Citations

PURPOSETo determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.MATERIALS AND METHODSThe study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).RESULTSThe frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.CONCLUSIONThe study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

Background: Meniscal tears are common in active patients, but treatment trends and surgical outcomes in young patients with lateral meniscal tears are lacking. Purpose: To evaluate treatment trends, outcomes, and failure rates in young patients with lateral meniscal tears. Study Design: Cohort study; Level of evidence, 3. Methods: Patients aged ≤25 years treated surgically for isolated lateral meniscal tears from 2001 to 2017 were identified. Treatment trends were compared over time. International Knee Documentation Committee (IKDC) scores and failure rates were compared by treatment modality (meniscectomy vs meniscal repair). Failure was defined as reoperation, symptomatic osteoarthritis, or a severely abnormal IKDC score. Univariate regression analyses were performed to predict failure and IKDC scores based on treatment, type and location of tear, or extent of meniscectomy. Results: Included were 217 patients (226 knees) with a mean age of 17.4 years (range, 7-25 years); of these patients, 144 knees (64%) were treated with meniscectomy and 82 knees (36%) with meniscal repair. Treatment with repair increased over time compared with meniscectomy ( P < .001). At a minimum 2-year follow-up (mean, 6.1 ± 3.9 years), 107 patients (110 knees) had IKDC scores, and analysis indicated that although scores in both groups improved from pre- to postoperatively (repair: from 69.5 ± 13.3 to 97.4 ± 4.3; meniscectomy: from 75.7 ± 9.0 to 97.3 ± 3.9; P < .001 for both), improvement in IKDC score was greater after repair (27.9 ± 13.9) versus meniscectomy (21.6 ± 9.4) ( P = .005). Included in the failure analysis were 184 patients (192 knees) at a mean follow-up of 8.4 ± 4.4 years. The rates of reoperation, symptomatic osteoarthritis, and failure were not significantly different between the meniscectomy and repair groups. Conclusion: An increase was seen in the rate of isolated lateral meniscal tear repair in young patients. IKDC score improvement was greater after repair than meniscectomy, although postoperative IKDC scores were similar. Symptomatic arthritis, reoperation, and failure rates were similar between groups; however, there was a trend for increased arthritis symptoms in patients treated with meniscectomy, especially total meniscectomy. Treatment modality, type and location of tear, and amount of meniscus removed were not predictive of final IKDC scores or failure.

Abstract Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis culminates in the production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by conversion to citrate and utilization in the TCA cycle. Alternatively, pyruvate can be metabolized to lactate under aerobic conditions, which had been considered to be the dominant route in the setting of classical macrophage activation. However, based on studies that used UK5099 as a MPC inhibitor and showed reduction in key inflammatory cytokines, the mitochondrial route has been considered to be of significance for M1 activation as well. Herein, using a genetic depletion model, we found that MPC is dispensable for metabolic reprogramming and the activation of M1. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2–5µM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Apart from MPC inhibition, UK5099 at high doses impairs glutamate oxidation, mitochondrial membrane potential and HIF-1α stabilization. Taken together, UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.

Abstract The external globus pallidus (GPe) is an integrative hub and gateway for behavioral flexibility in reward-related behaviors. However, it remains unknown whether enriched astrocytes in the GPe guide behavioral flexibility. Here, we trained mice to exhibit goal-directed and habitual reward-seeking behaviors using the behavior tasks with effort- and time-based reward delivery, respectively. Then, we examined the temporal dynamics of GPe astrocytes during goal-directed and habitual learning. Overall, GPe astrocytes were substantially silenced during habitual learning compared to goal-directed learning. In the timescale of action events, GPe astrocyte activities were increased immediately after termination of reward-taking behavior before the following action. However, during habitual learning, the increase of astrocyte activity was not evident. Moreover, support vector machine (SVM) analysis demonstrated that GPe astrocytes dynamics predicted whether mice perform goal-directed or habitual behaviors. Interestingly, chemogenetic activation of GPe astrocytes, which dampened GPe neuronal firings and habitual behaviors, exhibting goal-directed behaviors. Strikingly, brief and repeated attentional stimulations recapitulated the effect of chemogenetic activation of GPe in intervening the habitual reward-seeking behaviors with increased GPe astrocyte activities. Our findings reveal a novel insight that increasing GPe astrocytic activities attenuates habitual behavior and improves behavioral flexibility, which may provide a potential therapeutic target for decision-making-related disorders, such as obsessive-compulsive disorder and addiction.

