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Objectives: The positive expression of Cyclin D1 in immunohistochemical (IHC) staining serves as the cornerstone for diagnosing mantle cell lymphoma (MCL). However, existing literature does not conclusively establish whether the expression ratio and staining intensity significantly influence diagnostic outcomes or patient prognosis. In this retrospective study, the correlation between comprehensive Cyclin D1 quantification and the prognosis of MCL patients was studied., Methods: The Cyclin D1 protein level was assessed in 120 formalin-fixed paraffin-embedded samples from MCL patients using the quantitative dot blot (QDB) analysis technique. R language software was employed for statistical analysis to determine the optimal threshold with statistical significance. Additionally, Kaplan-Meier method was utilized to evaluate the relationship between the absolute level of Cyclin D1 protein and overall survival (OS) of patients. Furthermore, the Chi-square test was applied to analyze the causes of single and multiple fractures, with a significance level of p < 0.05. Finally, the Log-rank test was used to compare two survival curves, where a significance level of p < 0.05 was considered statistically significant., Results: At the optimized cutoff of 0.46 nmol/g, univariate analysis revealed a positive correlation between Cyclin D1 protein level and patient survival (OS). Specifically, in the subgroup with complete quantification of Cyclin D1 higher than the cutoff, the 5-year OS was 18%, whereas in the subgroup with complete quantification of Cyclin D1 lower than the cutoff, the 5-year OS was 4.8% (Log-rank test, P = 0.017). This indicates that patients with Cyclin D1 levels above the cutoff had significantly better overall survival compared to those below the cutoff. Additionally, in the Pearson distribution test, Ki-67 emerged as an independent prognostic factor for the complete quantification of Cyclin D1. Notably, Cyclin D1 complete quantification results remained unaffected by factors such as gender, age, LDH (Lactate Dehydrogenase) level, Ann Arbor stage(AAS), Ki-67, IPI(International prognostic index), MIPI(Mantle International prognostic index), and MIPI-c (MIPI Combined with Ki-67 Proliferation Index Chi-square test, p > 0.05)., Conclusions: Comprehensive Cyclin D1 quantification, especially above a threshold, significantly correlates with better overall survival in MCL. This highlights its prognostic importance in MCL management. Full quantification of CyclinD1 aids MCL prognosis, while QDB technology for biomarker quantification supports precise clinical prognostic stratification., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Studies have shown that Kaplan fibers (KFs) play a role in controlling anterolateral rotatory knee laxity in anterior cruciate ligament (ACL) injury. However, recent clinical studies have suggested that KF injuries are not associated with a higher-grade pivot shift in knees with acute ACL injuries., Purpose: To compare the effect of KF and anterolateral ligament injury on anterolateral rotatory laxity as measured by the pivot-shift test in both adult and adolescent patients with acute ACL injury., Study Design: Cross-sectional study; Level of evidence, 3., Methods: This study consisted of patients who experienced primary acute ACL tears between January 2019 and December 2021. The magnetic resonance imaging examinations and pivot-shift tests for these individuals were conducted within 14 days after injury. Variables associated with concomitant injury were included in a binary logistic regression model to evaluate risk factors of a high-grade pivot shift and a KF injury., Results: The study included 540 patients with acute ACL tears (64 adolescent patients and 476 adults). The main risk factor for a high-grade pivot shift after acute ACL injury in adults was partial or total disruption of anterolateral ligament continuity (odds ratio [OR], 2.271; 95% CI, 1.499-3.442). In adolescent patients, the main risk factor was KF injury (OR, 19.98; 95% CI, 2.367-168.669), including edema and disruption of continuity., Conclusion: The main risk factor for a high-grade pivot shift after acute ACL injury differs between adolescent patients and adults: the KF injury sign in adolescent patients indicates a higher-grade pivot shift., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was supported by the Scientific Research Program of Sichuan Medical and Health Care Promotion Institute (KY2022SJ0396) and Research Program of Sichuan Medical Association (Q22085). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2024.)

Objectives: Medial collateral ligament "pie-crusting" (MCLPC), selective release of the superficial MCL, has been shown to improve the arthroscopic access to the posterior horn of the medial meniscus without adversely affecting the outcomes of isolated meniscal surgery. However, whether MCL PC, to address concomitant meniscal lesions during anterior cruciate ligament reconstruction (ACLR) surgery, adversely affects ACLR outcomes is unknown. The aim of this study was to assess whether patients who had undergone MCLPC at the time of ACLR had similar post outcomes to patients undergoing isolated ACLR., Methods: 55 consecutive patients (33 male and 22 female), with minimum 2-year follow-up, who had undergone MCLPC with concomitant primary ACLR (PC group) were retrospectively matched on the basis of age, sex and follow-up with 55 patients who underwent isolated primary ACLR. Post-operative outcome measures (PROMs) included the Knee injury and Osteoarthritis Outcome Score, the International Knee Documentation Committee score, Tegner activity score, the EuroQol five-dimension health questionnaire and EuroQol visual analogue scale., Results: The two groups' median postoperative EQ 5D-VAS, EQ 5D-index and Tegner scores were similar. The difference between pre-operative and post-operative KOOS scores was similar for the two group for all subscales except the ADL subscale which was higher in the MCLPC group (24, IQR= 6-32) than in the isolated ACLR group (5, IQR= 0-9.74). The median post op IKDC score was 84 in the MCLPC group and compared with 90 in the isolated ACLR group. However, the difference between pre-operative and post-operative IKDC scores was higher in patients in the MCLPC group (40, IQR= 25-49) than in the isolated ACLR group (32, IQR=19.6-46.8)., Conclusions: MCLPC, performed at the time of ACLR does not appear to adversely affect the functional post-operative outcomes., Level of Evidence: IV., Competing Interests: Declaration of Competing Interest ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:James Robinson reports a relationship with Smith and Nephew Inc that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. James Robinson reports a relationship with CONMED Corporation that includes: speaking and lecture fees and travel reimbursement. James Robinson reports a relationship with Newclip Technics that includes: speaking and lecture fees and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Injuries of the superficial medial collateral ligament (sMCL) and anteromedial structures of the knee result in excess valgus rotation and external tibial rotation (ER) as well as tibial translation., Purpose: To evaluate a flat reconstruction of the sMCL and anteromedial structures in restoring knee kinematics in the combined MCL- and anteromedial-deficient knee., Study Design: Controlled laboratory study., Methods: Eight cadaveric knee specimens were tested in a 6 degrees of freedom robotic test setup. Force-controlled clinical laxity tests were performed with 200 N of axial compression in 0°, 30°, 60°, and 90° of flexion: 8 N·m valgus torque, 5 N·m ER torque, 89 N anterior tibial translation (ATT) force, and an anteromedial drawer test consisting of 89 N ATT force under 5 N·m ER torque. After determining the native knee kinematics, we transected the sMCL, followed by the deep medial collateral ligament (dMCL). Subsequently, a flat reconstruction of the sMCL with anteromedial limb, mimicking the function of the anteromedial corner, was performed. Mixed linear models were used for statistical analysis ( P < .05)., Results: Cutting of the sMCL led to statistically significant increases in laxity regarding valgus rotation, ER, and anteromedial translation in all tested flexion angles ( P < .05). ATT was significantly increased in all flexion angles but not at 60° after cutting of the sMCL. A combined instability of the sMCL and dMCL led to further increased knee laxity in all tested kinematics and flexion angles ( P < .05). After reconstruction, the knee kinematics were not significantly different from those of the native state., Conclusion: Insufficiency of the sMCL and dMCL led to excess valgus rotation, ER, ATT, and anteromedial tibial translation. A combined flat reconstruction of the sMCL and the anteromedial aspect restored this excess laxity to values not significantly different from those of the native knee., Clinical Relevance: The presented reconstruction might lead to favorable results for patients with MCL and anteromedial injuries with an anteromedial rotatory knee instability., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: The medial collateral ligament (MCL) is frequently involved in injuries around the knee but is uncommonly treated surgically. There are various techniques to reconstruct the medial side of the knee, which have varying outcomes., Purpose/hypothesis: The purpose of the present systematic review and meta-analysis is to describe the clinical results of surgical management of acute and chronic isolated grade III MCL injury using various functional scores, such as IKDC, Lysholm, and VAS, and to ascertain complication rates associated with these interventions., Methods: A systematic review was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines, and two independent authors (L.F and A.M) conducted a comprehensive search across multiple databases (PubMed, Web of Science, and Scopus). They reviewed each article's title and abstract for studies available until April 2024. The search terms used were "((MCL) OR (Medial collateral ligament)) AND (injuries) AND (treatment)". The full texts of the studies were evaluated when eligibility could not be assessed from the title and abstract., Results: The pooled proportion (percentage) of complications from the three studies reporting data on surgery for the MCL acute stage was 15.3% with 95% CI [6.1% to 24.6%]. No complications were reported in studies reporting surgery in the chronic stage. Marked resolution of pain was observed with the mean VAS Score for pain at the final follow-up after surgery for MCL injury in the acute stage was 0.4 with 95% CI [-0.04 to 0.84]. The mean IKDC score at the final follow-up in the three studies reporting data on surgery for the MCL in the acute stage was 79.39 with 95% CI [67.96 to 90.82], and in the chronic stage, was 85 with 95% CI [83.02 to 86.98]. The mean Lysholm Score at the final follow-up after surgery for MCL injury in the chronic stage was 83.04 with 95% CI [75.24 to 94.84], and in the acute stage was 95 with 95% CI [91.76 to 98.24]., Conclusion: This systematic review found that functional outcomes regarding IKDC and LYSHOLM scores were comparable for surgeries performed in acute and chronic MCL tears. There was a marginally increased risk of complication in surgeries performed for acute MCL tears. Compared to the acute phase, a marked resolution of pain was observed at the final follow-up after surgery for MCL injury., Study Design: Systematic review; level of evidence, 4.., Competing Interests: Conflict of InterestThe authors declare that there is no conflict of interest related to this study., (© Indian Orthopaedics Association 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Multi-ligament knee injury, involving complex destruction of structures like the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL), presents significant challenges in treatment as well as diagnosis. This case study focuses on a 55-year-old woman who was the victim of a severe traffic accident and had an ACL and PCL avulsion fracture, a medial condyle fracture, and a medial collateral ligament rupture. Afterward, open reduction and internal fixation of the right tibial plateau surgery was performed after a delay in order to manage the pain and swelling. Her rehabilitation was greatly helped by postoperative physical therapy, which focused on pain control, early mobilization, and gradual strength development. A well-structured rehabilitation plan was found to be beneficial, as indicated by the remarkable improvements in pain reduction and functional mobility. This case highlights the value of effective physical therapy in helping patients through the difficult recovery process following multiple ligament injuries with the goal of restoring function and improving their quality of life., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Thamke et al.)

