Motive and Opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements-an LLMPP study.

Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit": HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of, and mechanisms driving, IG vs non-IG MYC rearrangements have not been elucidated. Here we used custom targeted capture and/or whole genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, while BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because one IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

Clonal hematopoiesis-derived therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplant for lymphoid and non-lymphoid disorders.

Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk of tMN is high in recipients of autologous hematopoietic stem cell transplantation (aHSCT). Acquisition of genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly in the context of preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified. We studied a cohort of 1507 patients undergoing aHSCT and a cohort of 263 patients who developed tMN without aHSCT to determine clinico-molecular features unique to post-aHSCT tMN. We show that tMN occurs in up to 2.3% of patients at median of 2.6 years post-AHSCT. Age ≥ 60 years, male sex, radiotherapy, high treatment burden ( ≥ 3 lines of chemotherapy), and graft cellularity increased the risk of tMN. Time to evolution and overall survival were shorter in post-aHSCT tMN vs. other tMN, and the earlier group's mutational pattern was enriched in PPM1D and TP53 lesions. Preexisting CH increased the risk of adverse outcomes including post-aHSCT tMN. Particularly, antecedent lesions affecting PPM1D and TP53 predicted tMN evolution post-transplant. Notably, CH-derived tMN had worse outcomes than non CH-derived tMN. As such, screening for CH before aHSCT may inform individual patients' prognostic outcomes and influence their prospective treatment plans. Presented in part as an oral abstract at the 2022 American Society of Hematology Annual Meeting, New Orleans, LA, 2022.

Respiratory problems associated with liver disease in children.

Respiratory manifestations of chronic liver disease have a profound impact on patient clinical outcomes. Certain conditions within paediatric liver disease have an associated respiratory pathology. This overlap between liver and respiratory manifestations can result in complex challenges when managing patients and requires clinicians to be able to recognise when referral to specialists is required. While liver transplantation is at the centre of treatment, it opens up further potential for respiratory complications. It is established that these complications place patients at risk of longer stays in hospital and reduced survival. Additionally, late post-transplant complications can occur, including post-transplant lymphoproliferative disease and immunosuppression-induced interstitial lung disease. Although rare, it is important for clinicians to recognise these conditions to allow for prompt management. Finally, as liver disease progresses in children, respiratory complications can occur. Hepatopulmonary syndrome can occur in the context of portal hypertension, resulting in increased mortality and poorer quality of life for patients. Another consequence is portopulmonary hypertension, which can be associated with poor survival. Failure to recognise these complications in children may result in poorer outcomes and therefore it is vital that clinicians can establish when referral to a paediatric respiratory medicine specialist is required.

Patients with Classic Hodgkin Lymphoma and Follicular Lymphoma Compared to Single Malignancy Controls.

Classic Hodgkin lymphoma (CHL) can arise in patients with low-grade B-cell lymphoma. The features of CHL arising in follicular lymphoma (FL) and its outcome are still unclear, mainly due to the very few cases reported. This study compares 17 patients with CHL and FL to 2 control groups: 1 of 26 patients with FL and a second of 60 patients older than 40 when diagnosed with CHL. Of the FL and CHL patients, 8 had simultaneous FL and CHL, while 9 had FL first, followed by CHL 4.7 years later on average. The age at the diagnosis of FL was 61 years for patients with synchronous FL and CHL and of 60 years for FL, followed by CHL at 65 years. Patients with FL only were, on average, 59 years old at presentation, while CHL patients were 61. FL was grade 1-2 in 75% of FL and CHL patients and 67% of FL first and CHL second patients, lower proportions than in the FL control group-92%. Epstein-Barr virus (EBV) was detected in a lower fraction (29%) of the FL and CHL group than in CHL-only controls (46%). BCL2 translocations were detected in 4 of the 7 cases with FL, but in positive cases, the rearrangement was also present in the CHL component, indicating a clonal relationship between FL and CHL. Patients with FL and CHL treated for CHL had an initial outcome more similar to FL than to CHL controls.

Development of a point-of-care colorimetric metabolomic sensor platform.

