Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class "spinal ependymoma" (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

Fibrin clot and Leukocyte-rich platelet-rich fibrin show similar release kinetics and amount of growth factors: a pilot study.

BACKGROUND: In knee arthroscopic surgery, fibrin clot (FC) and leukocyte-rich platelet-rich fibrin (L-PRF) may be used in augmentation for meniscal repair. Studies have investigated growth factors released from FC and L-PRF; however, it is difficult to compare FC and L-PRF between different studies. Direct comparison of growth factors that may support meniscal healing released from FC and L-PRF may be beneficial in deciding whether to use FC or L-PRF. If no significant difference is seen, the surgeon may decide to use FC which is easier to prepare compared to L-PRF. The purpose of this pilot study is to investigate the release amount and pattern of basic fibroblast growth factor (bFGF), platelet-derived growth factor AB (PDGF-AB), transforming growth factor ß1 (TGF-ß1), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1) from FC and L-PRF. METHOD: Twenty milliliters (ml) of whole blood was collected from each of the four volunteers. Ten milliliters of whole blood was allocated for preparation of FC and 10 ml for L-PRF. FC and L-PRF were separately placed in 5 ml of culture media. Five milliliters of the culture media was sampled and refilled at 15 min, 1 day, 3 days, 1 week and 2 weeks. The collected culture was used to quantify bFGF, PDGF-AB, TGF-ß1, VEGF, and SDF-1 release by Enzyme-linked immune-sorbent assay (ELISA). Mann-Whitney U test was performed to assess significance of differences in amount of each growth factor released between FC and L-PRF. Significance was accepted at P value less than 0.05. RESULTS: At two weeks, the cumulative release of TGF-ß1 was the highest among all the growth factors in both FC and L-PRF (FC:19,738.21 pg/ml, L-PRF: 16,229.79 pg/ml). PDGF-AB (FC: 2328 pg/ml, L-PRF 1513.57 pg/ml) had the second largest amount, followed by VEGF (FC: 702.06 pg/ml, L-PRF 595.99 pg/ml) and bFGF (FC: 23.48 pg/ml, L-PRF 18.2 pg/ml), which order was also common in both FC and L-PRF. No significant difference in final release amount and pattern was seen between FC and L-PRF. CONCLUSION: The current pilot study showed that cumulative release amount and release pattern of PDGF-AB, VEGF, TGF-ß1, and bFGF did not significantly differ between FC and L-PRF during the two weeks of observation.

Cervical Lift-up Basket Laminoplasty after Resection of Spinal Intramedullary Tumors: A Finite Element Analysis and Clinical Image Evaluation.

Although reconstructive laminoplasty is commonly performed after resection of spinal intramedullary tumors of the cervical spine, its biomechanical rigidity of laminoplasty framework remains unclear. The objective of this study was to examine the structural reliability of our unique method of cervical lift-up basket laminoplasty by using computed tomography (CT)-based finite element analysis (FEA) and clinical radiological evaluation. A finite element model of cervical laminoplasty was created based on CT images using FEA software. Cervical lift-up basket laminoplasty (Basket) was compared with the standard style of open-door basket laminoplasty (Open-door). Clinical subjects for radiological evaluation comprised 33 patients who underwent cervical lift-up basket laminoplasty after resection of spinal intramedullary tumors. An FEA-equivalent stress histogram showed that stress was moderately dispersed around the basket. Virtual displacement of the spinous process of the Basket model was equivalent to that of the Open-door model in any direction of posterior-to-anterior, right-to-left, or top-to-bottom force. In the clinical analysis, radiological data with a minimum postoperative period of 6 months were obtained in a total of 28 out of 33 patients. No patients underwent revision surgery because of implant-related complications. No significant differences in C2-C7 angle or cervical tilt angle were observed between pre- and postoperatively. The structural rigidity of cervical lift-up basket laminoplasty was equivalent to the open-door style on the FEA. Clinical radiological evaluation suggested that there were no serious adverse events associated with cervical laminoplasty, although the longer postoperative follow-up is mandatory.

The incidence of tibial tunnel coalition is higher than femoral tunnel coalition in double-bundle anterior cruciate ligament reconstruction using hamstring autografts: A systematic review.

