Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase ...1b-2 study in patients with relapsed or refractory multiple myeloma.
In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival.
Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients.
Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).
Background:
Although various reconstruction techniques are available for anterior cruciate ligament (ACL) injuries, a long recovery time is required before patients return to sports activities, as ...the reconstructed ACL requires time to regain strength. To date, several studies have reported use of mesenchymal stem cells in orthopaedic surgery; however, no studies have used adipose-derived stem cell (ADSC) sheets in ACL reconstruction (ACLR).
Hypothesis:
ADSC sheet transplantation can improve biomechanical strength of the autograft used in ACLR.
Study Design:
Controlled laboratory study.
Methods:
A total of 68 healthy Japanese white rabbits underwent unilateral ACLR with a semitendinosus tendon autograft after random enrollment into a control group (no sheet; n = 34) and a sheet group (ADSC sheet; n = 34). At 2, 4, 8, 16, and 24 weeks after surgery, rabbits in each group were sacrificed to evaluate tendon-bone healing using histological staining, micro–computed tomography, and biomechanical testing. At 24 weeks, scanning transmission electron microscopy of the graft midsubstance was performed.
Results:
The ultimate failure load for the control and sheet groups, respectively, was as follows: 17.2 ± 5.5 versus 37.3 ± 10.3 (P = .01) at 2 weeks, 28.6 ± 1.9 versus 47.4 ± 10.4 (P = .003) at 4 weeks, 53.0 ± 14.3 versus 48.1 ± 9.3 (P = .59) at 8 weeks, 66.2 ± 9.3 versus 95.2 ± 43.1 (P = .24) at 16 weeks, and 66.7 ± 27.3 versus 85.3 ± 29.5 (P = .39) at 24 weeks. The histological score was also significantly higher in the sheet group compared with the control group at early stages up to 8 weeks. On micro–computed tomography, relative to the control group, the bone tunnel area was significantly narrower in the sheet group at 4 weeks, and the bone volume/tissue volume of the tendon-bone interface was significantly greater at 24 weeks. Scanning transmission electron microscopy at 24 weeks indicated that the mean collagen fiber diameter in the midsubstance was significantly greater, as was the occupation ratio of collagen fibers per field of view, in the sheet group.
Conclusion:
ADSC sheets improved biomechanical strength, prevented bone tunnel enlargement, and promoted tendon-bone interface healing and graft midsubstance healing in an in vivo rabbit model.
Clinical Relevance:
ADSC sheets may be useful for early tendon-bone healing and graft maturation in ACLR.
Pain is an undesirable sensory experience that can induce depression and limit individuals' activities of daily living, in turn negatively impacting the labor force. Affected people frequently feel ...pain during activity; however, pain is subjective and difficult to judge objectively, particularly during activity. Here, we developed a system to objectively judge pain levels in walking subjects by recording their quantitative electroencephalography (qEEG) and analyzing data by machine learning. To do so, we enrolled 23 patients who had undergone total hip replacement for pain, and recorded their qEEG during a five-minute walk via a wearable device with a single electrode placed over the Fp1 region, based on the 10-20 Electrode Placement System, before and three months after surgery. We also assessed subject hip pain using a numerical rating scale. Brain wave amplitude differed significantly among subjects with different levels of hip pain at frequencies ranging from 1 to 35 Hz. qEEG data were also analyzed by a support vector machine using the Radial Basis Functional Kernel, a function used in machine learning. That approach showed that an individual's hip pain during walking can be recognized and subdivided into pain quartiles with 79.6% recognition Accuracy. Overall, we have devised an objective and non-invasive tool to monitor an individual's pain during walking.
Due to their rarity and diversity, sarcomas are difficult to diagnose. Consequently, there is an urgent demand for a novel diagnostic test for these cancers. In this study, we investigated serum ...miRNA profiles from 1002 patients with bone and soft tissue tumors representing more than 43 histological subtypes, including sarcomas, intermediate tumors, and benign tumors, to determine whether serum miRNA profiles could be used to specifically detect sarcomas. Circulating serum miRNA profiles in sarcoma patients were clearly distinct from those in patients with other types of tumors. Using the serum levels of seven miRNAs, we developed a molecular detector, Index VI, that could distinguish sarcoma patients from benign and healthy controls with remarkably high sensitivity (90%) and specificity (95%), regardless of histological subtype. Index VI provides an approach to the early and precise detection of sarcomas, potentially leading to curative treatment and longer survival.
To prevent infections associated with medical implants, various antimicrobial silver-coated implant materials have been developed. However, these materials do not always provide consistent ...antibacterial effects in vivo despite having dramatic antibacterial effects in vitro, probably because the antibacterial effects involve silver-ion-mediated reactive oxygen species generation. Additionally, the silver application process often requires extremely high temperatures, which damage non-metal implant materials. We recently developed a bacteria-resistant coating consisting of hydroxyapatite film on which ionic silver is immobilized via inositol hexaphosphate chelation, using a series of immersion and drying steps performed at low heat. Here we applied this coating to a polymer, polyetheretherketone (PEEK), and analyzed the properties and antibacterial activity of the coated polymer in vitro and in vivo. The ionic silver coating demonstrated significant bactericidal activity and prevented bacterial biofilm formation in vitro. Bio-imaging of a soft tissue infection mouse model in which a silver-coated PEEK plate was implanted revealed a dramatic absence of bacterial signals 10 days after inoculation. These animals also showed a strong reduction in histological features of infection, compared to the control animals. This innovative coating can be applied to complex structures for clinical use, and could prevent infections associated with a variety of plastic implants.