Metabolomics is the large-scale study of small molecule metabolites within a biological system. It has applications in measuring dietary intake, predicting heart disease risk, and diagnosing cancer. Metabolites are often measured using high-end analytical tools such as mass spectrometers or large spectrophotometers. However, due to their size, cost, and need for skilled operators, using such equipment at the bedside is not practical. To address this issue, we have developed a low-cost, portable, optical color sensor platform for metabolite detection. This platform includes LEDs, sensors, microcontrollers, a power source, and a Bluetooth chip enclosed within a 3D-printed light-tight case. We evaluated the color sensor's performance using both a range of dyed water samples as well as well-established colorimetric reactions for specific metabolite detection. The sensor accurately measured creatinine, L-carnitine, ascorbate, and succinate well within normal human urine levels with accuracy and sensitivity equal to or better than a standard laboratory spectrophotometer. Our color sensor offers a cost-effective, portable alternative for measuring metabolites via colorimetric assays, thereby enabling low-cost, point-of-care metabolite testing.

Outcomes following open acetabular labrum reconstruction: Comparing fresh-frozen tendon with fresh meniscus allograft transplantation.

Background: Symptomatic acetabular labral insufficiency in young, active patients is often treated with labral repair or reconstruction using fresh-frozen allografts. However, fresh-frozen tendon allografts do not have tissue or material properties that closely mimic acetabular labral fibrocartilage. Recent studies suggest meniscal allografts may be a better biomechanical, geometric, and material alternative for acetabular labrum reconstruction (ALR). Hypothesis: Patients undergoing open ALR using fresh meniscus allograft transplants (MAT) will have better outcomes than those using fresh-frozen tendon allografts transplants (TAT) when comparing initial treatment success, diagnostic imaging assessments, and patient-reported pain and function scores. Study design: Cohort Study. Methods: With IRB approval, patients undergoing ALR with either TAT or MAT were included when initial (>1-year) outcomes data related to treatment success, pain, and function were available. In addition, a subcohort of patients underwent magnetic resonance imaging at least 6-months after surgery to evaluate allograft healing. Results: Initial success rate, defined as no need for ALR revision or conversion to total hip arthroplasty (THA), was 88.9% for the entire group (n = 27, TAT = 5, MAT = 22) with 1 (20%) patient in the TAT cohort and 2 patients (9.9%) in the MAT cohort undergoing THA. In the MAT cohort, significant improvements were documented for physical function and pain scores at 1 year and final follow-up (FFU)(mean 26.8 months). Improvements in pain and function were noted at 1-year, but not at FFU (mean 59.6 months) in the TAT group. MRIs completed at least 6 months after labrum reconstruction showed improved allograft integrity and integration in the MAT cohort over the TAT cohort. Conclusion: For acetabular labrum reconstructions, MAT was associated with a higher initial success rate, superior patient reported outcomes, and subjectively better MRI findings when compared to TAT.

Comparison of Outcomes After Primary Versus Salvage Osteochondral Allograft Transplantation for Femoral Condyle Osteochondritis Dissecans Lesions.

Background: Osteochondral allograft transplantation (OCAT) allows the restoration of femoral condyle osteochondritis dissecans (OCD) lesions using an osteochondral unit. When OCD lesions are irreparable, or treatments have failed, OCAT is an appropriate approach for revision or salvage surgery. Based on its relative availability, cost-effectiveness, lack of donor site morbidity, and advances in preservation methods, OCAT is also an attractive option for primary surgical treatment for femoral condyle OCD. Hypothesis: OCAT for large femoral condyle OCD lesions would be highly successful (>90%) based on significant improvements in knee pain and function, with no significant differences between primary and salvage procedure outcomes. Study Design: Cohort study; Level of evidence, 3. Methods: Patients were enrolled into a registry for assessing outcomes after OCAT. Those patients who underwent OCAT for femoral condyle OCD and had a minimum of 2-year follow-up were included. Reoperations, treatment failures, and patient-reported outcomes were compared between primary and salvage OCAT cohorts. Results: A total of 22 consecutive patients were included for analysis, with none lost to the 2-year follow-up (mean, 40.3 months; range, 24-82 months). OCD lesions of the medial femoral condyle (n = 17), lateral femoral condyle (n = 4), or both condyles (n = 1) were analyzed. The mean patient age was 25.3 years (range, 12-50 years), and the mean body mass index was 25.2 kg/m2 (range, 17-42 kg/m2). No statistically significant differences were observed between the primary (n = 11) and salvage (n = 11) OCAT cohorts in patient and surgical characteristics. Also, 91% of patients had successful outcomes at a mean of >3 years after OCAT with 1 revision in the primary OCAT cohort and 1 conversion to total knee arthroplasty in the salvage OCAT cohort. For both primary and salvage OCATs, patient-reported measures of pain and function significantly improved at the 1-year and final follow-up, and >90% of patients reported that they were satisfied and would choose OCAT again for treatment. Conclusion: Based on the low treatment failure rates in conjunction with statistically significant and clinically meaningful improvements in patient-reported outcomes, OCAT can be considered an appropriate option for both primary and salvage surgical treatment in patients with irreparable OCD lesions of the femoral condyles.

