Comparison of 3 Different Surgical Techniques for Rotator Cuff Repair in a Rabbit Model: Direct Suture, Inlay Suture, and Polyether Ether Ketone (PEEK) Suture Anchor.

BACKGROUND: Rotator cuff tears have been repaired using the transosseous method for decades. The direct suture (DS) technique has been widely used for rotator cuff tears; however, the retear rate is relatively high. Suture anchors are now used frequently for rotator cuff repair (RCR) in accordance with recent developments in materials. However, polyether ether ketone (PEEK) may still cause complications such as the formation of cysts and osteophytes. Some studies have developed the inlay suture (IS) technique for RCR. PURPOSE/HYPOTHESIS: To compare how 3 different surgical techniques-namely, the DS, IS, and PEEK suture anchor (PSA)-affect tendon-bone healing after RCR. We hypothesized that the IS technique would lead to better tendon-to-bone healing and that the repaired structure would be similar to the normal enthesis. STUDY DESIGN: Controlled laboratory study. METHODS: Acute infraspinatus tendon tears were created in 36 six-month-old male rabbits, which were divided into 3 groups based on the technique used for RCR: DS, IS, and PSA. Animals were euthanized at 6 and 12 weeks postoperatively and underwent a histological assessment and imaging. The expression of related proteins was demonstrated by immunohistochemistry and immunofluorescence staining. Mechanical properties were evaluated by biomechanical testing. RESULTS: At 12 weeks, regeneration of the enthesis was observed in the 3 groups. However, the DS group showed a lower type I collagen content than the PSA and IS groups, which was similar to the results for scleraxis. The DS group displayed a significantly inferior type II collagen expression and proteoglycan deposition after safranin O/fast green and sirius red staining. With regard to runt-related transcription factor 2 and alkaline phosphatase, the IS group showed upregulated expression levels compared with the other 2 groups. CONCLUSION: Compared with the DS technique, the PSA and IS techniques contributed to the improved maturation of tendons and fibrocartilage regeneration, while the IS technique particularly promoted osteogenesis at the enthesis. CLINICAL RELEVANCE: The IS and PSA techniques may be more beneficial for tendon-bone healing after RCR.

Fluorescence in situ hybridization reveals the evolutionary biology of minor clone of gain/amp(1q) in multiple myeloma.

Growing evidence suggests that gain or amplification [gain/amp(1q)] accumulates during disease progression of multiple myeloma (MM). Previous investigations have indicated that small gain/amp(1q) subclones present at the time of diagnosis may evolve into dominant clones upon MM relapse. However, the influence of a minor clone of gain/amp(1q) on MM survival, as well as the correlation between different clonal sizes of gain/amp(1q) and the chromosomal instability (CIN) of MM, remains poorly understood. In this study, we analyzed fluorescence in situ hybridization (FISH) results of 998 newly diagnosed MM (NDMM) patients. 513 patients were detected with gain/amp(1q) at diagnosis. Among these 513 patients, 55 had a minor clone (≤20%) of gain/amp(1q). Patients with a minor clone of gain/amp(1q) displayed similar survival outcomes compared to those without gain/amp(1q). Further analysis demonstrated patients with a minor clone of gain/amp(1q) exhibited a clonal architecture similar to those without gain/amp(1q). Lastly, our results showed a significant increase in the clonal size of the minor clone of gain/amp(1q), frequently observed in MM. These findings suggested that a minor clone of gain/amp(1q) might represent an earlier stage in the pathogenesis of gain/amp(1q) and propose a "two-step" process in the clonal size changes of gain/amp(1q) in MM.

Monitoring Minimal Residual Disease in Patients with Multiple Myeloma by Targeted Tracking Serum M-Protein Using Mass Spectrometry (EasyM).