Bacterial infection of biomaterials is a serious problem in the field of medical devices. It is urgently necessary to develop new biomaterials with bactericidal activity. Antimicrobial peptides and ...proteins (AMPs), alternative antibacterial agents, are expected to overcome the bacterial resistance. The aim of this study was to develop a new intelligent material in bone tissue engineering based on protamine-loaded hydroxyapatite (protamine/HAp) that uses AMPs rather than antibiotics. It was found that the adsorption of protamine to HAp followed the Langmuir adsorption model and was due to electrostatic and/or hydrophobic interactions. In vitro bacterial adhesion and growth on protamine/HAp was inhibited in a protamine dose-dependent manner. Adherent bacteria exhibited an aberrant morphology for high dosages of protamine/HAp, resulting in the formation of large aggregates and disintegration of the membrane. The released protamine from protamine/HAp also prevented the growth of planktonic bacteria in vitro. However, a high dosage of protamine from powders at loading concentrations over 1000 μg·mL
induced a cytotoxic effect in vitro, although those exhibited no apparent cytotoxicity in vivo. These data revealed that protamine/HAp (less than 1000 μg·mL
) had both antimicrobial activity and biocompatibility and can be applied for bone substitutes in orthopedic fields.
A retrospective review of 281 consecutive cases of adult spine deformity (ASD) surgery (age 55 ± 19 yrs, 91% female, follow-up 4.3 ± 1.9 yrs) from a multicenter database.
To compare the value and ...predictive ability of the 5-item modified frailty index (mFI-5) to the conventional 11-item modified frailty index (mFI-11) for severe adverse events (SAEs).
Several recent studies have described associations between frailty and surgical complications. However, the predictive power and usefulness of the mFI-5 have not been proven.
SAEs were defined as: Clavien-Dindo grade >3, reoperation required, deterioration of motor function at discharge, or new motor deficit within 2 years. The patients' frailty was categorized by the mFI-5 and mFI-11 (robust, prefrail, or frail). Spearman's rho was used to assess correlation between the mFI-5 and mFI-11. Univariate and multivariate Poisson regression analyses were conducted to analyze the relative risk of mFI-5 and mFI-11 as a predictor for SAEs in ASD surgery. Age, sex, and baseline sagittal alignment (Schwab-SRS classification subcategories) were used to adjust the baseline variance of the patients.
Of the 281 patients, 63 (22%) had developed SAE at 2 years. The weighted Kappa ratio between the mFI-5 and mFI-11 was 0.87, indicating excellent concordance across ASD surgery. Frailty was associated with increased total complications, perioperative complications, implant-related complications, and SAEs. Adjusted and unadjusted models showed similar c-statistics for mFI-5 and mFI-11 and a strong predictive ability for SAEs in ASD surgery. As the mFI-5 increased from 0 to ≥2, the rate of SAEs increased from 17% to 63% (P < 0.01), and the relative risk was 2.2 (95% CI: 1.3-3.7).
The mFI-5 and the mFI-11 were equally effective predictors of SEA development in ASD surgery. The evaluation of patient frailty using mFI-5 may help surgeons optimize procedures and counsel patients.
4.
Retrospective review of surgically treated 481 adult patients with spinal disorders.
The aim of this study was to elucidate the effect of frailty and comorbidities on postoperative health-related ...quality of life (HRQoL) and complication rates.
Elective surgeries for spinal disorders not only improve clinical outcomes but also have high complication rates.
We retrospectively reviewed the results of consecutive elective spine surgeries for 156 adult spinal deformities (ASDs: 65 ± 9 years), 152 degenerative spondylolisthesis (DS: 64 ± 10 years), or 173 lumbar spinal canal stenosis (LSCS: 71 ± 9 years) with follow-up of at least 2 years. Modified Frailty Index (mFI) and Charlson Comorbidity Index (CCI) were determined from baseline demographics. We compared the prevalence and the influence of mFI and CCI on postoperative outcomes and complication rates.
The mFI and CCI were significantly worse in ASD than in others (mFI: ASD 0.09 ± 0.12, DS 0.06 ± 0.06, LSCS 0.04 ± 0.05, P < 0.01. CCI: ASD 2.1 ± 1.6, DS 1.4 ± 0.7, LSCS 1.6 ± 0.9, P < 0.01). Postoperative HRQoL deteriorated as mFI worsened in ASD (nofrail: Oswestry Disability Index ODI 26 ± 11, Scoliosis Research Society Questionnaire SRS 3.7 ± 0.7; prefrail: ODI 32 ± 12, SRS 3.6 ± 0.6; frail: ODI 42 ± 15, SRS 3.2 ± 0.7). In DS and LSCS, however, SF-36 physical component score and mental component score improved regardless of mFI and CCI. The 2-year major complications rate increased with frailty (36%, 58%, and 81%) in ASD, but not in others.
ASDs were more frail and had more comorbidities than the other populations. In ASD, postsurgical outcomes and complication rates deteriorated as frailty and CCI increased, whereas surgery produced favorable outcomes and acceptable complication rates in DS and LSCS regardless of frailty and CCI. Careful patient selection and treatment of comorbidities before surgery may decrease complications and improve outcomes for the surgical treatment of ASD.
4.
Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly ...improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1-3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1-3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 95.4% Cl, 0.68-1.00; P = 0.0408 less than allotted α of 0.046), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1-3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2-3 prior LoTs.
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