Accelerated versus Standard Rehabilitation after Meniscus Allograft Transplantation in the Knee.

Meniscus allograft transplantation (MAT) is a proven treatment option for patients with symptomatic irreparable meniscus deficiency. When patients are adherent to prescribed postoperative restriction and rehabilitation protocols, outcomes after MAT are considered good to excellent. However, nonadherence to standard protocols is common and can be associated with undesirable outcomes and patient dissatisfaction. Based on demonstrated safety for early weight-bearing following MAT in conjunction with significant advances in graft preservation and surgical techniques, our joint preservation center implemented a shift in practice toward accelerated weight-bearing following MAT and designed this study to test the hypothesis that accelerated rehabilitation would be associated with superior adherence, patient-reported outcomes, and patient satisfaction, without diminishing patient safety, when compared with standard rehabilitation. Patients were included for analyses when they had undergone fresh or fresh-frozen MAT using a double bone plug technique for treatment of medial or lateral meniscus deficiency and had at least 1-year treatment outcomes recorded. The results of this study revealed that patients who were prescribed accelerated rehabilitation after MAT were significantly more adherent than patients who were prescribed standard rehabilitation and reported statistically significant and clinically meaningful improvements in knee pain and function for at least 1-year following MAT, whereas those in the standard cohort did not. While not statistically different, treatment failure rate was lower in the accelerated rehabilitation cohort when compared with the standard rehabilitation cohort (11 vs. 29%). Importantly, initial outcomes for revision MAT were associated with short-term success in all the patients who opted for this option in the study population. These data suggest that accelerated weight-bearing after MAT is safe, promotes patient adherence, and is associated with statistically significant and clinically meaningful improvements in patient-reported knee pain and function at early and mid-term follow-up.

Association of Residency Applicants' Hobbies and Subsequent Technical Proficiency Ratings as General Surgery Chief Residents: A Multi-Institutional Study.

OBJECTIVE: To determine whether participation in certain hobbies (e.g., participation in sports, playing musical instruments, or other hobbies requiring fine motor skills), preresidency, are associated with higher technical skills ratings at the time of residency graduation. DESIGN: Faculty members from 14 general surgery residency programs scored individual graduates from 2017 to 2020 on their technical skills using a 5-point Likert scale. Hobbies for these residents were collected from their Electronic Residency Application Service (ERAS) data. A single reviewer classified each ERAS hobby into predefined categories including musical instruments, sports requiring hand-eye coordination, team sports, and activities necessitating hand-eye coordination. Spearman correlation coefficients were calculated for the relationship between each category of hobby-as well as the total number of hobbies in each category-and the outcome of surgical faculty ratings of residents' technical surgical skills during their last year of residency. A proportional odds model including the above predictive variables was also fit to the data. SETTING: Fourteen general surgery residency programs. PARTICIPANTS: General surgery residency graduates from 14 different programs from 2017 to 2020. RESULTS: There were 296 residents across 14 institutions. The average ranking of residents' technical skills was 3.24 (SD 1.1). A total of 40% of residents played sports involving hand-eye coordination, 31% played team sports, 28% participated in nonsport hobbies that require eye-hand coordination, and 20% played musical instruments. Correlation coefficients were not statistically significant for any of the categories. In the proportional odds model, none of the variables were associated with statistically significant increased odds of a higher technical skills rating. CONCLUSIONS: There was no correlation between general surgery chief residents' technical skills as rated by faculty, and self-reported pre-residency hobbies on the ERAS application. These findings suggest such hobbies prior to residency are unlikely to predict future technical skills prowess.

KRM-II-81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy.

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM-II-81, a novel α2/3 subtype preferring GABAA receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM-II-81 might reduce seizure burden in pharmacoresistant patients.

Outcomes after Anatomic Double-Bundle Posterior Cruciate Ligament Reconstructions Using Transtibial and Tibial Inlay Techniques.