PURPOSE: We investigated both the clinical utilities and the prognostic impacts of the clonotypic peptide mass spectrometry (MS)-EasyM, a blood-based minimal residual disease (MRD) monitoring protocol in multiple myeloma. EXPERIMENTAL DESIGN: A total of 447 sequential serum samples from 56 patients with multiple myeloma were analyzed using EasyM. Patient-specific M-protein peptides were sequenced from diagnostic samples; sequential samples were quantified by EasyM to monitor the M-protein. The performance of EasyM was compared with serum immunofixation electrophoresis (IFE), bone marrow multiparameter flow cytometry (MFC), and next-generation flow cytometry (NGF) detection. The optimal balance of EasyM sensitivity/specificity versus NGF (10-5 sensitivity) was determined and the prognostic impact of MS-MRD status was investigated. RESULTS: Of the 447 serum samples detected and measured by EasyM, 397, 126, and 92 had time-matching results for comparison with serum IFE, MFC-MRD, and NGF-MRD, respectively. Using a dotp >0.9 as the MS-MRD positive, sensitivity was 99.6% versus IFE and 100.0% versus MFC and NGF. Using an MS negative cutoff informed by ROC analysis (<1.86% of that at diagnosis), EasyM sensitivity remained high versus IFE (88.3%), MFC (85.1%), and NGF (93.2%), whereas specificity increased to 90.4%, 55.8%, and 93.2%, respectively. In the multivariate analysis, older diagnostic age was an independent predictor for progression-free survival [PFS; high risk (HR), 3.15; 1.26-7.86], the best MS-MRD status (MS-MRD negative) was independent predictor for both PFS (HR, 0.25; 0.12-0.52) and overall survival (HR, 0.16; 0.06-0.40). CONCLUSIONS: EasyM is a highly sensitive and minimal invasive method of MRD monitoring in multiple myeloma; MS-MRD had significant predictive ability for survival outcomes.

Development and validation of an individualized and weighted Myeloma Prognostic Score System (MPSS) in patients with newly diagnosed multiple myeloma.

Current standard predictive models of disease risk do not adequately account for the heterogeneity of survival outcomes in patients with new-diagnosed multiple myeloma (NDMM). In this retrospective, multicohort study, we collected clinical and genetic data from 1792 NDMM patients and identified the prognostic impact of all features. Using the top-ranked predictive features, a weighted Myeloma Prognostic Score System (MPSS) risk model was formulated and validated to predict overall survival (OS). In the training cohort, elevated lactate dehydrogenase level (LDH), International Staging System (ISS) Stage III, thrombocytopenia, and cumulative high-risk cytogenetic aberration (HRA) numbers were found to have independent prognostic significance. Each risk factor was defined as its weighted value respectively according to their hazard ratio for OS (thrombocytopenia 2, elevated LDH 1, ISS III 2, one HRA 1, and ≥2 HRA 2, points). Patients were further stratified into four risk groups: MPSS I (22.5%, 0 points), II (17.6%, 1 points), III (38.6%, 2-3 points), and IV (21.3%, 4-7 points). MPSS risk stratification showed optimal discrimination, as well as calibration, of four risk groups with median OS of 91.0, 69.8, 45.0, and 28.0 months, for patients in MPSS I to IV groups (p < .001), respectively. Importantly, the MPSS model retained its prognostic value in the internal validation cohort and an independent external validation cohort, and exhibited significant risk distribution compared with conventional prognostic models (R-ISS, R2-ISS, and MASS). Utilization of the MPSS model in clinical practice could improve risk estimation in NDMM patients, thus prompting individualized treatment strategies.

MAF translocation remains a strong prognostic factor despite concurrent chromosomal abnormalities.

Not available.

Longitudinal genetically detectable minimal residual disease by fluorescence in situ hybridization confers a poor prognosis in myeloma.

