A NOTCH3-CXCL12-driven myeloma-tumor niche signaling axis promotes chemoresistance in multiple myeloma.

Multiple myeloma (MM) remains incurable due to disease relapse and drug resistance. Notch signals from the tumor microenvironment (TME) confer chemoresistance, but the cellular and molecular mechanisms are not entirely understood. Using clinical and transcriptomic datasets, we found that NOTCH3 is upregulated in CD138+ cells from newly diagnosed MM (NDMM) patients compared to healthy individuals and increased in progression/relapsed MM (PRMM) patients. Further, NDMM patients with high NOTCH3 expression exhibited worse responses to bortezomib (BOR)-based therapies. Cells of the TME, including osteocytes, upregulated NOTCH3 in MM cells and protected them from apoptosis induced by BOR. NOTCH3 activation (NOTCH3OE) in MM cells decreased BOR anti-MM efficacy and its ability to improve survival in in vivo myeloma models. Molecular analyses revealed that NDMM and PRMM patients with high NOTCH3 exhibit CXCL12 upregulation. TME cells upregulated CXCL12 and activated the CXCR4 pathway in MM cells in a NOTCH3-dependent manner. Moreover, genetic or pharmacologic inhibition of CXCL12 in NOTCH3OE MM cells restored sensitivity to BOR regimes in vitro and in human bones bearing NOTCH3OE MM tumors cultured ex vivo. Our clinical and preclinical data unravel a novel NOTCH3-CXCL12 pro-survival signaling axis in the TME and suggest that osteocytes transmit chemoresistance signals to MM cells.

Systemic Inflammatory Response Syndrome and Prosthetic Joint Infection.

BACKGROUND: The development of systemic inflammatory response syndrome (SIRS) criteria leads to increased mortality. Little is known about development of SIRS in patients who have prosthetic joint infection (PJI). We aimed to determine the incidence, risk factors, clinical outcomes, and causative organisms in patients who develop SIRS with PJI. METHODS: We retrospectively identified 655 patients (321 men, 334 women; 382 total hip, 273 total knee) who have hip or knee PJI at 1 institution between July 1, 2015 and December 31, 2020. We formed 2 groups: patients who have SIRS alert (PJI + SIRS) and patients who do not have SIRS alert (PJI). We analyzed clinical outcomes, comorbidities, and operating room culture results. RESULTS: Of 655 patients, 63 developed SIRS with PJI (9.6%). Intensive care unit (ICU) admission rates (27.0 versus. 6.9%, P < .001) and length of stay (7.7 versus. 5.6 days, P = .003) were greater in PJI + SIRS. At 2 years, reoperation (36.5 versus. 22.3%, P = .01) and mortality rates (17.5 versus. 8.8%, P = .03) were greater in PJI + SIRS. Risk factors included deficiency anemia (P = .001), blood loss anemia (P = .013), uncomplicated diabetes (P = .006), diabetes with complication (P = .001), electrolyte disorder (P < .00001), neurological disorder (P = .0001), paralysis (P = .026), renal failure (P = .005), and peptic ulcer disease (P = .004). Staphylococcus aureus more commonly speciated on tissue cultures in PJI + SIRS (P = .002). CONCLUSION: The incidence of SIRS is 10% among patients who have PJI. Development of PJI + SIRS is associated with increased lengths of stay, ICU admissions, and 2-year reoperation and mortality rates. Identifying certain comorbidities can stratify patients' risk of developing PJI + SIRS.

The Use of General Anesthesia in Revision Joint Arthroplasty.

BACKGROUND: Several studies have suggested that spinal anesthesia gives superior outcomes for primary total joint arthroplasty (TJA). However, there is a lack of available data regarding contemporary general anesthesia (GA) approaches for revision TJA utilized at high-volume joint arthroplasty centers. METHODS: We retrospectively reviewed a series of 850 consecutive revision TJAs (405 revision total hip arthroplasties and 445 revision total knee arthroplasties) performed over 4 years at a single institution that uses a contemporary GA protocol and reported on the lengths of stay, early recovery rates, perioperative complications, and readmissions. RESULTS: Of the revision arthroplasty patients, 74.4% (632 of 850) were discharged on postoperative day 1 and 68.5% (582 of 850) of subjects were able to participate in physical therapy on the day of surgery. Only 6 patients (0.7%) required an intensive care unit stay postoperatively. The 90-day readmission rate over this time was 11.3% (n = 96), while the reoperation rate was 9.4% (n = 80). CONCLUSIONS: While neuraxial anesthesia is commonly preferred when performing revision TJA, we have demonstrated favorable safety and efficiency metrics utilizing GA in conjunction with contemporary enhanced recovery pathways. Our data support the notion that modern GA techniques can be successfully used in revision TJA.