Surgical reconstruction is recommended for symptomatic posterior cruciate ligament (PCL) deficiency. While anatomic double-bundle PCL reconstruction (PCLR) has been reported to be associated with biomechanical and clinical advantages over other methods, there is still debate regarding the optimal technique for tibial positioning and fixation. Based on reported advantages and disadvantages, we employed two tibial fixation techniques, transtibial (TT) and tibial inlay (TI) for anatomic double-bundle PCLR with technique selection based on body mass index, comorbidities, and primary versus revision surgery. This study aimed to compare clinical outcomes following PCLR utilizing either TT or TI techniques to validate relative advantages, disadvantages, and indications for each based on the review of prospectively collected registry data. For 37 patients meeting inclusion criteria, 26 underwent arthroscopic TT PCLR using all-soft- tissue allograft with suspensory fixation in the tibia and 11 patients underwent open TI PCLR using an allograft with calcaneal bone block and screw fixation in the tibia. There were no significant preoperative differences between cohorts. Success rates were 96% for TT and 91% for TI with all successful cases documented to be associated with good-to-excellent posterior stability and range of motion in the knee at the final follow-up. In addition, patient-reported outcome scores were within clinically meaningful ranges for pain, function, and mental health after PCLR in both cohorts, suggesting similarly favorable functional, social, and psychological outcomes. Patient-reported pain scores at 6 months postoperatively were significantly (p = 0.042) lower in the TT cohort, which was the only statistically significant difference in outcomes noted. The results of this study support the use of TT and TI techniques for double-bundle anatomic PCLR in restoring knee stability and patient function when used for the treatment of isolated and multiligamentous PCL injuries. The choice between tibial fixation methods for PCLR can be appropriately based on patient and injury characteristics that optimize respective advantages for each technique.

Short-Term Outcomes After Bipolar Osteochondral Allograft Transplantation (OCAT) in the Ankle.

Treatment options for symptomatic cartilage loss in the ankle are not consistently effective. This study documents initial outcomes for patients undergoing bipolar OCAT in the ankle after advances in tissue preservation, transplantation techniques, and patient management strategies were implemented. Patients were prospectively enrolled into a registry designed to follow outcomes after OCAT in the ankle. Fourteen patients were included for analyses (12 primary OCAT, 2 revision OCAT). Four patients underwent Bipolar OCAT (tibia, talus) and 10 Bipolar+ OCAT (tibia, talus, fibula). Short-term (median follow-up 43, range 13-73 months) success was documented for 13 patients. Radiographic assessments indicated OCA integration and maintenance of joint space in 12 patients. Statistically significant (p < .030) and clinically meaningful improvements in AAOS and VAS pain scores were noted at 3 months, 6 months, 1 year, and 2 years following OCA transplantation when compared to preoperative measures. For patients that were nonadherent to postoperative restriction and rehabilitation protocols, all 1-year postoperative PROs were significantly lower (p < .050) than for patients who were adherent. The successful outcomes documented in 13 of 14 patients in conjunction with significant and clinically meaningful improvements in patient-reported measures of pain and function support OCA transplantation as an appropriate treatment option in indicated patients. These improvements in outcomes were associated with advances in OCA preservation, preimplantation treatment, transplantation techniques, and patient management strategies, suggesting this shift in practice be considered for OCA transplantation in the ankle.

Characterizing Osteochondral Allograft Biomechanics for Optimizing Transplant Success: A Systematic Review.

Osteochondral allograft (OCA) transplantation has been largely successful in treating symptomatic articular cartilage lesions; however, treatment failures persist. While OCA biomechanics have been consistently cited as mechanisms of treatment failure, the relationships among mechanical and biological variables that contribute to success after OCA transplantation have yet to be fully characterized. The purpose of this systematic review was to synthesize the clinically relevant peer-reviewed evidence targeting the biomechanics of OCAs and the impact on graft integration and functional survival toward developing and implementing strategies for improving patient outcomes. The Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, MEDLINE, PubMed, Cumulative Index to Nursing and Allied Health (CINAHL), Google Scholar, and EMBASE were searched to identify articles for systematic review. This review of relevant peer-reviewed literature provided evidence that the biomechanics related to OCA transplantation in the knee have direct and indirect effects on functional graft survival and patient outcomes. The evidence suggests that biomechanical variables can be optimized further to enhance benefits and mitigate detrimental effects. Each of these modifiable variables should be considered regarding indications, patient selection criteria, graft preservation methodology, graft preparation, transplantation, fixation techniques, and prescribed postoperative restriction and rehabilitation protocols. Criteria, methods, techniques, and protocols should target OCA quality (chondrocyte viability, extracellular matrix integrity, material properties), favorable patient and joint characteristics, rigid fixation with protected loading, and innovative ways to foster rapid and complete OCA cartilage and bone integration to optimize outcomes for OCA transplant patients.