Background: Deeper depth of response (DpR) after induction therapy, especially gain of negative minimal residual disease (MRD), has been linked to prolonged survival in multiple myeloma (MM). However, flow-MRD examination focuses on the numbers but not on the biological characteristics of residual plasma cells (PCs). Objectives: To explore whether the genetic features of residual tumor cells affect the survival time of patients with MM. Design: A retrospective cohort study. Methods: We investigated the clonality of cytogenetic abnormalities (CAs) of the residual PCs using interphase fluorescence in situ hybridization (iFISH) in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Here, a longitudinal cohort of 269 patients with patient-paired diagnostic and post-induction iFISH results was analyzed. Results: Persistent CAs after induction therapy were detected in about half of the patients (118/269, 43%), and patients with undetectable CAs showed significantly improved survival compared with those with genetically detectable MRD [median progression-free survival (mPFS): 59.7 versus 35.7 months, p < 0.001; median overall survival (mOS): 97.1 versus 68.8 months, p = 0.011]. In addition, different patterns of therapy-induced clonal evolution were observed by comparing the clonal structure of residual PCs with paired baseline samples. Patients who maintained at a high risk during follow-up had the worst survival (mPFS: 30.5 months; mOS: 54.4 months), while those who returned to lower risk or had iFISH- at both time points had the best survival (mPFS: 62.0 months, mOS: not reached). Conclusion: These findings highlighted the prognostic value of genetic testing in residual tumor cells, which may provide a deep understanding of clonal evolution and guide clinical therapeutic strategies.

Study using fluorescence in situ hybridization (iFISH) to investigate the clonality of cytogenetic abnormalities of the residual plasma cells in multiple myeloma Gain of negative minimal residual disease (MRD) has been linked to prolonged survival in cancer treatment. However, in multiple myeloma (MM), detection of MRD-negativity (MRD-) using multiparameter flow cytometry (MFC) only reflects the quantitative characteristics of residual plasma cells (PCs), while the biological and genetic features of MRD are neglected. To address this gap, our study has employed interphase fluorescence in situ hybridization (iFISH) to evaluate the clonality of cytogenetic abnormalities (CAs) of the bone marrow residual PCs after induction therapy, in combined with MRD detection by MFC to predict the prognosis of MM patients. A total of 396 patients from the database of National Longitudinal Cohort of Hematological Diseases in China (ClinicalTrials.gov identifiers: NCT04645199) were enrolled. Persistent CAs after induction therapy were detected in about half of the patients (118/269, 43%), and patients with undetectable CAs showed significantly improved survival compared with those without genetically detectable MRD. In addition, different patterns of therapy-induced clonal evolution were observed by comparing the clonal structure of residual PCs with paired baseline samples. And therapy-induced clonal evolution exerted a significant impact on patient outcomes. These findings highlighted the importance of genetic testing of residual tumor cells after induction therapy, which may represent a reliable complementary technique for flow-MRD detection and provide a further understanding of clonal evolution.

Early relapse within 18 months is a powerful dynamic predictor for prognosis and could revise static risk distribution in multiple myeloma.

BACKGROUND: The duration of response to treatment is a major prognostic factor, and early relapse (ER) strongly predicts inferior survival in multiple myeloma (MM). However, the definitions of ER in MM vary from study to study and how to dynamically integrate risk distribution is still unsolved. METHODS: This study evaluated these ER definitions and further investigated the underlying relationship with static risk distribution in 629 newly diagnosed MM (NDMM) patients from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). RESULTS: These data indicated that early relapse within 18 months (ER18) after initial treatment was the best time point for identifying early progression and dynamic high-risk in MM. The ER18 population (114 of 587, 19.4%) presented with more aggressive biologic features and the inferior response to treatment compared to a reference cohort (p < .001), with a significantly short median overall survival (OS) of 28.9 months. Multivariate analyses confirmed the most significant prognostic value of ER18 on OS in the context of International Staging System stage, elevated lactate dehydrogenase, thrombocytopenia, cytogenetic abnormalities, and treatment (hazard ratio, 4.467; p < .001). The authors also described the specific transitions from static risk profile to dynamic risk distribution and then constructed a mixed-risk-pattern to identify four novel populations with distinct survival (p < .001). Additionally, the authors proposed a second-state model that predicts dynamic risk changes, enabling a complementary role to the Revised International Staging System model in facilitating individualized systematic treatment. CONCLUSIONS: Collectively, this study concludes that ER18 is a simple and dynamic prognostic predictor in MM. In addition to static risk assessment, dynamic risk plays an important role in survival prediction.