INTRODUCTION: Intra-operative and postoperative coalition of tunnels may occur in double-bundle (DB) anterior cruciate ligament reconstruction (ACLR). However, the incidence and effect on clinical outcomes of tunnel coalition following primary DB ACLR using a hamstring autograft has yet be analyzed, and thus remains unknown. The objective of this systematic review was to identify the incidence of tunnel coalition upon DB ACLR using hamstring autografts and to elucidate any clinical outcomes and/or complications that tunnel coalition may have postoperatively. HYPOTHESIS: The incidence of tunnel coalition would increase in respect to time from the index surgery, and that tunnel coalition would be related to poorer clinical outcomes compared to non-coalition cases. METHODS: Three databases (PubMed, EMBASE, Cochrane Library) were searched in accordance with PRISMA and R-AMSTAR guidelines on June 15, 2020. Relevant studies were screened in duplicate and data regarding patient demographics, incidence of femoral and tibial tunnel coalition, and outcomes were extracted. Coalition rate was also compared between follow up at 1 month or less defined as "shorter-term", and 6 months or greater as "longer-term". Coalition is defined as the missing of a bony bridge between the two tunnels. RESULTS: Thirty-six studies examining 1,574 patients, mean age 29.1 years, were included in this study. 29 studies (1,110 knees) reported the incidence of femoral coalition with a pooled rate of coalition of 8% (95% CI=4-12%). 28 studies (1,129 knees) reported an incidence of tibial coalition with a pooled rate of coalition of 21% (95% CI=13-30%). The incidence of tibial coalition was significantly higher than the incidence of femoral coalition across 21 comparative studies (OR=3.37, 95% CI=1.41-8.09, p=0.0065). Only two studies (111 knees) compared tunnel coalition and non-coalition groups for clinical outcome and no significant differences were observed with regards to Lysholm score, Tegner activity scale, and knee laxity measured with a KT-1000 arthrometer. DISCUSSION: The rate of tibial tunnel coalition in DB ACLR is higher than femoral tunnel coalition, particularly at longer-term follow-up. Despite the higher radiographic evidence of coalition, the clinical effects of such remain to be ascertained, and further comparative studies are required to facilitate this understanding. LEVEL OF EVIDENCE: IV, systematic review.

Direct suturing quadriceps tendon to a continuous loop with a suspensory button provides biomechanically superior fixation in ACL reconstruction.

PURPOSE: To compare the biomechanical strength of different fixation configurations using suspensory buttons in a soft-tissue quadriceps tendon (QT) grafts in anterior cruciate ligament (ACL) reconstruction. METHODS: Forty bovine QTs, 6-cm long and 10-mm wide, were allocated into four groups with different suture configurations using suspensory buttons (n = 10 in each group): Group A, a baseball suture with a knot tied to the continuous loop with a suspensory button; Group B, same configuration as in Group A but with the knot tied at the opposite end of the baseball suture; Group C, a continuous loop with a suspensory button stitched directly to the QT with simple sutures, and Group D, a baseball suture tied directly to a suspensory button. Biomechanical testing was performed by preloading followed by cyclic loading for 500 cycles between 10 and 100 N. The length of elongation (mm) and maximum load to failure (N) were recorded, and compared among the four groups. RESULTS: Group C showed significantly smaller elongation (4.1 mm [95% CI 3.1-5.2]) than Group A (8.2 mm [95% CI 7.0-9.4]), Group B (10.5 mm [95% CI 7.7-13.3]), and Group D (8.5 mm [95% CI 7.0-9.9]) (A-C; P = 0.004, B-C; P = 0.0001, C-D; P = 0.0018). The maximum load to failure in Group C (386 N [95%CI 306-466]) was significantly higher than that in Group A (196 N [95% CI 141-251]), Group B (226 N [95% CI 164-289]), and Group D (212 N [95%CI 171-253]) (A-C; P = 0.0001, B-C; P = 0.0009, C-D; P = 0.0002). No significant differences were observed between Group A, B, and D in terms of elongation and maximum load to failure. CONCLUSION: The soft-tissue QT graft fixation configuration stitched directly to a continuous loop with suspensory button using simple sutures exhibits small elongation and high maximum load to failure among the four configurations. Regarding clinical relevance, direct suturing of the soft-tissue QT to a continuous loop with a suspensory button may be advantageous for femoral fixation in ACL reconstruction from a biomechanical perspective, and warrant future development of a novel fixation device using this principle.