Pericapsular Nerve Group Block Did Not Reduce Postoperative Pain or Opioid Use After Total Hip Arthroplasty.

BACKGROUND: The pericapsular nerve group (PENG) block is a newly developed regional anesthesia technique designed to manage postoperative hip pain following a fracture or surgery while also maintaining quadriceps strength and mobility. The goal of our study was to compare postoperative pain scores and opioid usage during the postoperative period before discharge following total hip arthroplasty (THA) using the posterior approach between patients who received a PENG block and those who did not. METHODS: We conducted a retrospective study on patients undergoing elective, posterior approach THA at a single tertiary-care academic center. The 2 groups included a study group (THA with PENG block in 2021; n = 66) and a control group (THA before PENG block implementation in 2019; n = 70). RESULTS: There were no significant differences in pain scores during postoperative minutes 0 to 59 (study group 6.8; control group 6.6; P = .81) or during postoperative minutes 60 to 119 (study group 6.2; control group 5.6; P = .40). There were no significant differences in total postoperative in-hospital morphine milliequivalent opioid consumption (study group 55.8 morphine milligram equivalents; control group 75.0 morphine milligram equivalents; P = .14). The study group was found to have a shorter length of stay (study group 17.0 hours; control group 32.6 hours; P < .0001) and faster mobilization (study group 3.0 hours; control group 4.9 hours; P < .0001) than the control group. CONCLUSIONS: Our results show that use of the PENG block did not result in lower postoperative pain scores or opioid consumption after THA using the posterior surgical approach. The study group had a shorter length of stay and time to mobilization than the control group, though this was likely due to standard hospital procedure shifting to same-day discharge for THA between 2019 and 2021 due to COVID-19.

Do Quality Measures or Hospital Characteristics Predict Readmission Penalties for Hip and Knee Arthroplasty?

BACKGROUND: Quality rating systems exist to grade the value of care provided by hospitals, but the extent to which these rating systems correlate with patient outcomes is unclear. The association of quality rating systems and hospital characteristics with excess readmission penalties for total hip arthroplasty (THA) and total knee arthroplasty (TKA) was studied. METHODS: The fiscal year 2022 Inpatient Prospective Payment System final rule was used to identify 2,286 hospitals subject to the Hospital Readmissions Reduction Program. Overall, 6 hospital quality rating systems and 5 hospital characteristics were obtained. These factors were analyzed to determine the effect on hospital penalties for THA and TKA excess readmissions. RESULTS: Hospitals that achieved a higher Medicare Overall Hospital Quality Star Rating demonstrated a significantly lower likelihood of receiving THA and TKA readmission penalties (Cramer's V = 0.236 and Rp = -0.233; P < .001 for both). Hospitals ranked among the US News & World Report's top 50 best hospitals for orthopaedics were significantly less likely to be penalized (V = 0.042; P = .043). The remaining 4 quality rating systems were not associated with readmission penalties. Penalization was more likely for hospitals with fewer THA and TKA discharges (Rp = -0.142; P < .001), medium-sized institutions (100 to 499 beds; V = 0.075; P = .002), teaching hospitals (V = 0.049; P = .019), and safety net hospitals (V = 0.043; P = .039). Penalization was less likely for West and Midwest hospitals (V = 0.112; P < .001). CONCLUSIONS: A higher Overall Hospital Quality Star Rating and recognition among the US News & World Report's top 50 orthopaedic hospitals were associated with a reduced likelihood of THA and TKA readmission penalties. The other 4 widely accepted quality rating systems did not correlate with readmission penalties. Teaching and safety net hospitals may be biased toward higher readmission rates.

Treatment of Hip and Knee Periprosthetic Joint Infection Requires Extensive Administrative Work.