Minor clone of del(17p) provides a reservoir for relapse in multiple myeloma.

The deletion of chromosome 17p (del(17p)) is considered a crucial prognostic factor at the time of diagnosis in patients with multiple myeloma (MM). However, the impact of del(17p) on survival at different clonal sizes at relapse, as well as the patterns of clonal evolution between diagnosis and relapse and their prognostic value, has not been well described. To address these issues, we analyzed the interphase fluorescence in situ hybridization (iFISH) results of 995 newly diagnosed MM (NDMM) patients and 293 patients with MM at their first relapse. Among these patients, 197 had paired iFISH data at diagnosis and first relapse. Our analysis of paired iFISH revealed that a minor clone of del(17p) at relapse but not at diagnosis was associated with poor prognosis in MM (hazard ratio for median overall survival 1.64 vs. 1.44). Fifty-six and 12 patients developed one or more new cytogenetic abnormalities at relapse, mainly del(17p) and gain/amp(1q), respectively. We classified the patients into six groups based on the change patterns in the clonal size of del(17p) between the two time points. Patients who did not have del(17p) during follow-up showed the best outcomes, whereas those who acquired del(17p) during their disease course, experienced compromised survival (median overall survival: 61.3 vs. 49.4 months; hazard ratio =1.64; 95% confidence interval: 1.06-2.56; P<0.05). In conclusion, our data confirmed the adverse impact of a minor clone of del(17p) at relapse and highlighted the importance of designing optimal therapeutic strategies to eliminate high-risk cytogenetic abnormalities (clinicaltrials gov. identifier: NCT04645199).

Ultrasound-Controlled Delivery of Growth Factor-Loaded Cerasomes Combined with Polycaprolactone Scaffolds Seeded with Bone Marrow Mesenchymal Stem Cells for Biomimetic Tendon-to-Bone Interface Engineering.

Rotator cuff tear (RCT) is a prevalent shoulder injury that poses challenges for achieving continuous and functional regeneration of the tendon-to-bone interface (TBI). In this study, we controlled the delivery of growth factors (GFs) from liposomal nanohybrid cerasomes by ultrasound and implanted three-dimensional printed polycaprolactone (PCL) scaffolds modified with polydopamine loaded with bone marrow mesenchymal stem cells (BMSCs) to repair tears of the infraspinatus tendon in a lapine model. Direct suturing (control, CTL) was used as a control. The PCL/BMSC/cerasome (PBC) devices are sutured with the enthesis of the infraspinatus tendon. The cerasomes and PCL scaffolds are highly stable with excellent biocompatibility. The roles of GFs BMP2, TGFß1, and FGF2 in tissue-specific differentiation are validated. Compared with the CTL group, the PBC group had significantly greater proteoglycan deposition (P = 0.0218), collagen volume fraction (P = 0.0078), and proportions of collagen I (P = 0.0085) and collagen III (P = 0.0048). Biotin-labeled in situ hybridization revealed a high rate of survival for transplanted BMSCs. Collagen type co-staining at the TBI is consistent with multiple collagen regeneration. Our studies demonstrate the validity of biomimetic scaffolds of TBI with BMSC-seeded PCL scaffolds and GF-loaded cerasomes to enhance the treatment outcomes for RCTs.

Immunophenotypic profile defines cytogenetic stability and unveils distinct prognoses in patients with newly-diagnosed multiple myeloma (NDMM).