Association of coffee, green tea, and caffeine with the risk of dementia in older Japanese people.

OBJECTIVES: Coffee, green tea, and caffeine are potential preventive factors for dementia, but the underlying evidence is insufficient. This study aimed to examine associations between the consumption of coffee, green tea, and caffeine and dementia risk in middle-aged and older people. METHODS: This was a cohort study with an 8.0-year follow-up. Participants were community-dwelling individuals (n = 13,757) aged 40-74 years. A self-administered questionnaire survey was conducted in 2011-2013. Predictors were the consumption of coffee/green tea, from which caffeine consumption was estimated. The outcome was incident dementia obtained from the long-term care insurance database. Covariates were demographic factors, body mass index, physical activity, energy, smoking, drinking, and disease history. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards models. HRs were also calculated using a Cox model with delayed entry. RESULTS: The number of dementia cases during the study period was 309. Participants with higher coffee consumption had lower HRs (adjusted p for trend = 0.0014), with the fifth quintile (≥326 ml/day) having a significantly lower HR (0.49, 95% confidence interval [CI]: 0.30-0.79) than the first quintile (<26 ml/day, reference). Similarly, participants with higher caffeine consumption had a significantly lower HR (adjusted p for trend = 0.0004) than the reference. The Cox model with delayed entry yielded similar results. These associations were significant in men, but not in women. Moreover, participants who consumed 2-2.9 cups/day and ≥3 cups/day of coffee had lower HRs (0.69, 95% CI: 0.48-0.98 and 0.53, 95% CI: 0.31-0.89, respectively) than those who consumed 0 cup/day. The association between green tea consumption and reduced dementia risk was significant (adjusted p for trend = 0.0146) only in the 60-69 years age subgroup. CONCLUSIONS: High levels of coffee and caffeine consumption were significantly associated with a reduced dementia risk in a dose-dependent manner, especially in men. Moreover, coffee consumption of ≥3 cups/day was associated with a 50% reduction in dementia risk.

Greater knee joint laxity remains in teenagers after anatomical double-bundle anterior cruciate ligament reconstruction compared to young adults.

PURPOSE: There is paucity in studies regarding double-bundle anterior cruciate ligament reconstruction (DB-ACLR) in teenagers. The purpose of this study is to investigate clinical outcome after DB-ACLR and analyze whether any differences exist between teenagers and young adults. METHODS: A retrospective study was performed between 2009 and 2017. Teenagers were defined as patients between 15 and 19 years and young adults between 20 and 25 years old. Isolated anterior cruciate ligament (ACL) injuries with DB-ACLR with minimum two-year follow up were included. Pre and post-operative Lysholm score, Tegner activity scale, KT-2000 arthrometer, manual pivot-shift grade, were assessed with post-operative one-leg hop test, isokinetic knee extensor strength test at 60°/sec, International Knee Documentation Committee Score (IKDC score), and re-injury rate. RESULTS: One-hundred and thirty-one patients, 75 patients in the teenage group (Group A) and 56 patients in the young adult group (Group B), were enrolled. Lysholm score was significantly lower in Group A (89.6 ± 21.1) compared to Group B (95.9 ± 4.6) (p = 0.04). Side to side difference in KT-2000 arthrometer (2.3 ± 2.2 mm vs 1.0 ± 2.3 mm, Group A vs Group B, respectively, p < 0.01) and ratio of post-operative positive pivot shift was significantly greater in Group A (30.7%) compared to Group B (7.1%) (p < 0.01). No significant difference was seen in re-injury rate (n.s.). CONCLUSION: Teenage patients have a greater tendency for residual knee joint laxity after DB-ACLR. Although teenagers and patients in the early twenties are close in age, characteristic in knee joint laxity may be different and, therefore, may require attention upon surgery and post-operative follow-up. LEVEL OF EVIDENCE: III.

Health-Related Quality of Life After Microscopic Total Removal of Spinal Intramedullary Ependymomas in a Single-Institute 3-Year Prospective Study.