Background: Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation. Methods: The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index. Results: The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P =0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04–1.34], P =0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6–65.7], P <0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P <0.001; net reclassification index 1.05, P <0.001; integrated discrimination index 0.20, P <0.001). Conclusions: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02798731.

Background: Prospective studies evaluating second-look imaging of meniscus root repair using a transtibial pull-out technique are limited; therefore, optimal surgical indications and the technique for meniscus root repair remain uncertain. Hypothesis: It was hypothesized that there would be a high rate of healing, improvement in meniscal extrusion, and prevention of articular cartilage degeneration and subchondral bone abnormalities after meniscus root repair. Study Design: Case series; Level of evidence, 4. Methods: Consecutive patients undergoing transtibial root repair were prospectively enrolled at 2 orthopaedic centers between March 2017 and January 2019. Pre- and postoperative magnetic resonance imaging (MRI) scans were reviewed by a musculoskeletal radiologist in a blinded fashion for meniscal healing, quantification of extrusion, articular cartilage grade, subchondral bone changes, and coronary/meniscotibial ligament abnormalities. Given persistent extrusion observed on postoperative MRI scans, an additional 10 patients gave consent and were enrolled for immediate (before weightbearing) postoperative MRI scans. Results: A total of 45 patients (16 male, 29 female; mean ± standard deviation age, 42.3 ± 12.9 years; body mass index, 31.6) were prospectively enrolled in the study; there were 47 meniscus root repairs: 29 medial and 18 lateral (2 with both). Postoperative MRI was obtained at an average of 6.3 months (range, 5.1-8 months); 98% of meniscal repairs had evidence of healing. Mean extrusion increased significantly, from 1.9 ± 1.5 mm preoperatively to 2.6 ± 1.4 mm postoperatively ( P = .03). There was no significant progression of chondromalacia grade, subchondral edema, insufficiency fracture, subchondral cysts, or subchondral collapse. In the additional 10-patient cohort, the mean preoperative extrusion (1.6 ± 1.2 mm) was not significantly different from that immediately postoperatively (2.0 ± 1.0 mm; P = .23). Conclusion: Prospective MRI analysis of transtibial meniscus root repair confirmed a high rate of meniscal healing and no observable progression of cartilage degeneration or subchondral bone abnormalities at the short-term follow-up. However, meniscal extrusion worsened in the first 6 months after surgery. Registration: NCT03037242 ( ClinicalTrials.gov identifier).

Objectives: Meniscus root tears are increasingly being recognized. Meniscus extrusion has previously been associated with medial root tears; however, the relationship between secondary meniscus restraints, such as the meniscotibial (MT) ligament, extrusion, and root tears has yet to be formally evaluated. The purpose of this study was to better understand the association between MT ligament competence, medial meniscus extrusion, and medial meniscus posterior root tears (MMPRT), as well as to determine the progression of meniscus extrusion over time. Methods: Serial MRI’s from our institution were reviewed for patients who showed evidence of medial meniscus extrusion and MMPRT on at least one of 2+ available MRI’s. All patients were symptomatic at the time of diagnosis. All MRI’s were analyzed independently by two board-certified musculoskeletal radiologists. MT ligament disruption, medial meniscus extrusion, and MMPRT presence was recorded for each MRI. The time between MRI’s, presence of insufficiency fractures, and Outerbridge classification for the medial femur and tibia were also evaluated. Results: 27 knees in 26 patients were included in this study, with a total of 63 MRI’s analyzed (21 knees with 2 MRI’s, 3 with 3 MRI’s, and 3 with 4 MRI’s). All patients demonstrated clear medial meniscus extrusion and meniscotibial ligament disruption prior to the subsequent development of MMPRTs (p < 0.001). Mean extrusion at the time of initial MRI was 3.3 ± 1.1 mm, and increased significantly to 5.5 ± 1.8 mm at the time of first imaging with an identified MMPRT (p < 0.001). The average time between initial MRI and the first identification of MMPRT on a later MRI was 1.7 ± 1.6 years. Conclusions: In a sample of 27 symptomatic knees with serial MRI’s both before and after MMPRT diagnosis, all patients demonstrated MT ligament disruption and associated meniscus extrusion prior to the development of subsequent medial meniscus root tears. These findings suggest that MT ligament disruption and medial meniscus extrusion represent early and predisposing events contributing to MMPRT. Therefore, this provides a possible explanation of why meniscus extrusion is not corrected with medial meniscus root repair.