLUSION The global CSF proteome can be longitudinally accessed to evaluate response to standard-of-care and experimental therapies. Further studies are ongoing to identify signatures of therapeutic resistance and to assess the impact of novel immunotherapeutic combinations on the CSF proteome.

Abstract BACKGROUND D-2-hydroxyglutarate (D-2-HG) is a well-established oncometabolite of isocitrate dehydrogenase (IDH) mutant gliomas. While prior studies have demonstrated that D-2-HG is elevated in the cerebrospinal fluid (CSF) of patients with IDH-mutant gliomas, no study has evaluated the ability of CSF D-2-HG to quantitatively monitor tumor burden and therapeutic response. Toward this goal, we are routinely obtaining CSF samples from patients prior to, during, and after treatment via intra-operative collection and CSF-access devices. MATERIAL AND METHODS Patients were enrolled into our Ommaya reservoir study (NCT04692337), which enables longitudinal access to CSF. The catheter for the implanted reservoir was placed within the surgical resection cavity following a standard-of-care resection. Intra-operatively collected CSF samples were also biobanked through Mayo Clinic’s Neuro-Oncology biorepository. CSF samples were also acquired via clinically indicated ventriculoperitoneal shunts (VP shunts) or external ventricular drains via our ongoing CSF biomarkers study (NCT04692324). D-and-L-2-HG were assayed from each CSF sample via gas chromatography-mass spectrometry (GC-MS) at Mayo Clinic’s Biochemical Genetics Laboratory. RESULTS CSF was collected prior to and after resection in patients via Ommaya reservoirs or VP shunts, all of whom underwent near gross total resections (>95% of tumor volume). D-2-HG and the D/L ratio fell on average by 57.9% (range: 15.1%-98.6%) and 68.8% (range: 49.3%-98.9%), respectively, following resection. In one patient with a largely intraventricular grade 4 IDH-mutant astrocytoma, D-and-L-2-HG fell by 99.1% and 99.3% by post-operative day 2, consistent with the impact of ventricular contact on baseline CSF D-2-HG levels. In patients for whom CSF was collected throughout chemoradiation, with or without immunotherapy, D-2-HG and the D/L ratio continued to decrease over time, despite concern for pseudoprogression versus progression on imaging. CONCLUSION Our early experience with this strategy demonstrates the potential for intracranial CSF D-2-HG as a monitoring biomarker for IDH-mutant gliomas. Work is ongoing to evaluate the reproducibility of these findings in a larger cohort of patients with low or high-grade gliomas, in addition to the impact of tumor recurrence on 2-HG. Future studies will evaluate the impact of IDH inhibitors and other experimental therapies on CSF 2-HG levels for pharmacodynamic monitoring of treatment response.

Abstract BACKGROUND Few methods exist via which to assess treatment response with high fidelity in gliomas. Cell-free DNA (cfDNA) is of growing interest as a liquid biomarker in plasma and CSF and has been used in other cancer types to optimize therapeutic regimens for individual patients. While CSF has previously been used as a source of cfDNA for gliomas, it remains unknown how cfDNA abundance and sequencing change throughout treatment and inevitable recurrence. To that end, we leveraged our growing biobank of longitudinal CSF specimens, acquired via CSF access devices, to determine the potential utility of CSF cfDNA as a monitoring tool for treatment response in patients with gliomas. MATERIAL AND METHODS Longitudinal CSF specimens were acquired via Ommaya reservoirs (NCT04692337) or ventriculoperitoneal shunts (NCT04692324) in patients with brain tumors, including gliomas. cfDNA was extracted from 1-5 mL of CSF based on available sample volumes and quantified via Qubit. Next-Generation sequencing (PredicineCARE) or low-pass whole genome sequencing (LPWGS) was performed by Predicine, Inc based on the amount of cfDNA available. RESULTS CSF acquired prior to versus after resection demonstrated an increase in quantified cfDNA (2.97x, range: 1.58-5.26x), consistent with the impact of increased parenchymal disruption and closer contact with CSF. Thereafter, CSF cfDNA continued to decrease throughout chemoradiation and adjuvant treatment and increased at recurrence, including in patients co-enrolled in immunotherapy trials for IL-7 agonists and pembrolizumab. Interestingly, copy number burden (CNB) increased by the time of recurrence in three patients with known disease progression, and continued to decrease throughout immunotherapy treatment in one patient despite concerns of pseudoprogression. In one patient with a hypermutated glioblastoma, CSF cfDNA revealed over 59 genomic alterations, including MAP2K1, KIT, and PDGFRA, and over 100 more variants of unknown significance, each of which had been detected in sequencing of the tissue acquired at resection and subsequently decreased with chemoradiation. In another patient with a known progressing EGFR-amplified GBM, over 200 new variants were identified by the patient’s final sample and EGFR copy number increased from 2 to over 30. CONCLUSION Analysis of cfDNA over a patient’s disease course, including resection and treatment with standard-of-care and experimental therapies, may be of use for disease monitoring and treatment response. Further work is needed to evaluate these findings in a larger cohort of patients and to determine the sensitivity of changes in mutations, CNB, and cfDNA quantity for glioma disease burden.