Mantle cell lymphoma (MCL), representing 5% of cases, is an aggressive B-cell non-Hodgkin lymphoma. Rarely, it can spread to other areas. This case illustrates a unique occurrence of MCL involving the appendix, leading to obstructive symptoms. Additionally, its presentation as volvulus added complexity to diagnosis and treatment. A 72-year-old man with a history of MCL came to the ER with right lower quadrant abdominal pain and nausea for 7 days. A computed tomography scan showed a swirling sign, concerning for volvulus. The patient required emergent surgery for exploratory laparotomy. Intraoperatively, the patient was found to have an enlarged appendix measuring 16.5 cm in length and 5 cm in diameter. An appendectomy was performed, and the pathology was confirmed to be MCL. This is a rare case of MCL presenting in the appendix as a volvulus, resulting in obstructive symptoms. This distinctive manifestation posed significant challenges in diagnosis and management. Appreciating such cases is pivotal for accurate diagnosis and effective medical and surgical interventions for this aggressive lymphoma subtype., Competing Interests: None declared., (Published by Oxford University Press on behalf of JSCR Publishing Ltd 2024.)

Purpose: The objective of this study was to conduct a comprehensive assessment of MLKI outcome studies in order to ascertain the overall rates of return to sport following MLKI., Methods: A systematic review was conducted based on the PRISMA guidelines. Quality assessment of the systematic review was performed using the MINORS Score. The following search terms were browsed in the title, abstract, and keyword fields: "multiligament knee" or "MLKI" AND "return to sport" or "sports activity" or "athletes" or "sports" or "sportsman". The resulting measures extracted from the studies were the rate of RTS, level of RTS, complications, revision surgery, Tegner, International Knee Documentation Committee (IKDC) Lysholm and anterior cruciate ligament-return to sport after injury (ACL-RSI)., Results: A total of 439 patients were included in the study, of whom 383 (87.2%) were male and 56 (22.8%) were female. The mean age at surgery was 28.06 ± 8.93 years. The mean time from injury to surgery was 97.68 ± 127.81 weeks, while the mean follow-up was 42.83 ± 39.22 months. Of 312 patients who completed the follow-up and reported to be sportsmen before surgery, 184 (58.97%) returned to the same or higher pre-injury level, 58 (18.58%) returned to a lower level, while 69 (22.11%) did not return to sports activity. The author analysed the Tegner score in three studies and noted a decrease compared to the pre-injury level (from 7.12 ± 0.8 pre-injury to 4.59 ± 0.57 at the final follow-up; p < 0.001). At the final follow-up, 4 studies analysed IKDC with a mean value of 75.14 ± 9.6, 3 reported a mean Lysholm of 51.81 ± 27.6, and two reported a mean ACL-RSI of 64.82 ± 0.149. Among the 439 patients, a total of 90 (20.5%) complications/re-operations were reported, while a total of 29 (6.6%) failures were recorded., Conclusions: Return to sport after MLKI occurs in approximately 75% of surgically treated patients, though return to high-level sport is about 60% of the patients. Furthermore, one in five patients report complications, while the failure rate is relatively low (< 7%)., Level of Evidence: Systematic review of level 4., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© The Author(s) 2024.)

B-cell non-Hodgkins lymphomas (BCNHLs) are a category of B-cell cancers that show heterogeneity. These blood disorders are derived from different levels of B-cell maturity. Among NHL cases, ∼80-90 % are derived from B-cells. Recent studies have demonstrated that noncoding RNAs (ncRNAs) contribute to almost all parts of mechanisms and are essential in tumorigenesis, including B-cell non-Hodgkins lymphomas. The study of ncRNA dysregulations in B-cell lymphoma unravels important mysteries in lymphoma's molecular etiology. It seems also necessary for discovering novel trials as well as investigating the potential of ncRNAs as markers for their diagnosis and prognosis. In the current study, we summarize the role of ncRNAs involving miRNAs, long noncoding RNAs, as well as circular RNAs in the development or progression of BCNHLs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anterior cruciate ligament and meniscus tears are common among sports injuries. There are different techniques for addressing anterior cruciate ligament and meniscus tears, with distinct indications, advantages, and disadvantages. We present the case of a 23-year-old male who underwent right anterior cruciate ligament reconstruction and posterior horn medial meniscus repair using an all-inside technique via superficial medial collateral ligament (sMCL) pie-crusting. Clinical examination and radiological investigations a few months later identified calcifications on the medial side of the right knee. We diagnosed the patient with heterotopic ossification post-sMCL pie-crusting; no apparent causal factors were present. To our knowledge, there have been no documented instances of heterotopic ossification following sMCL pie-crusting. In conclusion, heterotopic ossification may occur after sMCL pie-crusting; further studies are needed on this subject., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory mantle cell lymphoma (MCL). During a fludarabine shortage, we used bendamustine as an alternative to standard cyclophosphamide/fludarabine (cy/flu) lymphodepletion (LD) prior to brexu-cel. We assessed MCL patient outcomes as well as CAR T-cell expansion and persistence after brexu-cel following bendamustine or cy/flu LD at our center. This was a retrospective single institution study that utilized prospectively banked blood and tissue samples. Clinical efficacy was assessed by 2014 Lugano guidelines. CAR T-cell expansion and persistence in peripheral blood were assessed on day 7 and at ≥month 6 for patients with available samples. Seventeen patients received bendamustine and 5 received cy/flu. For the bendamustine cohort, 14 (82%) received bridging therapy and 4 (24%) had CNS involvement. Fifteen patients (88%) developed CRS with 4 (24%) ≥grade 3 events. Six (35%) patients developed ICANS with 4 (24%) events ≥grade 3. No patient had ≥grade 3 cytopenias at day 90. Best objective (BOR) and complete response (CRR) rates were 82% and 65%, respectively. At 24.5 months median follow-up, 12-month progression-free survival (PFS) was 45%, 24-month PFS was 25%, and median duration of response was 19 months. Median OS was not reached. BOR was 25% (1/4) for patients with CNS involvement. CAR transgene expansion after bendamustine LD was observed on day 7 in all (4/4) patients tested and persisted at ≥6 months (2/2), regardless of response. Bendamustine LD before brexu-cel for MCL is feasible and safe with a lower frequency and shorter duration of cytopenias than reported for cy/flu. Both CAR T-cell expansion and persistence were observed after bendamustine LD. Outcomes appear comparable to the real world outcomes reported with cy/flu LD., (Copyright © 2024. Published by Elsevier Inc.)