Fusion of Rabies Virus Glycoprotein or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a mutation in the IDS gene, resulting in deficiency of the enzyme iduronate-2-sulfatase (IDS) causing heparan sulfate (HS) and dermatan sulfate (DS) accumulation in all cells. This leads to skeletal and cardiorespiratory disease with severe neurodegeneration in two thirds of sufferers. Enzyme replacement therapy is ineffective at treating neurological disease, as intravenously delivered IDS is unable to cross the blood-brain barrier (BBB). Hematopoietic stem cell transplant is also unsuccessful, presumably due to insufficient IDS enzyme production from transplanted cells engrafting in the brain. We used two different peptide sequences (rabies virus glycoprotein [RVG] and gh625), both previously published as BBB-crossing peptides, fused to IDS and delivered via hematopoietic stem cell gene therapy (HSCGT). HSCGT with LV.IDS.RVG and LV.IDS.gh625 was compared with LV.IDS.ApoEII and LV.IDS in MPS II mice at 6 months post-transplant. Levels of IDS enzyme activity in the brain and peripheral tissues were lower in LV.IDS.RVG- and LV.IDS.gh625-treated mice than in LV.IDS.ApoEII- and LV.IDS-treated mice, despite comparable vector copy numbers. Microgliosis, astrocytosis, and lysosomal swelling were partially normalized in MPS II mice treated with LV.IDS.RVG and LV.IDS.gh625. Skeletal thickening was normalized by both treatments to wild-type levels. Although reductions in skeletal abnormalities and neuropathology are encouraging, given the low levels of enzyme activity compared with control tissue from LV.IDS- and LV.IDS.ApoEII-transplanted mice, the RVG and gh625 peptides are unlikely to be ideal candidates for HSCGT in MPS II and are inferior to the ApoEII peptide that we have previously demonstrated to be more effective at correcting MPS II disease than IDS alone.

Development and validation of an LC-MS/MS method for the determination of ARN14988, an acid ceramidase inhibitor, and its application to a pharmacokinetic study in a mouse model.

Despite aggressive treatment approaches, the overall survival of glioblastoma (GBM) patients remained poor with a strong need for more effective chemotherapeutic agents. A previous study has shown that ARN14988 is more cytotoxic to GBM cells compared to US Food and Drug Administration-approved temozolomide. This finding makes ARN14988 a desirable candidate for further pharmacological assessment. Therefore, an efficient analytical method is needed to quantify ARN14988. Herein, we have developed and validated sample preparation and LC-MS/MS triple quadrupole (QQQ) method for quantification of ARN14988 in mouse plasma. In this method, the liquid-liquid extraction of ARN14988 from mouse plasma was performed using 5% ethyl acetate in hexane. The chromatographic separation was achieved using a C18 -column with mobile phases of 10 mm ammonium acetate (pH 5) and 0.1% formic acid in methanol, within a runtime of 10 min. The monitored transitions were m/z 391.20 → m/z 147.00 for ARN14988, and m/z 455.30 → m/z 165.00 for verapamil (internal standard) in positive electrospray ionization. The developed method for ARN14988 showed linearity over the range of 10-5,000 ng/ml (r2 > 0.99). The selectivity, sensitivity, matrix effect, recovery, stability, inter-day and intraday accuracy and precision were determined using four quality control samples. This validated method was successfully applied to the pharmacokinetic study of ARN14988 in mice.

Impacts of Knee Arthroplasty on Activity Level and Knee Function in Young Patients: A Systematic Review.