Prognostic significance of multiple immune antigens in multiple myeloma has been well established. However, a level of uncertainty remains regarding the intrinsic relationship between immunophenotypes and cytogenetic stability and precise risk stratification. To address these unresolved issues, we conducted a study involving 1389 patients enrolled in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Our results revealed that the correlation between antigen expression and cytogenetics is more prominent than cytopenia or organ dysfunction. Most immune antigens, apart from CD38, CD138, and CD81, exhibit significant associations with the incidence of at least one cytogenetic abnormality. In turn, we identified CD138-low/CD27-neg as specific adverse immunophenotypic profile, which remaining independent impact on progression-free survival (HR, 1.49; P = 0.007) and overall survival (HR, 1.77; P < 0.001) even in the context of cytogenetics. Importantly, CD138-low/CD27-neg profile was also associated with inferior survival after first relapse (P < 0.001). Moreover, the antigen expression profiles were not strictly similar when comparing diagnosis and relapse; in particular, the CD138-low/CD27-neg pattern was notably increased after disease progression (19.1 to 29.1%; P = 0.005). Overall, our study demonstrates that diverse immune profiles are strongly associated with cytogenetic stability, and a specific immunophenotype (CD138-low/CD27-neg) could effectively predict prognoses across different disease stages.

Characteristics of Sports Injuries in Athletes During the Winter Olympics: A Systematic Review and Meta-analysis.

Background: Athletes in the Winter Olympic Games are subject to high injury rates given the physical demands of sports. Comprehensive data regarding injury characteristics in these athletes are limited. Purpose: To summarize and analyze data regarding the incidence and characteristics of sports injuries occurring in the Winter Olympic Games. Study Design: Scoping review; Level of evidence, 4. Methods: A systematic review of the PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure databases was conducted. Included were studies reporting the incidence of sports injuries during the Winter Olympics Games from 1995 through 2021. From 168 studies initially retrieved, 4 studies (8824 athletes, 1057 injured athletes) were included. A single-group meta-analysis of sports injury characteristics was performed, with subgroup analysis performed according to the different sports, injury locations, and injury types. Injury severity (time lost from sport) and mechanism were also assessed. Result: The overall injury incidence rate (IIR) during the Winter Olympic Games was 9.6% (95% CI, 4.1%-19.8%). Snow sports were associated with the highest IIR (11.3%), with the top 3 events being the snowboard cross event in snowboarding (31.4%), the aerials event in freestyle skiing (28.6%), and the slopestyle event in snowboarding (27.7%). The most common injury locations were the knee (IIR = 20.0%; 95% CI 17.9%-22.0%), head (IIR = 10.6%; 95% CI, 9.4%-11.9%), and ankle (IIR = 8.2%; 95% CI 7.8%-8.7%). The most common injury types were contusion/hematoma/bruise (IIR = 29.9%; 95% CI 29.7%-30.0%), sprain (dislocation, subluxation, instability, ligamentous, rupture) (IIR = 21.9%; 95% CI 21.4%-22.3%), and strain (muscle rupture, tear, tendon rupture) (IIR = 11.3%; 95% CI 11.0%-11.6%). Regarding injury severity, most athletes had no time lost from sport (64.5%); 24.0% lost fewer than 7 days, and 11.5% lost more than 7 days. The most common injury mechanism was noncontact-related injury (63.3%). Conclusion: In Winter Olympics sports, snow-sport injuries were more common than those associated with other sports, and the most common injury location was the knee. Most injuries did not require time loss, and the most were noncontact-related injuries.

Comparison of Bone Bruise Pattern Epidemiology between Anterior Cruciate Ligament Rupture and Patellar Dislocation Patients-Implications of Injury Mechanism.