With the approval of the first CAR T-cell products for hematological malignancies in 2017, these autologous cell therapies have changed the treatment paradigm for patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL), who have a poor prognosis and few effective treatment options. Despite the demonstrated clinical benefit in patients with r/r diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma, many patients who are eligible for CAR T-cell therapies do not receive them or are treated with CAR T cells as a later line of therapy at advanced stages of disease. Several barriers exist for referring patients to an authorized treatment center (ATC) for CAR T-cell therapy. Although most patients with NHL are treated by community-based oncologists, educational gaps may exist for some community oncologists about the availability of CAR T-cell therapies in certain indications, the overall treatment process, and how they can access these therapies for their patients. In addition to navigation of the referral process from the community setting to the ATC, other barriers include timely identification of candidates eligible for CAR T-cell therapy and logistical and reimbursement concerns. Here, we examine the patient CAR T-cell experience, which begins and ends in the community setting, and identify and discuss opportunities for improved collaboration between community oncologists and ATC physicians to help address barriers to treatment and enhance patient outcomes. Treatment decisions for a patient's second or third line of therapy for NHL are critically important, owing to declining probabilities for favorable outcomes with each successive line of therapy. For patients who are eligible, CAR T-cell therapies should be considered as early as possible in their treatment course. A better understanding of the CAR T-cell process, the patient's experience, and the collaboration necessary for timely patient identification, better access, and successful outcomes will enable more patients to benefit from CAR T-cell therapies., Competing Interests: Declaration of competing interest M. R. Bishop has received consulting or advisory fees from Kite/Gilead, Novartis, Bristol Myers Squibb, CRISPR Therapeutics, Sana Therapeutics, Iovance, Servier, and In8Bio; has been paid to participate in a speakers’ bureau by Agios, Sanofi, Servier, Bristol Myers Squibb, and AstraZeneca; and has had travel expenses paid by Incyte and Sanofi. G. E. Kay has received consulting or advisory fees from Kite; has been paid to participate in a speakers’ bureau by Eli Lilly, Amgen, Sobi, and Seagen; and is an employee of and holds an ownership interest in Northwest Oncology., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

B-cell non-Hodgkin's lymphoma (NHL) refers to a heterogenous group of diseases, all of which have a wide range of treatment strategies and patient outcomes. There have been multiple novel, immune-based therapies approved in NHL in the last decade, including bispecific antibodies (BsAbs) and chimeric antigen receptor therapy (CAR-T). With a host of new therapies, an important next step will be determining how these therapies should be sequenced in contemporary management strategies. This review seeks to offer a framework for the ways in which BsABs can be incorporated into the current management paradigm for NHL, with special attention paid to diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL).

Introduction: The varus and valgus knee deformities result from imbalance in tension between medial and lateral soft tissue compartments. These conditions need to be addressed during total knee arthroplasty (TKA). However, there is no consensus on optimal soft-tissue release techniques for correcting varus and valgus deformities during TKA. We assessed the efficacy of a novel grid-based pie-crusting technique on soft-tissue release., Methods: Cadaver knees were dissected, leaving only the femur and tibia connected by an isolated MCL or the femur and fibula connected by an isolated LCL. Bone cuts were made as performed during primary TKA. Mechanical testing was performed using an MTS machine. A 3D-printed 12-hole grid was placed directly over the MCL and LCL. Using an 18-gauge needle, horizontal in-out perforations were made 3 mm apart. Deformation and stiffness of the ligaments were collected after every 2 perforations. Means were calculated, and regression analyses were performed., Results: A total of 7 MCL and 6 LCL knees were included in our analysis. The mean medial femorotibial (MFT) space increased from 6.018 ± 1.4 mm-7.078 ± 1.414 mm ( R = 0.937) following 12 perforations. The mean MCL stiffness decreased from 32.15 N/mm-26.57 N/mm ( 2  = 0.937) following 12 perforations. The mean MCL stiffness decreased from 32.15 N/mm-26.57 N/mm ( R 2  = 0.965). For the LCL group, the mean gap between the femur and fibula increased from 4.287 mm-4.550 mm following 8 perforations. The mean LCL stiffness decreased from 29.955 N/mm-25.851 N/mm. LCL stiffness displayed a strong inverse relationship with the number of holes performed ( R 2  = 0.988)., Discussion: Our results suggest that using this novel grid for pie-crusting of the MCL and LCL allows for gradual lengthening of the ligaments without sacrificing their structural integrity. Our proposed technique may serve as a valuable piece in the soft-tissue release toolkit for orthopaedic surgeons performing TKA in varus and valgus deformed knees., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Rezaei, Moon, Lichtig, Mera, Drake, Choubey, Kim, Tueni, Piponov, Koh, Karam and Amirouche.)