The annual demand for knee arthroplasty has been steadily rising, particularly in younger patients. The primary objective of this systematic review was to determine the impact of knee arthroplasties on knee function and activity levels in young (≤55 years) patients. A PubMed search from inception (1977) to March 2022 to identify eligible studies produced 640 peer-reviewed studies for consideration. A total of 18 studies including 4,186 knee arthroplasties in 3,200 patients (mean patient age at the time of surgery: 47.4 years, range: 18-55 years) were ultimately included for analysis. Mean final follow-up (FFU) duration was 5.8 years (range: 2-25.1 years). Mean FFU improvement in Knee Society Clinical Score was 48.0 (1,625 knees, range: 20.9-69.0), Knee Society Function Score was 37.4 (1,284 knees, range: 20-65). Mean FFU for the Tegner and Lysholm activity scale was 2.8 (4 studies, 548 knees, range: 0.7-4.2); University of California Los Angeles Physical Activity Questionnaire score was 2.8 (3 studies, 387 knees, range: 1.2-5); lower extremity activity scale was 1.84 (529 knees). The available evidence suggest that young patients typically realize sustained improvements in knee function compared to preoperative levels; however, these improvements do not typically translate into a return to desired activity levels or quality of life, and this patient population should expect a higher and earlier risk for revision than their older counterparts. Further research, including robust registry data, is needed to establish evidence-based indications, expectations, and prognoses for outcomes after knee arthroplasty in young and active patients.

BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases.

The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.

Evaluation of clinical parameters and biomarkers in older, untreated mantle cell lymphoma patients receiving bendamustine-rituximab.

Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high-risk call by a simplified MCL international prognostic index (s-MIPI) (HR: 3.32, 95% CI: 1.65-6.68 compared to low risk), a high-risk call by MCL35 (HR: 10.34, 95% CI: 2.37-45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92-9.22 compared to classic). Patients called high risk by both the s-MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10-32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49-5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk-stratify older MCL patients in future clinical trials.

Treatment failures (revision or arthroplasty) after knee osteochondral allograft transplantation with minimum two-year follow-up.

BACKGROUND: Knee osteochondral allograft transplantation (OCAT) has been associated with good short- to mid-term outcomes, however, treatment failures occur more frequently than desired. This study used data from a lifelong outcomes registry to analyze knee OCAT treatment failure rates, variables associated with knee OCAT treatment failures, and outcomes after revision or arthroplasty surgery for knee OCAT treatment failures. METHODS: Patient outcomes were followed after knee OCAT performed using standard preservation (SP) or Missouri Osteochondral Preservation System (MOPS®) allografts. The study population consisted of patients undergoing primary OCAT with ≥ 2-year follow-up. For comparisons, the treatment failure population was defined by patients in the study population with documented treatment failure (revision or arthroplasty) with ≥ 2-year follow-up after failure. Functional graft survival was defined as no further need for revision surgery after primary or revision OCAT. RESULTS: A total of 262 patients (n = 136 males; 51.9%) were analyzed. SP grafts were used for 59 cases and MOPS grafts were used for 203 cases. Treatment failure was documented in 61 cases (23.3%). MOPS grafts were 3.3 times more likely to be associated with functional graft survival. SP grafts, older patient age, higher BMI, tibiofemoral bipolar OCAT and non-adherence to the postoperative rehabilitation protocol were significantly associated with treatment failure. CONCLUSIONS: Knee OCAT resulted in functional graft survival at short- to mid-term follow-up in the majority (70-88%) of cases. In addition, revision of primary OCAT resulted in functional graft survival for at least 2 years after revision surgery in the majority (66%) of patients. LEVEL OF EVIDENCE: 2, prospective cohort study.

GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiation-sensitize primary and brain-metastatic lung adenocarcinoma tumors.

In non-small cell lung cancer (NSCLC) treatment, targeted therapies benefit only a subset of NSCLC, while radiotherapy responses are not durable and toxicity limits therapy. We find that a GABA(A) receptor activator, AM-101, impairs viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing an ex vivo 'chip', AM-101 is as efficacious as the chemotherapeutic docetaxel, which is used with radiotherapy for advanced-stage NSCLC. In vivo , AM-101 potentiates radiation, including conferring a survival benefit to mice bearing NSCLC intracranial tumors. GABA(A) receptor activation stimulates a selective-autophagic response via multimerization of GABA(A) Receptor-Associated Protein (GABARAP), stabilization of mitochondrial receptor Nix, and utilization of ubiquitin-binding protein p62. A targeted-peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis triggering autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. Highlights: Activating GABA(A) receptors intrinsic to lung primary and metastatic brain cancer cells triggers a cytotoxic response. GABA(A) receptor activation works as well as chemotherapeutic docetaxel in impairing lung cancer viability ex vivo . GABA(A) receptor activation increases survival of mice bearing lung metastatic brain tumors.A selective-autophagic response is stimulated by GABA(A) receptor activation that includes multimerization of GABARAP and Nix.Employing a new nanomolar affinity peptide that abrogates autophagosome formation inhibits cytotoxicity elicited by GABA(A) receptor activation.