OBJECTIVE: Health-related quality of life (HRQOL) after surgery for spinal intramedullary benign encapsulated tumors remains unclear. A single-institute, 3-year, prospective study was conducted to examine HRQOL after microscopic total removal of spinal intramedullary ependymomas using a safe and precise strategy. METHODS: A cohort of 20 patients with a possible diagnosis of spinal intramedullary benign ependymomas was recruited. Patients who underwent microscopic total removal of the tumor and for whom the pathologic diagnosis was verified as World Health Organization grade II benign ependymoma were included. Sixteen patients (average age, 48.7 years) were eligible for study analysis. Careful assessment was performed for all patients before and 6-12 months after surgery. The 36-Item Short Form Health Survey was used to assess HRQOL, with the surveyor recording answers as reported by the individual patient. RESULTS: Average total HRQOL score was 431.1 before surgery and was maintained at 434.2 at 6-12 months postoperatively. Patients with mild functional symptoms tended to demonstrate a higher total HRQOL score preoperatively compared with patients with moderate to severe functional symptoms. A strong correlation was noted between postoperative functional conditions and preservation of HRQOL. CONCLUSIONS: This is the first study focusing on HRQOL after microscopic total removal of spinal intramedullary ependymomas. This study suggested that radical surgery using a safe and precise strategy appears justifiable and that preservation of neurologic function after surgery may lead to maintenance of postoperative HRQOL.

Safety of anterior cervical discectomy and fusion using titanium-coated polyetheretherketone stand-alone cages: Multicenter prospective study of incidence of cage subsidence.

This multicenter prospective study investigated cage subsidence in anterior cervical discectomy and fusion (ACDF) using titanium-coated polyetheretherketone (PEEK) stand-alone cages. This study recruited patients who underwent 1- or 2-level ACDF using titanium-coated PEEK stand-alone cages for cervical disc disease. Patients with acute trauma or past cervical spine operations were excluded. Sixty-two cages in 42 patients were eligible for analysis. Minimum follow-up was 6 months after ACDF. Significant cage subsidence was recognized in 11 of 62 cages (17.7%). Cage subsidence was predominantly moderate (14.5%), with severe subsidence found in only 2 cages (3.2%). The slowest occurrence of cage subsidence was 6 months after surgery, in 4 of 11 cages. Frequency of cage subsidence did not differ significantly between patients <65 and ≥65 years old. Patients with and without cage subsidence both demonstrated significant improvement of neurological function. Cage subsidence resulted in aggravation of local angle, but finally did not affect C2-7 angle or cervical tilt angle. Severe cage subsidence was found in only 3.2% of patients within 6 months after ACDF. Cage subsidence aggravated local angle, but finally did not affect C2-7 angle or cervical tilt angle. One- or 2-level ACDF using titanium-coated PEEK stand-alone cages appears safe and justified, even in elderly patients.

Valgus Subsidence of the Tibial Component Caused by Tibial Component Malpositioning in Cementless Oxford Mobile-Bearing Unicompartmental Knee Arthroplasty.

BACKGROUND: Valgus subsidence (VS) of the tibial component is a rare complication of unicompartmental knee arthroplasty (UKA), and surgeons might consider revision surgery. The present study aimed to identify the factors related to VS of the tibial component after cementless Oxford mobile-bearing UKA. METHODS: The study included 120 patients who underwent Oxford mobile-bearing UKA using a cementless tibial component in our center between September 2015 and September 2016. Six showed VS of >2° after surgery. Patients were stratified into 2 groups according to the occurrence of VS of the tibial component (VS group, n = 6; no-subsidence group, n = 114). Postoperative radiographic evaluations were conducted to assess the varus/valgus alignment, rotation, and mediolateral position of the tibial and femoral components. The Oxford Knee Score (OKS) was assessed at 3, 6, and 12 months postoperatively. Positional parameters and sequential change in OKS were compared between the two groups using unpaired t-test (P < .05, statistically significant). RESULTS: At 3 months postoperatively, an average VS of 3.4° in the VS group was observed, with a significant decrease in OKS. VS was associated with a significantly more medial position and external rotation of the tibial component. After 3 months, VS stopped, and the OKS gradually improved without revision surgery. CONCLUSIONS: VS might be caused by the malpositioning of the tibial component. VS of the tibial component after UKA appears to stop, with simultaneous pain relief, even without revision after 3 months postoperatively.

Additional Visualization via Smart Glasses Improves Accuracy of Wire Insertion in Fracture Surgery.