Purpose: The purpose of this study was to retrospectively analyse the pattern of injury to the medial knee structures in anterior cruciate ligament (ACL) injured patients. It was hypothesised that anteromedial injuries would be more common than posteromedial lesions., Methods: One hundred and twenty subjects aged 18-25 years with a primary ACL injury were included. Patients were excluded if the time between injury and magnetic resonance imaging (MRI) was more than 28 days or if a knee dislocation or fracture was present. The MRIs were analysed with particular emphasis on injuries to the medial knee structures, menisci and bone bruise patterns. Injuries to the ligaments and anteromedial retinaculum (AMR) were graded according to severity, ranging from periligamentous oedema (grade I), partial fibre disruption of less or more than 50% (grade IIa or IIb) to complete tears (grade III)., Results: AMR injury was seen in 87 subjects (72.5%) on the coronal plane and in 88 (73.3%) on the axial plane, with grade III lesions observed in 27 (22.5%) and 29 knees (24.2%). Injuries to the superficial medial collateral ligament (sMCL), deep MCL (dMCL) and posterior oblique ligament (POL) were detected in 60 patients (50%), 93 patients (77.5%) and 38 patients (31.6%). However, grade III injuries to the POL were observed in only seven knees (5.8%). Medial meniscus injuries were associated with lesions of the sMCL and AMR (p < 0.05), while lateral meniscus injuries were significantly more common in patients with dMCL rupture (p < 0.05)., Conclusion: Data from this study suggest that injuries to the AMR are much more common than posteromedial lesions in subjects with ACL injuries., Level of Evidence: Level IV., (© 2024 The Authors. Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Anteromedial rotatory instability (AMRI) of the knee is a complex and severe condition caused by injury to the anterior cruciate ligament and/or the medial collateral ligament. Clinical studies dealing with AMRI are rare, and objective measurements are nonexistent., Purpose/hypothesis: The objectives of this study were, first, to quantify anteromedial rotatory knee laxity in healthy individuals using a noninvasive image analysis software and, second, to assess intra- and interrater reliability and equivalence in measuring anteromedial knee translation (AMT). It was hypothesized that AMT could be reliably quantified using a noninvasive image analysis software., Study Design: Cohort study; Level of evidence, 3., Methods: This prospective proof-of-concept study included healthy individuals aged 16 to 40 years with no history of knee injury or surgery. Three adhesive surface markers were placed on predefined landmarks on the medial side of the knee. Three independent investigators examined anteromedial rotatory knee laxity with an anterior drawer test in different tibial rotations (neutral tibial rotation, 15° of external tibial rotation, and 15° of internal tibial rotation). The entire examination of each knee was recorded, and AMT including the side-to-side difference (SSD) was assessed using a freely available and validated image analysis software (PIVOT iPad application). Group comparisons were performed using a 1-way analysis of variance with Bonferroni-adjusted post hoc analysis. Intraclass correlation coefficients (ICCs) were calculated to assess inter- and intrarater reliability of AMT measurements. Equivalence of measurements was evaluated using the 2 one-sided t -test procedure., Results: Anteromedial rotatory knee laxity was assessed in 30 knees of 15 participants (53% male) with a mean age of 26.2 ± 3.5 years. In all 3 raters, the highest AMT was observed in neutral tibial rotation (range of means, 2.2-3.0 mm), followed by external tibial rotation (range of means, 2.0-2.4 mm) and internal tibial rotation (range of means, 1.8-2.2 mm; P < .05). Intrarater reliability of AMT (ICC, 0.88-0.96) and SSD (ICC, 0.61-0.96) measurements was good to excellent and moderate to excellent, respectively. However, interrater reliability was poor to moderate for AMT (ICC, 0.44-0.73) and SSD (ICC, 0.12-0.69) measurements. Statistically significant equivalence of AMT and SSD measurements was observed between and within raters for almost all testing conditions., Conclusion: Anteromedial rotatory knee laxity could be quantified using a noninvasive image analysis software, with the highest AMT observed during neutral tibial rotation in uninjured individuals. Reliability and equivalence of measurements were good to excellent within raters and moderate between raters., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: S.S. has received consulting fees from Arthrex GmbH, KLS Martin Group, Medartios AG, and medi GmnH. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: Micheliolide (MCL), which is the active metabolite of parthenolide, has demonstrated promising clinical application potential. However, the effects and underlying mechanisms of MCL on atherosclerosis are still unclear., Method: ApoE -/- mice were fed with high fat diet, with or without MCL oral administration, then the plaque area, lipid deposition and collagen content were determined. In vitro, MCL was used to pretreat macrophages combined by ox-LDL, the levels of ferroptosis related proteins, NRF2 activation, mitochondrial function and oxidative stress were detected., Results: MCL administration significantly attenuated atherosclerotic plaque progress, which characteristics with decreased plaque area, less lipid deposition and increased collagen. Compared with HD group, the level of GPX4 and xCT in atherosclerotic root macrophages were increased in MCL group obviously. In vitro experiment demonstrated that MCL increased GPX4 and xCT level, improved mitochondrial function, attenuated oxidative stress and inhibited lipid peroxidation to suppress macrophage ferroptosis induced with ox-LDL. Moreover, MCL inhibited KEAP1/NRF2 complex formation and enhanced NRF2 nucleus translocation, while the protective effect of MCL on macrophage ferroptosis was abolished by NRF2 inhibition. Additionally, molecular docking suggests that MCL may bind to the Arg483 site of KEAP1, which also contributes to KEAP1/NRF2 binding. Furthermore, Transfection Arg483 (KEAP1-R483S) mutant plasmid can abrogate the anti-ferroptosis and anti-oxidative effects of MC in macrophages. KEAP1-R483S mutation also limited the protective effect of MCL on atherosclerosis progress and macrophage ferroptosis in ApoE -/- mice., Conclusion: MCL suppressed atherosclerosis by inhibiting macrophage ferroptosis via activating NRF2 pathway, the related mechanism is through binding to the Arg483 site of KEAP1 competitively., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest in this study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Combined injury of the anterior cruciate ligament (ACL) and the medial collateral ligament (MCL) is a common injury pattern and accounts for 20% of all ligamentous knee injuries. Despite advancements in surgical technique, there is no up-to-date consensus regarding the superiority of nonoperative versus operative management in higher-grade MCL tears of combined ACL-MCL injuries., Purpose: To interpret recent literature on treatment options and to provide an updated evidence-based approach for management of combined ACL-MCL knee injuries., Study Design: Systematic review and meta-analysis; Level of evidence, 4., Methods: We performed a systematic review on outcomes following treatment of concomitant ACL and MCL injuries. A computerized search was conducted in PubMed, Embase.com, and Scopus.com. Authors independently assessed eligible studies and screened titles and abstracts. Articles reporting on patients with concomitant ACL and MCL injuries with or without concomitant procedures were included. Data regarding study design, sample size, patient age and sex, length of follow-up, timing of surgery, indications, surgical methods, concomitant procedures, outcomes, and complications were recorded. Patient-reported outcomes (PROs) and functional outcomes, including Knee injury and Osteoarthritis Outcome Score, International Knee Documentation Committee scores, Lysholm and Tegner scores, and range of motion, were estimated via meta-analysis and compared statistically by surgical approach., Results: In total, 18 studies were included in the systematic review with level 1 to level 4 evidence, with a total of 1,534 cases, were included in the systematic review. Of these, 16 studies with sufficient statistical reporting including 997 cases with sufficient follow-up were included in meta-analysis. Three different approaches to combined ACL-MCL injuries were identified: ACL reconstruction with (1) nonoperative MCL, (2) MCL repair, and (3) MCL reconstruction. There was no statistical difference between nonoperative versus surgically managed MCL injuries for PROs, range of motion at final follow up, or quadriceps strength., Conclusion: Reconstruction of combined injury in a delayed fashion facilitates return of range of motion and may allow time for low-grade MCL tears to heal. If residual valgus or anteromedial rotatory laxity remains after a period of rehabilitation, then concomitant surgical management of ACL and MCL injuries is warranted. Avulsion MCL injuries and Stener-type lesions may benefit from early repair techniques., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Calcification of the medial collateral ligament is a rare cause of medial knee pain along with functional impairment. Most cases are asymptomatic but those that are symptomatic typically respond to conservative management. However, in those instances with persistent symptoms that desire further intervention but want to minimize the risks associated with surgery, we present a novel approach for calcium removal with an ultrasound-guided percutaneous needle tenotomy with TenJet™ as a reasonable treatment modality.