Different bone bruise patterns observed using magnetic resonance imaging (MRI) after non-contact anterior cruciate ligament (ACL) rupture and lateral patellar dislocation may indicate different knee injury mechanisms. In this study, 77 ACL ruptures and 77 patellar dislocations in knee MR images taken from patients with bone bruises at our institution between August 2020 and March 2022 were selected and analyzed. In order to determine typical bone bruising patterns following by ACL rupture and patellar dislocation, sagittal- and transverse-plane images were used to determine bone bruise locations in the directions of medial-lateral and superior-inferior with MR images. The presence, intensity, and location of the bone bruises in specific areas of the femur and tibial after ACL rupture and patellar dislocation were recorded. Relative bone bruise patterns after ACL rupture and patellar dislocation were classified. The results showed that there were four kinds of bone bruise patterns (1-, 2-, 3-, and 4- bone bruises) after ACL rupture. The most common two patterns after ACL rupture were 3- bone bruises (including the lateral femoral condyle and both the lateral-medial tibial plateau, LF + BT; both the lateral-medial femoral condyle and the lateral tibial plateau, BF + LT; and the medial femoral condyle and both the medial and lateral tibial plateau, MF + BT) followed by 4- bone bruises (both the lateral-medial femoral condyle and the tibial plateau, BF + BT), 2- bone bruises (the lateral femoral condyle and tibial plateau, LF + LT; the medial femoral condyle and the lateral tibial plateau, MF + LT; the lateral femoral condyle and the medial tibial plateau, LF + MT; the medial femoral condyle and the tibial plateau, MF + MT; both the lateral-medial tibial plateau, 0 + BT), and 1- bone bruise (only the lateral tibial plateau, 0 + LT). There was only a 1- bone bruise (the latera femoral condyle and medial patella bone bruise) for patellar dislocation, and the most common pattern of patellar dislocation was in the inferior medial patella and the lateral anterior inferior femur. The results suggested that bone bruise patterns after ACL rupture and patellar dislocation are completely different. There were four kinds of bone bruise patterns after non-contact ACL rupture, while there was only one kind of bone bruise pattern after patellar dislocation in patients, which was in the inferior medial patella and lateral anterior inferior femur.

Anti-Apoptosis Therapy for Meniscal Avascular Zone Repair: A Proof-of-Concept Study in a Lapine Model.

In the present study, 24 rabbits were firstly used to evaluate the apoptosis index and matrix degeneration after untreated adult meniscal tears. Vertical tears (0.25 cm in length) were prepared in the avascular zone of the anterior horn. Specimens were harvested at 1, 3, 6, 12 weeks postoperatively. The apoptosis index around tear sites stayed at a high level throughout the whole follow-up period. The depletion of glycosaminoglycans (GAG) and aggrecan at the tear site was observed, while the deposition of COL I and COL II was not affected, even at the last follow-up of 12 weeks after operation. The expression of SOX9 decreased significantly; no cellularity was observed at the wound interface at all timepoints. Secondly, another 20 rabbits were included to evaluate the effects of anti-apoptosis therapy on rescuing meniscal cells and enhancing meniscus repair. Longitudinal vertical tears (0.5 cm in length) were made in the meniscal avascular body. Tears were repaired by the inside-out suture technique, or repaired with sutures in addition to fibrin gel and blank silica nanoparticles, or silica nanoparticles encapsulating apoptosis inhibitors (z-vad-fmk). Samples were harvested at 12 months postoperatively. We found the locally administered z-vad-fmk agent at the wound interface significantly alleviated meniscal cell apoptosis and matrix degradation, and enhanced meniscal repair in the avascular zone at 12 months after operation. Thus, local administration of caspase inhibitors (z-vad-fmk) is a promising therapeutic strategy for alleviating meniscal cell loss and enhancing meniscal repair after adult meniscal tears in the avascular zone.

Meniscal fibrocartilage regeneration inspired by meniscal maturational and regenerative process.

Meniscus is a complex and crucial fibrocartilaginous tissue within the knee joint. Meniscal regeneration remains to be a scientific and translational challenge. We clarified that mesenchymal stem cells (MSCs) participated in meniscal maturation and regeneration using MSC-tracing transgenic mice model. Here, inspired by meniscal natural maturational and regenerative process, we developed an effective and translational strategy to facilitate meniscal regeneration by three-dimensionally printing biomimetic meniscal scaffold combining autologous synovium transplant, which contained abundant intrinsic MSCs. We verified that this facilitated anisotropic meniscus-like tissue regeneration and protected cartilage from degeneration in large animal model. Mechanistically, the biomechanics and matrix stiffness up-regulated Piezo1 expression, facilitating concerted activation of calcineurin and NFATc1, further activated YAP-pSmad2/3-SOX9 axis, and consequently facilitated fibrochondrogenesis of MSCs during meniscal regeneration. In addition, Piezo1 induced by biomechanics and matrix stiffness up-regulated collagen cross-link enzyme expression, which catalyzed collagen cross-link and thereby enhanced mechanical properties of regenerated tissue.