BACKGROUND: Treatment of periprosthetic joint infections (PJIs) typically requires more resource utilization than primary total joint arthroplasty. This study quantifies the amount of time spent in the electronic medical record (EMR) for patients who have PJI requiring surgical intervention. METHODS: A retrospective analysis of EMR activity for 165 hip and knee PJIs was performed to capture work during the preoperative and postoperative time periods. Independent sample t tests were conducted to compare total time based on procedure, age, insurance, health literacy, sex, race, and ethnicity. RESULTS: The EMR work performed by the orthopaedic team was 338.4 minutes (min) (SD 130.3), with 119.4 minutes (SD 62.8) occurring preoperatively and 219.0 minutes (SD 112.9) postoperatively. Preoperatively, the surgeon's work accounted for 35.7 minutes (SD 25.4), mid-level providers 21.3 minutes (SD 15.9), nurses 38.6 minutes (SD 36.8), and office staff 32.7 minutes (SD 29.9). Infectious disease colleagues independently performed 158.9 minutes (SD 108.5) of postoperative work. Overall, PJI of the knees required more postoperative work. Secondary analysis revealed that patients who have hip PJI and a body mass index <30 and patients <65 years of age required more work when compared to the PJI of heavier and older individuals. There was no difference in total work based on insurance, health literacy, race, or ethnicity. CONCLUSIONS: Over 8 hours of administrative work is required for surgical management of PJI. Surgeons alone performed 451% more work for PJI during the preoperative period (7.9 versus 35.7 min) compared to primary total joint arthroplasty. In efforts to provide best care for our sickest patients, much work is required perioperatively. This work is necessary to consider when assigning value and physician reimbursement.

The Chitranjan S. Ranawat Award: Manipulation Under Anesthesia to Treat Postoperative Stiffness After Total Knee Arthroplasty: A Multicenter Randomized Clinical Trial.

BACKGROUND: Manipulation under anesthesia (MUA) occurs in 4% of patients after total knee arthroplasty (TKA). Anti-inflammatory medications may target arthrofibrosis pathogenesis, but the data are limited. This multicenter randomized clinical trial investigated the effect of adjuvant anti-inflammatory medications with MUA and physical therapy on range of motion (ROM) and outcomes. METHODS: There were 124 patients (124 TKAs) who developed stiffness after primary TKA for osteoarthritis enrolled across 15 institutions. All received MUA when ROM was < 90° at 4 to 12 weeks postoperatively. Randomization proceeded via a permuted block design. Controls received MUA and physical therapy, while the treatment group also received one dose of pre-MUA intravenous dexamethasone (8 mg) and 14 days of oral celecoxib (200 mg). The ROM and clinical outcomes were assessed at 6 weeks and 1 year. This trial was registered with ClinicalTrials.gov. RESULTS: The ROM significantly improved a mean of 46° from a pre-MUA ROM of 72 to 118° immediately after MUA (P < .001). The ROM was similar between the treatment and control groups at 6 weeks following MUA (101 versus 99°, respectively; P = .35) and at one year following MUA (108 versus 108°, respectively; P = .98). Clinical outcomes were similar at both end points. CONCLUSIONS: In this multicenter randomized clinical trial, the addition of intravenous dexamethasone and a short course of oral celecoxib after MUA did not improve ROM or outcomes. However, MUA provided a mean ROM improvement of 46° immediately, 28° at 6 weeks, and 37° at 1 year. Further investigation in regards to dosing, duration, and route of administration of anti-inflammatory medications remains warranted. LEVEL OF EVIDENCE: Level 1, RCT.

Robotic Total Knee Arthroplasty Surgeon Marketing: Do Claims Align With the Literature?

Background: Robotic total knee arthroplasty (R-TKA) utilization and marketing continue to rise. We examined the marketing on surgeon websites regarding R-TKA benefits and sought to determine if the claims were supported by existing literature. Methods: A Google search identified 10 physician websites from each of the 5 largest U.S. markets by population with the term "robotic total knee arthroplasty city, state." Claims on websites about R-TKA were categorized. Literature from 2012-2022 was reviewed for data "for" or "against" each claim. Level of evidence for each publication was collected. Results: Fifty websites were captured that included 59 surgeons. A specific R-TKA platform was mentioned on 68% of websites. Website claims about robotics were placed into 8 major categories. Literature review supported the claims of more precise/accurate, reduced injury to tissue, and less pain with more literature "for" than "against" the claims. Conclusions: Claims made on physician websites regarding the benefits of R-TKA are variable and not definitively supported by existing literature. Most available data can be categorized into levels of evidence III, IV, and V. There is a paucity of level I evidence to support the various marketing statements. Physicians should be cognizant of both the claims made on their websites and the literature that could be used to support or refute those specific claims.