A review article summarizes the existing literature on intraoperative injury to medial collateral ligament (MCL) during total knee arthroplasty (TKA), methods of fixation, repair, and the outcomes after these injuries. The options for increasing implant constraint and repair of the MCL injury are discussed with the potential indications for each. There is also a review of risk factors for MCL injury during TKA to help anticipate potential issues preoperatively. The proper use of retractors during total knee replacement is also discussed with a focus on careful protection of the MCL during surgery., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: There remains controversy regarding the optimal surgical treatment for acute complete (grade III) posterolateral corner (PLC) injuries. The purpose of this article is to systematically review the contemporary literature regarding surgical options and subsequent outcomes of acute grade III PLC injuries., Methods: A systematic review was performed using the following search terms: posterolateral corner knee, posterolateral knee, posterolateral instability, multi-ligament knee, and knee dislocation. Inclusion criteria consisted of studies with level I-IV evidence, reporting on human patients with acute grade III PLC injuries undergoing operative management within 4 weeks from injury, with subjective and/or objective outcomes (including varus stress examinations or varus stress radiographs) reported at a minimum 2-year follow-up. Two investigators independently performed the search by sequentially screening articles. Accepted definitions of varus stability on examination or stress radiographs and revision surgery were used to determine success and failure of treatment., Results: A total of 12 studies, consisting of 288 patients were included. Ten studies reported primary repair, while reconstruction techniques were reported in seven studies. Overall, 43% (n = 125/288) of injuries involved the PLC, ACL and PCL. Staged reconstruction was reported in 25% (n = 3/12) of studies. The Lysholm score was the most commonly reported outcome measure. An overall failure rate of 12.4% (n = 35/282) was observed. Surgical failure was significantly higher in patients undergoing repair (21.9%; n = 21/96) compared to reconstruction (7.1%; n = 6/84) (p = 0.0058). Return to sport was greater in patients undergoing reconstruction (100%; n = 22/22) compared to repair (94%; n = 48/51) (n.s). The most common post-operative complication was arthrofibrosis requiring manipulation under anesthesia (8.7%; n = 25/288). A total of 3.8% (n = 11/288) of patients underwent revision PLC reconstruction., Conclusion: There remains substantial heterogeneity in the surgical techniques of acute, grade III PLC injuries with an overall failure rate of 12.4%. Failure rates were significantly lower, and return to sport rates higher in patients undergoing PLC reconstruction compared to repair. The most common postoperative complication was arthrofibrosis requiring manipulation under anesthesia., Level of Evidence: Level IV., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Background: Multiligament knee injuries involving the medial side are common. When performing surgical reconstruction, use of the medial hamstrings (HS) as grafts remains controversial in this setting., Purpose: To determine the role of the medial HS in stabilizing the valgus knee for different types of medial-sided knee injury., Study Design: Controlled laboratory study., Methods: A biomechanical study on 10 cadaveric knees was performed. Valgus load (force moment of 10 N/m) was applied at 0°, 30°, and 60° of flexion, and the resultant rotation was recorded using an optoelectronic motion analysis system. Measurements were repeated for 4 different knee states: intact knee, superficial medial collateral ligament (sMCL) injury, deep medial collateral ligament (dMCL) injury, and posterior oblique ligament (POL) injury. For each state, 4 loading conditions (+ loaded; - unloaded) of the semitendinosus (ST) and gracilis (GRA) tendons were tested: ST+/GRA+, ST+/GRA-, ST-/GRA+, and ST-/GRA-., Results: At 0° of flexion, combined unloading of the ST and GRA (ST-/GRA-) increased valgus laxity on the intact knee compared with the ST+/GRA+ condition ( P < .05). For all medial-sided injury states (isolated sMCL; combined sMCL and dMCL; and combined sMCL, dMCL, and POL damage), ST-/GRA- increased valgus laxity at 0° and 30° of flexion versus ST+/GRA+ ( P < .05 for all). The absolute value of valgus laxity increased with the severity of medial-sided ligament injury. Isolated ST unloading increased valgus laxity for the intact knee and the MCL-injured knee (combined sMCL and dMCL) at 0° of flexion ( P < .05 vs ST+/GRA+). Isolated unloading of the GRA had no effect on valgus knee stability., Conclusion: The medial HS tendons contributed to the stabilization of the knee in valgus, and this was even more important when the medial side was severely affected (POL damage). This stabilizing effect was greater between 0° and 30°, in which the POL is the main valgus stabilizer., Clinical Relevance: When deciding on graft selection for multiligament knee injury reconstruction, the surgeon should be aware of the effect of harvesting the medial HS tendon on valgus laxity., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: A.K. has received consulting fees from Stryker and speaking fees from Implantcast. R.P. has received consulting fees from Lepine. B.S.-C. has received consulting fees and royalties from Arthrex. T.N. has received consulting fees from Lepine. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval was not sought for the present study., (© The Author(s) 2023.)

Non-Hodgkin lymphoma's (NHL) incidence is rising over time, and B cell lymphomas comprise the majority of lymphomas. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue 1 (Akt)/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in a variety of cellular processes, such as cell proliferation and survival. Its role in lymphomagenesis is confirmed in many different types of B cell lymphomas. This review is mainly focused on the PI3K/v-akt/mTOR pathway-related oncogenic mechanisms in B cell NHLs with an emphasis on common B cell lymphoma types [diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)]. Furthermore, it summarizes the literature regarding the clinical applications of the mTOR inhibitors temsirolimus and everolimus in B cell NHLs, which have been tested in a range of clinical trials enrolling patients with B cell malignancies, either as monotherapy or in combination with other agents or regimens.

Purpose: The purpose of this study is to report on the biomechanical durability and strength of an MCL internal brace construct. The null hypothesis is that there will be no difference between this construct and the intact MCL in terms of deflection during fatigue testing and the ultimate failure load., Methods: Eight cadaver knees were used. A grade 3 equivalent MCL tear was created with both the superficial and deep femoral MCL severed. An internal brace was created by placing a cortical button and loop through the center of the femoral MCL origin and secured on the lateral cortex of the distal femur. A FiberTape (Arthrex, Naples, FL) was looped through the cortical button loop and was secured in the center of the tibial insertion of the MCL. After pre-cycling, the specimens underwent 1000 cycles of compressive load between 100 and 300 N, using four point bending testing into direct valgus. Pre and post testing deflection was measured using three dimensional motion data from two sets of reflective markers. A load-to-failure test was then conducted with failure defined as the first significant decrease in the load-displacement curve., Results: The mean increase in deflection between pre- and post-testing was 0.6° (SD ± 0.3°). The mean failure bending moment was 122.4 Nm (SD ± 29 Nm)., Conclusion: The internal brace construct employed in this study was able to withstand cyclic fatigue loading and recorded a valgus load to failure similar to that of intact knees. It is important for clinicians who are considering using this commercially available technique to be aware of how the construct performs under cyclic loading compared to the intact MCL., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Purpose: The null hypothesis is that there would be no difference in medial gapping under valgus load between the intact MCL and the ruptured MCL with an internal brace in place., Methods: Eight pairs of cadaver knees were used (16 knees). Alternating sides, one knee from each pair was used for one of two "internal brace" constructs. The constructs involved different methods of fixation for securing FiberTape (Arthrex, Naples, FL) to both the femur and tibia in an effort to brace the MCL. The knees were then subjected to valgus stress by applying 10 N m of torque with the knee at 20 degrees of flexion. The amount of medial joint space opening was measured on radiographs. The stress testing was conducted with three MCL states: intact, grade 2 tear, and grade 3 tear., Results: In the Construct I specimens, gapping increased from 0.7 mm with the MCL intact to 1.1 mm with grade 2 tearing (p < 0.01), and to 1.3 mm with grade 3 tearing (p < 0.01). In the Construct II specimens, gapping increased from 0.7 mm with the MCL intact to 1.0 mm with grade 2 tearing (p < 0.01), and to 1.1 mm with grade 3 tearing (n.s.). Construct I specimens failed primarily at the femoral attachment. All Construct II specimens survived the valgus stress testing., Conclusion: Construct I did not maintain tension. Construct II did maintain tension during application of valgus load, but did not restore valgus opening to the intact state. It is important for clinicians who are considering using this commercially available technique to be aware of how the construct performs under valgus stress testing compared to the intact MCL., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Purpose: Ligament balancing is a prerequisite for good function and survival in total knee arthroplasty (TKA). Various balancing techniques exist, but none have shown superior results. The pie-crusting technique by Bellemans of the medial collateral ligament is commonly utilized; however, it can be difficult to achieve repeatable ligament lengthening with this technique. Therefore, we invented a novel instrument to standardize the pie-crusting technique of the superficial and deep medial collateral ligament (hereafter MCL). The purpose was to examine if pie-crusting with the instrument could produce repeatable ligament lengthening., Methods: The MCL was isolated in 16 human cadaveric knees, and subjected to axial tension. The instrument was composed of a specific grid of holes in rows, used to guide sequential pie-crusting puncturing of the MCL with a Ø1.6 mm end-cutting cannula. Ligament lengthening was measured after each row of punctures. Regression analysis was performed on the results., Results: Mean lengthening ± SD in human cadaveric MCL for puncturing of row 1 in the instrument was 0.06 ± 0.09 mm, 0.06 ± 0.04 mm for row 2, 0.09 ± 0.08 mm for row 3, 0.06 ± 0.05 mm for row 4 and 0.06 ± 0.04 mm for row 5, giving a mean total lengthening of 0.33 ± 0.20 mm. Linear regression revealed that MCLs were repeatably lengthened by 0.07 mm per row when punctured using the instrument., Conclusions: MCLs showed linear lengthening in human cadavers for subsequent use of the instrument. Our instrument shows promising results for repeatable ligament lengthening., (© 2023. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Seth L. Sherman, MD, reports relationships with American Orthopedic Society for Sports Medicine; Arthrex; Arthoscopy; BioVentus; Biologics Alliance; CONMED Linvatec; Current Reviews in Musculoskeletal Medicine; DJO; Epic Bio; International Cartilage Regeneration & Joint Preservation Society; Icarus Bracing; International Society of Arthroscopy, Knee Surgery, and Orthopedic Sports Medicine; International Sports Medicine Fellows Conference; JRF Ortho; Kinamed; LifeNet, NewClip, Ostesys; Patellofemoral Foundation; Reparel; Sarcio; Smith & Nephew; Sparta Biomedical; Vericel; and Vivorte. The other authors declare no potential conflicts of interest.