Impact of residual tumor cells in the stem cell collection on multiple myeloma patients receiving autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) is the standard therapy for patients with transplant-eligible multiple myeloma (TEMM). However, the ideal depth of response required before ASCT and the impact of residual tumor cells in the stem cell collection (SCC) on survival remains unclear. Here we collected data of 89 patients with TEMM undergoing ASCT and analyzed the minimal residual disease of SCC (cMRD) and bone marrow (BM) (mMRD) before transplantation. Before ASCT, 31.5% and 76.4% of patients achieved MRD negativity in BM and SCC, respectively. Tumor cells were less in SCC samples than that in BM samples. Neoplastic cells in SCC could be observed in patients with different responses after induction therapy, and there were no significant differences in the percentage and level of cMRD among these subgroups (P > 0.05). No correlation was found between the cMRD status and the response patients achieved after ASCT (P > 0.05). The median follow-up was 26.8 months. mMRD negativity before ASCT was associated with longer PFS (55.9 vs. 27.1 months; P = 0.009) but not OS (not reached vs. 58.9 months; P = 0.115). Patients with different cMRD statuses before ASCT experienced similar PFS (40.5 vs. 76.4 months for negativity vs. positivity; P = 0.685) and OS (not reached vs. 58.8 months for negativity vs. positivity; P = 0.889). These results suggested that detectable cMRD does not significantly predict the inferior post-ASCT response or shorter survival, and patients are eligible to undergo ASCT upon achieving partial response.

Clinical Benefit of Autologous Stem Cell Transplantation for Patients with Multiple Myeloma Achieving Undetectable Minimal Residual Disease after Induction Treatment.

Attaining undetectable minimal residual disease (MRD) is the current therapeutic goal for multiple myeloma. But there is a current lack of data regarding the clinical benefit of autologous stem cell transplantation (ASCT) for patients with myeloma achieving early MRD-negative status after induction treatment, in addition to the interaction of longitudinal MRD status with ASCT. The current study included 407 patients with transplant-eligible multiple myeloma with available MRD status from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199), of whom 147 (34.4%) achieved early undetectable MRD and 182 (44.7%) received ASCT. Early MRD-negative status was associated with a lower risk of disease progression [HR = 0.447; 95% confidence interval (CI), 0.333-0.600; P < 0.001] and death (HR = 0.473; 95% CI, 0.320-0.700; P < 0.001). Of note, patients who achieved undetectable MRD early still benefitted from ASCT, with a remarkable improvement in the median MRD-negative duration (33.5-58.0 months, P < 0.001), progression-free survival (PFS; 46.0-88.3 months, P < 0.001), and overall survival (OS; 76.4 months to not reached, P = 0.003). These clinical benefits were more pronounced in patients with aggressive features (high-risk cytogenetic abnormalities or high tumor burden) compared with standard-risk patients. Similar results were observed in patients with detectable MRD after induction treatment. In addition, we identified four MRD-status transformation patterns following ASCT, which were strongly correlated with diverse survival outcomes (P < 0.001). Our study revealed the enhanced clinical significance of ASCT in patients with transplant-eligible myeloma, regardless of early MRD status, particularly for high-risk patients. Subsequent prospective trials are essential to validate these observations. Significance: Achieving and maintaining undetectable MRD is the current treatment goal for multiple myeloma. Our results emphasized the remarkable clinical benefit of ASCT on MRD-negative duration, PFS, and OS in patients with multiple myeloma regardless of early MRD status. These favorable impacts were more evident in patients with aggressive features. Importantly, dynamic MRD monitoring among ASCT could facilitate personalized stratification of therapeutic approaches.

Meniscal Fibrocartilage Repair Based on Developmental Characteristics: A Proof-of-Concept Study.