BACKGROUND: Smart glasses (SG) are a wearable device consisting of a small computer built into a head-mounted monitor (HMM) that can display various kinds of information. Lateral side visualization is displayed on the HMM of SG so the operator may also see it and the anteroposterior (AP) direction simultaneously. The present pilot study aimed to investigate the usefulness of SG in wire insertion for bone fracture. METHODS: We marked both the front and lateral sides of the shaft of an artificial femur bone. From the tip of the greater trochanter, we inserted a 2.4-mm Kirschner wire (K-wire) so that it could be directed toward the marks in both planes. Three surgeons enrolled in the study each performed 10 trials, both with SG (SG arm) and without (direct vision arm). We defined the error angle as the angle between the K-wire and the line connecting the marking point from the insertion point in both the front and lateral view images. We also measured the time it took to insert the K-wire in both arms. RESULTS: The SG had a significantly reduced (mean = 3.2°) error angle ( P = .02) when compared to the direct vision group (mean = 4.8°). However, no significant difference was found between direct vision (mean = 17.5 seconds) and SG arms (mean = 14.9 seconds) in the insertion time. CONCLUSION: While keeping the AP image view in primary focus, simultaneously viewing the lateral side of the surgical field using SG helps achieve more accurate wire insertion in surgery.

The Use of Smart Glasses for Surgical Video Streaming.

Observation of surgical procedures performed by experts is extremely important for acquisition and improvement of surgical skills. Smart glasses are small computers, which comprise a head-mounted monitor and video camera, and can be connected to the internet. They can be used for remote observation of surgeries by video streaming. Although Google Glass is the most commonly used smart glasses for medical purposes, it is still unavailable commercially and has some limitations. This article reports the use of a different type of smart glasses, InfoLinker, for surgical video streaming. InfoLinker has been commercially available in Japan for industrial purposes for more than 2 years. It is connected to a video server via wireless internet directly, and streaming video can be seen anywhere an internet connection is available. We have attempted live video streaming of knee arthroplasty operations that were viewed at several different locations, including foreign countries, on a common web browser. Although the quality of video images depended on the resolution and dynamic range of the video camera, speed of internet connection, and the wearer's attention to minimize image shaking, video streaming could be easily performed throughout the procedure. The wearer could confirm the quality of the video as the video was being shot by the head-mounted display. The time and cost for observation of surgical procedures can be reduced by InfoLinker, and further improvement of hardware as well as the wearer's video shooting technique is expected. We believe that this can be used in other medical settings.

Functional Outcomes of Salvage Surgery for Vestibular Schwannomas after Failed Gamma Knife Radiosurgery.

OBJECTIVE: We reviewed our experience with salvage surgery following failed gamma knife radiosurgery (GKS) for vestibular schwannomas. METHODS: The study comprised 18 patients with unilateral vestibular schwannomas. The median prescribed radiation dose was 12 Gy (range, 10-12.5 Gy). Nine patients had regrowth after GKS, and 9 had regrowth after surgical resection plus GKS. The median interval between GKS and surgical resection was 26 months (range: 4-66 months). The maximum tumor diameter of all patients ranged 25-43 mm (median 35.5 mm). The tumor was removed subtotally in 2 patients and partially in the other 16 patients. The median follow-up period after surgical resection was 60 months (range: 12-144 months). RESULTS: Among the 17 patients with preoperative preserved facial nerve function (House-Brackmann [HB] grade I-III), 14 of them (82%) had an HB score of grade I at the last follow-up. There were no differences in facial nerve preservation between those with failed GKS and those with failed GKS plus surgery (78% vs. 100%, P = 0.156). At the post-salvage surgery follow-up, the residual tumor was unchanged or decreased in 15 patients (83%) and increased in 3 patients (17%). CONCLUSION: A surgical indication after GKS should be carefully considered because of the natural regression of transient tumor expansion with time, and surgical resection is limited to subtotal or partial removal for functional preservation. Careful follow-up is necessary in patients with tumor regrowth several years after GKS due to delayed radiation effects.

Peptide HIV-1 integrase inhibitors from HIV-1 gene products.

Anti-HIV peptides with inhibitory activity against HIV-1 integrase (IN) have been found in overlapping peptide libraries derived from HIV-1 gene products. In a strand transfer assay using IN, inhibitory active peptides with certain sequential motifs related to Vpr- and Env-derived peptides were found. The addition of an octa-arginyl group to the inhibitory peptides caused a remarkable inhibition of the strand transfer and 3'-end-processing reactions catalyzed by IN and significant inhibition against HIV replication.