Objectives: We assessed real-world healthcare resource utilization (HRU) and costs among US patients with relapsed or refractory mantle cell lymphoma (R/R MCL) by line of therapy (LoT)., Methods: We selected patients from MarketScan® (1/1/2016-12/31/2020): ≥1 claims of MCL-indicated first line (1L) therapies, ≥1 diagnoses of MCL pre-index date (1L initiation date), ≥6-month continuous enrollment pre-index date, second line (2L) therapy initiation, ≥18 years old at 2L, and no clinical trial enrollment. Outcomes included time to next treatment (TTNT), all-cause HRU, and costs., Results: The cohort ( N  = 142) was 77.5% male, aged 62 years (median). Sixty-six percent and 23% advanced to 3L and 4L+, respectively. Mean (median) TTNT was 9.7 (5.9), 9.3 (5.0), and 6.3 (4.2) months for 2L, 3L, and 4L+, respectively. Mean (median) per patient per month (PPPM) costs were $29,999 ($21,313), $29,352 ($20,033), and $30,633 ($23,662) for 2L, 3L, and 4L+, respectively. Among those who received Bruton tyrosine kinase inhibitors, mean (median) PPPM costs were $24,702 ($17,203), $31,801 ($20,363), and $36,710 ($25,899) for 2L, 3L, and 4L+, respectively., Conclusions: During the period ending in 2020, patients relapsed frequently, incurring high HRU and costs across LoTs. More effective treatments with long-lasting remissions in R/R MCL may reduce healthcare burden.

Despite major progress in mantle cell lymphoma (MCL) therapeutics, MCL remains a deadly disease with a median survival not exceeding four years. No single driver genetic lesion has been described to solely give rise to MCL. The hallmark translocation t(11;14)(q13;q32) requires additional genetic alterations for the malignant transformation. A short list of recurrently mutated genes including ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1, NOTCH2, and TRAF2 recently emerged as contributors to the pathogenesis of MCL. Notably, NOTCH1 and NOTCH2 were found to be mutated in multiple B cell lymphomas, including 5-10% of MCL, with most of these mutations occurring within the PEST domain of the protein. The NOTCH genes play a critical role in the early and late phases of normal B cell differentiation. In MCL, mutations in the PEST domain stabilize NOTCH proteins, rendering them resistant to degradation, which subsequently results in the upregulation of genes involved in angiogenesis, cell cycle progression, and cell migration and adhesion. At the clinical level, mutated NOTCH genes are associated with aggressive features in MCL, such as the blastoid and pleomorphic variants, a shorter response to treatment, and inferior survival. In this article, we explore in detail the role of NOTCH signaling in MCL biology and the ongoing efforts toward targeted therapeutic interventions.