BACKGROUND: Unlike the adult meniscus, the fetal meniscus possesses robust healing capacity. The dense and stiff matrix of the adult meniscus provides a biophysical barrier for cell migration, which is not present in the fetal meniscus. Inspired by developmental characteristics, modifying the matrix of the adult meniscus into a fetal-like, loose and soft microenvironment holds opportunity to facilitate repair, especially in the avascular zone. HYPOTHESIS: Modifying the dense and stiff matrix of the adult meniscus into a fetal-like, loose and soft microenvironment could enhance cell migration to the tear interface and subsequent robust healing capacity. STUDY DESIGN: Controlled laboratory study. METHODS: Fresh porcine menisci were treated with hyaluronidase or collagenase. The density and arrangement of collagen fibers were assessed. The degradation of proteoglycans and collagen was evaluated histologically. Cell migration within the meniscus or the infiltration of exogenous cells into the meniscus was examined. Dendritic silica nanoparticles with relatively large pores were used to encapsulate hyaluronidase for rapid release. Mesoporous silica nanoparticles with relatively small pores were used to encapsulate transforming growth factor-beta 3 (TGF-ß3) for slow release. A total of 24 mature male rabbits were included. A longitudinal vertical tear (0.5 cm in length) was prepared in the avascular zone of the medial meniscus. The tear was repaired with suture, repaired with suture in addition to blank silica nanoparticles, or repaired with suture in addition to silica nanoparticles releasing hyaluronidase and TGF-ß3. Animals were sacrificed at 12 months postoperatively. Meniscal repair was evaluated macroscopically and histologically. RESULTS: The gaps between collagen bundles increased after hyaluronidase treatment, while collagenase treatment resulted in collagen disruption. Proteoglycans degraded after hyaluronidase treatment in a dose-dependent manner, but collagen integrity was maintained. Hyaluronidase treatment enhanced the migration and infiltration of cells within meniscal tissue. Last, the application of fibrin gel and the delivery system of silica nanoparticles encapsulating hyaluronidase and TGF-ß3 enhanced meniscal repair responses in an orthotopic longitudinal vertical tear model. CONCLUSION: The gradient release of hyaluronidase and TGF-ß3 removed biophysical barriers for cell migration, creating a fetal-like, loose and soft microenvironment, and enhanced the fibrochondrogenic phenotype of reparative cells, facilitating the synthesis of matrix and tissue integration. CLINICAL RELEVANCE: Modifying the adult matrix into a fetal-like, loose and soft microenvironment via the local gradient release of hyaluronidase and TGF-ß3 enhanced the healing capacity of the meniscus.

Enhanced osteochondral repair with hyaline cartilage formation using an extracellular matrix-inspired natural scaffold.

Osteochondral defects pose a great challenge and a satisfactory strategy for their repair has yet to be identified. In particular, poor repair could result in the generation of fibrous cartilage and subchondral bone, causing the degeneration of osteochondral tissue and eventually leading to repair failure. Herein, taking inspiration from the chemical elements inherent in the natural extracellular matrix (ECM), we proposed a novel ECM-mimicking scaffold composed of natural polysaccharides and polypeptides for osteochondral repair. By meticulously modifying natural biopolymers to form reversible guest-host and rigid covalent networks, the scaffold not only exhibited outstanding biocompatibility, cell adaptability, and biodegradability, but also had excellent mechanical properties that can cater to the environment of osteochondral tissue. Additionally, benefiting from the drug-loading group, chondrogenic and osteogenic drugs could be precisely integrated into the specific zone of the scaffold, providing a tissue-specific microenvironment to facilitate bone and cartilage differentiation. In rabbit osteochondral defects, the ECM-inspired scaffold not only showed a strong capacity to promote hyaline cartilage formation with typical lacuna structure, sufficient mechanical strength, good elasticity, and cartilage-specific ECM deposition, but also accelerated the regeneration of quality subchondral bone with high bone mineralization density. Furthermore, the new cartilage and subchondral bone were heterogeneous, a trait that is typical of the natural landscape, reflecting the gradual progression from cartilage to subchondral bone. These results suggest the potential value of this bioinspired osteochondral scaffold for clinical applications.