TNF blockade constitutes an effective therapy for inflammatory bowel disease, yet increases the risk for infection, including active tuberculosis. The DECTIN2 family C-type lectin receptors MINCLE, MCL, and DECTIN2 sense mycobacterial ligands and activate myeloid cells. In mice, upregulation of DECTIN2 family C-type lectin receptor after stimulation with Mycobacterium bovis Bacille Calmette-Guérin requires TNF. Here, we investigated whether TNF controls inducible C-type lectin receptor expression in human myeloid cells. Monocyte-derived macrophages were stimulated with Bacille Calmette-Guérin and the TLR4 ligand lipopolysaccharide, and expression of C-type lectin receptor was analyzed. Bacille Calmette-Guérin and lipopolysaccharide strongly upregulated messenger RNA expression of DECTIN2 family C-type lectin receptor but not of DECTIN1. Bacille Calmette-Guérin and lipopolysaccharide also induced robust production of TNF. Recombinant TNF was sufficient to upregulate expression of DECTIN2 family C-type lectin receptor. Blocking TNF with the TNFR2-Fc fusion protein etanercept abrogated, as expected, the effect of recombinant TNF and impaired induction of DECTIN2 family C-type lectin receptor by Bacille Calmette-Guérin and lipopolysaccharide. Flow cytometry confirmed upregulation of MCL at the protein level by recombinant TNF and showed inhibition of Bacille Calmette-Guérin-induced MCL by etanercept. To investigate the impact of TNF on C-type lectin receptor expression in vivo, we analyzed peripheral blood mononuclear cells of patients with inflammatory bowel disease and observed downregulation of MINCLE and MCL expression after therapeutic TNF blockade. Together, TNF is sufficient to upregulate DECTIN2 family C-type lectin receptor in human myeloid cells and contributes to this process after encounter with Bacille Calmette-Guérin or lipopolysaccharide. Impaired C-type lectin receptor expression in patients receiving TNF blockade may dampen the sensing of microbes and defense against infection., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mantle cell lymphoma (MCL) is clinically characterized by its heterogenous behavior with courses ranging from indolent cases that do not require therapy for years to highly aggressive MCL with very limited prognosis. The development and implementation of new targeted and immunotherapeutic approaches have already improved therapeutic options especially for refractory or relapsed disease. Nevertheless, to further optimize MCL treatment, early identification of individual risk profile and risk-adapted, patient-tailored choice of therapeutic strategy needs to be prospectively incorporated in clinical patient management. This review summarizes the current knowledge and standard of care regarding biology and clinical management of MCL, highlighting the implementation of new therapeutic approaches especially targeting the immune system., (© 2023 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Background: Mantle cell lymphoma (MCL) is a heterogeneous disease belonging to non-Hodgkin's lymphoma. In recent years, the morbidity rate of MCL is ascending, and the prognosis remains unfavorable. Ubiquitin-specific proteases14 (USP14) has been evidenced to be engaged in the process of malignant tumors. In this article, the role of USP14 in the malignant process of MCL and the mechanism of ibrutinib resistance were discussed. Methods: Through qRT-PCR and western blot, the mRNA and protein expressions of USP14 in MCL cells were tested. USP14 interference plasmid was constructed by cell transfection technology, and then CCK8 and EdU assays were applied to appraise cell proliferation. Cell cycle and cell apoptosis were estimated by flow cytometry and western blot. The sensitivity of MCL cells to ibrutinib was also investigated. Next, western blot, co-IP, Cycloheximide (CHX) assay and other techniques were used to detect the relationship between USP14 and XPO1. Finally, by simultaneously inhibiting USP14 and overexpressing XPO1, the impacts of USP14 on the malignant process of MCL and the regulatory mechanism of ibrutinib sensitivity in MCL were discussed. Results: USP14 expression was markedly fortified in MCL cell lines. Interference of USP14 suppressed MCL cell viability, potentiated cell cycle arrest, apoptosis, and ibrutinib sensitivity. This process might be achieved by USP14 deubiquitination through enhancing XPO1 stability. Conclusion: USP14 can promote the malignant progression and ibrutinib sensitivity of MCL by stabilizing XPO1., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The Worldwide spread of the Omicron lineage variants has now been confirmed. It is crucial to understand the process of cellular life and to discover new drugs need to identify the important proteins in a protein interaction network (PPIN). PPINs are often represented by graphs in bioinformatics, which describe cell processes. There are some proteins that have significant influences on these tissues, and which play a crucial role in regulating them. The discovery of new drugs is aided by the study of significant proteins. These significant proteins can be found by reducing the graph and using graph analysis. Studies examining protein interactions in the Omicron lineage (B.1.1.529) and its variants (BA.5, BA.4, BA.3, BA.2, BA.1.1, BA.1) are not yet available. Studying Omicron has been intended to find a significant protein. 68 nodes represent 68 proteins and 52 edges represent the relationship among the protein in the network. A few centrality measures are computed namely page rank centrality (PRC), degree centrality (DC), closeness centrality (CC), and betweenness centrality (BC) together with node degree and Local clustering coefficient (LCC). We also discover 18 network clusters using Markov clustering. 8 significant proteins (candidate gene of Omicron lineage variants) were detected among the 68 proteins, including AHSG, KCNK1, KCNQ1, MAPT, NR1H4, PSMC2, PTPN11 and, UBE21 which scored the highest among the Omicron proteins. It is found that in the variant of Omicron protein-protein interaction networks, the MAPT protein's impact is the most significant., Competing Interests: Conflict of interestOn behalf of all the authors, the corresponding author states that there is no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Irreducible knee dislocations (IKD) are rare and can often be missed or misdiagnosed. The incidence of knee dislocation is quoted between 0.01% and 0.2% of all orthopaedic injuries, with up to 4% of these dislocations sub-classified as irreducible. The primary aim of this systematic review was to analyse cases of IKD described in the literature, with a secondary aim of producing a streamlined approach for managing these patients., Patients and Methods: A systematic review of the literature was conducted on 1st September 2021 in accordance with the PRISMA guidelines using the online databases Medline and EMBASE. The review was registered prospectively in the PROSPERO database. Case reports or clinical studies or reporting on IKD were included. The studies were appraised using the Methodological Index for Non-Randomized Studies (MINORS) tool and Newcastle-Ottawa quality assessment scale., Results: The search strategy identified 60 studies eligible for inclusion, giving a total of 114 cases of IKD. Posterolateral dislocation was most common, seen in 85% of cases. The dimple sign was present in 70%. All cases required surgical intervention to achieve joint reduction. The most commonly involved structure blocking reduction was the medial collateral ligament (MCL)±medial structures, seen in 52.4%. MCL reconstruction or repair was carried out in 32.3% cases. The overall incidence of neurovascular injury was 9% and the overall complication rate was 14.4%., Conclusion: Based on the findings of this SR we conclude that: the most common type of IKDs are PL dislocations, and the MCL, medial retinaculum and capsule and vastus medialis oblique form the most common structures involved in block to reduction and often will require open reduction and repair in acute setting if arthroscopic reduction fails. The most common pattern of injury to ligament is likely to be ACL, PCL, MCL±other structures but the MCL will be the most commonly repaired ligament. The dimple sign is often present and is highly pathognomonic of IKD. The incidence of neurovascular injury is uncommon. The most common post-operative complications likely to be encountered is medial skin necrosis and postoperative knee stiffness. Therefore, patients should be mobilised as early as possible with ROM in hinge brace., Level of Evidence: IV., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: The purpose of this study was to compare the combined reconstruction of the superficial medial collateral ligament (sMCL) and the posterior oblique ligament (POL) with the reconstruction of the sMCL associated with the advancement of the posteromedial capsule in a complex knee injury scenario. We hypothesized that both techniques would present similar knee stability and failure rates., Methods: This is a retrospective case-control study designed to compare the results of the two reported techniques for grade III MCL instability. Patients undergoing MCL reconstruction associated with anterior cruciate ligament, posterior cruciate ligament, or both, from 2010 to 2019, were included. The following parameters were evaluated: demographic data, type of graft, time from injury to surgery, associated meniscus injuries, follow up time, mechanism of trauma, postoperative objective IKDC, subjective IKDC and Lysholm scales, range of motion, reconstruction failure and complications., Results: Seventy-eight patients were evaluated, 37 of whom underwent reconstruction of the sMCL and POL, and 41 of whom underwent reconstruction of the sMCL with advancement of posteromedial structures. There was no difference in any preoperative variable. Patients undergoing reconstruction of the sMCL + advancement had greater loss of flexion (Group 1 3.4 ± 4.6 vs Group 2 8.4 ± 7.9; P = 0.002) and more individuals with flexion loss greater than 10° (Group 1, seven patients (18.9%) vs Group 2, 17 patients (41.5%); P = 0.031). Postoperative knee stability, failures and complications were similar between groups., Conclusion: Both techniques presented good functional results and low rates of complications. However, the advancement technique showed greater flexion loss, which should be considered when choosing the best surgical option., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Ligament bracing augments ligament repair using a non-absorbable suture tape. Although biomechanically an increase in primary stability has been proven, there is a lack of clinical evidence. Purpose of this study was to evaluate clinical results of patients treated with ligament bracing due to primary elbow instability, including an analysis of complications. Furthermore, clinical results for patients treated with and without early functional mobilization were compared., Materials and Methods: This prospective case-series evaluated clinical and functional results from patients treated with ligament bracing due to primary elbow instability. Clinical outcome measures were range of motion (ROM) as well as objective and subjective elbow scores [Mayo Elbow Performance Score (MEPS); Disabilities of Arm, Shoulder and Hand Score (DASH score)]. Stability was evaluated sonographically by humero-radial gapping under varus stress., Results: This study involved 34 patients treated with ligament bracing. After a mean follow-up of 12.9 months ROM was 112° ± 29, MEPS 88 ± 13 points, DASH 91 ± 11 points, and 84% were satisfied with their result. Lateral joint gapping was 2.4 mm. No significant difference was observed regarding a postoperative mobilization with and without limitations. Most common complication after ligament bracing was elbow stiffness including heterotopic ossifications in four patients (12%)., Conclusion: Operatively treated elbow instability with additional ligament bracing results in good clinical outcomes with high patient satisfaction and recovery of elbow stability. The high primary stability of the ligament bracing allows early functional mobilization without bracing, which facilitates postoperative rehabilitation. Elbow stiffness with heterotopic ossification seems to be a potential complication. Furthermore, the optimal tensioning of the ligament bracing remains challenging, including the risk of an over tensioning., Level of Evidence: III., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Compared with the large number of single-function materials such as aggregation-induced emission (AIE), mechanochromic luminescence (MCL), or thermally activated delayed fluorescence (TADF) emitters, multifunctional emitting materials offer more opportunities in practical applications. In this report, we provide a simple molecular design strategy towards the conversion of a MCL building block to a multifunctional emitter. Through altering the substituent sites and increasing the number of electron donors and steric hindrance on a normal MCL backbone benzo[ d , e ]benzo[4,5]imidazo[2,1- a ]isoquinolin-7-one, a novel multifunctional material 10,11-bis-(4-diphenylamino-phenyl)-benzo[ d , e ]benzo[4,5]imidazo[2,1- a ]isoquinolin-7-one (10,11-2TPA-BBI) is designed and synthesized. 10,11-2TPA-BBI exhibits simultaneous polymorphism, AIE, MCL and TADF properties. It can form four different aggregate species: yellow solid (YS) and orange solid (OS), orange flake-shaped crystal (OC), and red prism-like crystal (RC). Among them, because of the small energy gaps (Δ E ST s < 0.3 eV) between the singlet and triplet excited states, OS, OC and RC exhibit TADF properties, while YS show normal fluorescence characteristics with a large Δ E ST of 0.33 eV. OS can be reversibly transformed into YS upon external stimuli, which can be attributed to the emission switch between local excited state and charge transfer state. Crystallographic study indicates that the bulky structure and weak intermolecular interactions account for polymorphism and AIE properties. This work will provide a simple molecular design strategy for multifunctional materials., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3Kδ/AKT/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL.

An expert panel convened by the European Alliance for Personalized Medicine (EAPM) reflected on achievements and outstanding challenges in Europe in mantle cell lymphoma (MCL). Through the prism of member state experience, the panel noted advances in outcomes over the last decade, but highlighted issues constituting barriers to better care. The list notably included availability of newer treatments, infrastructure and funding for related testing, and shortages of relevant skills and of research support. The prospect of improvements was held to reside in closer coordination and cooperation within and between individual countries, and in changes in policy and scale of investment at both national and EU levels.

Background: Both the superficial medial collateral ligament (sMCL) and the deep MCL (dMCL) contribute to the restraint of anteromedial (AM) rotatory instability (AMRI). Previous studies have not investigated how MCL reconstructions control AMRI., Purpose/hypothesis: The purpose was to establish the optimal medial reconstruction for restoring normal knee kinematics in an sMCL- and dMCL-deficient knee. It was hypothesized that AMRI would be better controlled with the addition of an anatomically shaped (flat) sMCL reconstruction and with the addition of an AM reconstruction replicating the function of the dMCL., Study Design: Controlled laboratory study., Methods: A 6 degrees of freedom robotic system equipped with a force-torque sensor was used to test 8 unpaired knees in the intact, sMCL/dMCL sectioned, and reconstructed states. Four different reconstructions were assessed. The sMCL was reconstructed with either a single-bundle (SB) or a flattened hamstring graft aimed at better replicating the appearance of the native ligament. These reconstructions were tested with and without an additional AM reconstruction. Simulated laxity tests were performed at 0°, 30°, 60°, and 90° of flexion: 10 N·m valgus rotation, 5 N·m internal and external rotation (ER), and an AM drawer test (combined 134-N anterior tibial drawer in 5 N·m ER). The primary outcome measures of this force-controlled setup were anterior tibial translation (ATT; in mm) and axial tibial rotation (in degrees)., Results: Sectioning the sMCL/dMCL increased valgus rotation, ER, and ATT with the simulated AM draw test at all flexion angles. SB sMCL reconstruction was unable to restore ATT, valgus rotation, and ER at 30°, 60°, and 90° of flexion to the intact state ( P < .05). Flat MCL reconstruction restored valgus rotation at all flexion angles to the intact state ( P > .05). ER was restored at all angles except at 90°, but ATT laxity in response to the AM drawer persisted. Addition of an AM reconstruction improved control of ATT relative to the intact state at all flexion angles ( P > .05). Combined flat MCL and AM reconstruction restored knee kinematics closest to the intact state., Conclusion: In a cadaveric model, AMRI resulting from an injured sMCL and dMCL complex could not be restored by an isolated SB sMCL reconstruction. A flat MCL reconstruction or an additional AM procedure, however, better restored medial knee stability., Clinical Relevance: In patients evaluated with a combined valgus and AM rotatory instability, a flat sMCL and an additional AM reconstruction may be superior to an isolated SB sMCL reconstruction.

Multi ligament knee injuries (MLKIs) are highly complex injuries with associated complications and often present with difficult management strategies. MLKIs may affect the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (or posteromedial corner (PMC)), and lateral collateral ligament (or posterolateral corner (PLC)) in addition to other structures including the menisci, common peroneal nerve, and popliteal artery. MLKIs are highly associated with the male sex and are commonly seen in high-velocity motor vehicle accidents and low-velocity sports injuries. Given the multiple planes of movement in the knee and various primary and secondary stabilizers throughout those planes, there is great heterogeneity in an injury pattern and most involve the ACL and PCL. Initial evaluation of this injury includes assessment of lower extremity sensation, distal pulses, and ankle-brachial index (ABI). If vascular compromise is suspected, computed tomography angiography (CTA) or magnetic resonance angiography (MRA) are indicated to evaluate the vasculature. As opposed to CTA, MRA offers visualization of the soft-tissue structures that are commonly damaged in MLKIs. Initial management typically includes closed reduction of the knee with subsequent external fixation. Classification systems guide initial assessments; however, further management is unclear and leads the surgical team to decide the best, individualized management option for each patient. As a result, optimal surgical and postoperative treatment options remain complicated, and clinical outcomes remain difficult to predict. The purpose of this review is to consolidate the most up-to-date practices of the diagnostic workup, management, and treatment of MLKIs.

Lymphoma with secondary central nervous system (CNS) involvement represents one of the most aggressive malignancies, with poor prognosis and high mortality. New diagnostic tools for its early detection, response evaluation, and CNS relapse prediction are needed. We analyzed circulating microRNAs in the cerebrospinal fluid (CSF) and plasma of 162 patients with aggressive B-cell non-Hodgkin's lymphomas (B-NHL) and compared their levels in CNS-involving lymphomas versus in systemic lymphomas, at diagnosis and during treatment and CNS relapse. We identified a set of five oncogenic microRNAs (miR-19a, miR-20a, miR-21, miR-92a, and miR-155) in CSF that detect, with high sensitivity, secondary CNS lymphoma involvement in aggressive B-NHL, including DLBCL, MCL, and Burkitt lymphoma. Their combination into an oncomiR index enables the separation of CNS lymphomas from systemic lymphomas or nonmalignant controls with high sensitivity and specificity, and high Receiver Operating Characteristics (DLBCL AUC = 0.96, MCL = 0.93, BL = 1.0). Longitudinal analysis showed that oncomiR levels reflect treatment efficacy and clinical outcomes, allowing their monitoring and prediction. In contrast to conventional methods, CSF oncomiRs enable detection of early and residual CNS involvement, as well as parenchymal involvement. These circulating oncomiRs increase 1-4 months before CNS relapse, allowing its early detection and improving the prediction of CNS relapse risk in DLBCL. Similar effects were detectable, to a lesser extent, in plasma.

Lymphocyte enhancer-binding factor 1 (LEF1) and SRY-Box 11 (SOX11) are highly sensitive and specific for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) including the cyclin D1-negative subtype, respectively. We assessed the utility of these markers in a large cohort of small B-cell lymphomas (SBCLs) on varied sample types. Immunohistochemistry (IHC) was performed for LEF1 and SOX11 on 354 SBCLs (129 CLL/SLLs, 33 MCLs, 142 marginal zone lymphomas [MZLs]-nodal MZL [NMZL]: 40, extranodal MZL [ENMZL]: 28, splenic MZL [SMZL]: 74 cases-and 50 lymphoplasmacytic lymphomas [LPLs]/Waldenstrom macroglobulinemias [WMs]). Ninety-eight percent of CLL/SLLs were LEF1 positive. SOX11 showed good sensitivity (82%) and excellent specificity for MCL (99%), with only 2 of 142 MZLs (both SMZLs) showing SOX11 expression. The low sensitivity for SOX11 was on account of inclusion of 4 non-nodal cases. All 50 LPL/WMs were negative for both LEF1 and SOX11. The expression of SOX11 and LEF1 was not always mutually exclusive, as 2 confirmed MCLs expressed both markers. LEF1 and SOX11 have excellent utility as diagnostic markers especially for atypical CD5-positive SBCLs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma (NHL) that is aggressive and incurable with existing therapies, presenting a significant unmet clinical need. MCL occurs mainly in elderly patients with comorbidities; thus, intense treatment options including allogeneic stem cell transplantation (Allo-SCT) are not feasible. New treatment options are emerging for this elderly/unfit treatment group, we therefore conducted a systematic review to determine whether they offered an advance on the existing recommended treatment, R-CHOP. The search strategies to identify MCL therapies were designed to capture the most relevant studies from 2013 to 2020. Following preferred reporting items for systematic reviews and meta-analyses and population,interventions, observations and study design analysis, R-CHOP, ibrutinib and bendamustine plus rituximab (BR) were taken forward for critical and statistical analysis. All three therapies were effective in increasing the overall survival (OS) and progression-free survival of elderly/unfit patients with MCL. However, none resulted in a significant increase in OS compared to R-CHOP. In addition, R-CHOP had a better toxicity profile when compared to both ibrutinib and BR. We therefore conclude that treatment of elderly/unfit patients with MCL is still a significant unmet clinical need; and suggest that outside of the clinical trial setting, R-CHOP should remain the recommended front-line treatment for this patient group., Competing Interests: The authors report no conflicts of interest., (© 2021 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0-163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34 + cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (< 12 months) after first-line therapy showed a trend towards an inferior PFS and OS. Deaths after ASCT were predominantly caused by lymphoma relapse and/or progression (64%) or due to infections (23%). In conclusion, high-dose chemotherapy followed by ASCT in the era of novel targeted agents remains a feasible and effective approach for patients with high-risk or relapsed aggressive B-cell lymphomas. Remission status and age at ASCT, and the number of infused stem cells were of prognostic relevance., (© 2021. The Author(s).)