Successful Transition to Same Calendar Day Discharge in Total Joint Arthroplasty at an Academic Center.

Background: There has been a shift toward same-day discharge (SDD) in total joint arthroplasty (TJA) in recent years. Our clinical standard had been next-day discharge, but the COVID pandemic led to a hospital bed shortage, causing us to shift to SDD directly from the Post-Anesthesia Care Unit (PACU). The aim of our project was to investigate if the SDD protocol was successful and if it changed complications or 90-day readmission rates. Our secondary aim was to investigate if the protocol created disparities in patient selection. Methods: A retrospective review compared the first 100 patients intended to discharge from PACU to the 100 patients prior to the SDD protocol undergoing elective primary TJA procedures at our academic institution from September 1, 2020, to March 23, 2021. The SDD protocol started on November 19, 2020. Results: During this SDD period, 98% (98/100) of patients were successfully discharged from the PACU. The 90-day readmission rate changed from 0% to 2% (P = .4975), and the overall complication rate changed from 2% to 5% (P = .4448). Most complications were manipulation under anesthesia to improve range of motion. Manipulations under anesthesia changed from 1% to 4% (P = .3687). Conclusions: The transition to same SDD in TJA at our academic institution was successfully implemented without markedly increasing complications, readmissions, or changing patient selection. The COVID-19 pandemic likely influenced the recovery of patients before and after the protocol. Future studies are needed to validate this data during the post-COVID era.

Functional Articulating Antibiotic Spacers for Chronic Native Septic Knee Arthritis.

Background: Semipermanent functional spacers are now utilized for prosthetic joint infection in an attempt to avoid another surgery with 2-stage treatment. This study evaluates the results of metal-on-polyethylene articulating spacers for the treatment of chronic native septic knee arthritis. Methods: This is a retrospective review of 18 patients treated with metal-on-polyethylene articulating antibiotic spacers constructed with all-polyethylene tibial components or with polyethylene inserts (PIs) with Steinmann pins or screws for chronic native knee infection. Demographic information, spacer construct type, prior knee surgery, complications, infecting organisms, infection eradication, and functional results were analyzed. Results: Of 18, 8 (44%) spacers were all-polyethylene tibial components and 10 (56%) were PI. Of 18 patients, 5 (28%) experienced spacer complications. Of 18 patients, 12 (67%) underwent a second reimplantation surgery (mean 106 days), while 6 (33%) retained their spacer (average duration 425 days). The PI group performed better in Knee Injury and Osteoarthritis Outcome score for Joint Replacement according to minimum clinically important difference and patient acceptable symptom state (PASS) criteria. The overall reimplantation group achieved Knee Injury and Osteoarthritis Outcome score for Joint Replacement PASS criteria and minimum clinically important difference criteria, while the maintained articulating spacer group did not achieve PASS criteria; however, they did reach minimum clinically important difference. Conclusions: Functional articulating spacers are a viable treatment for chronic, native knee septic arthritis. The PI patient group had a greater improvement in Knee Injury and Osteoarthritis Outcome score for Joint Replacement scores and had no significant difference in reimplantation rate as the all-polyethylene tibial components patient group. Both planned 2-stage reimplantation and longer-term spacer retention show promising results for this difficult clinical problem.

Single-cell Transcriptome Analysis Identifies Senescent Osteocytes as Contributors to Bone Destruction in Breast Cancer Metastasis.

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression that disrupts the balance between osteoclasts and osteoblasts, leading to bone lesions. Whether such reprogramming affects matrix-embedded osteocytes remains poorly understood. Here, we demonstrate that osteocytes in breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified osteocytes from mice with breast cancer bone metastasis enriched in senescence and SASP markers and pro-osteoclastogenic genes. Using multiplex in situ hybridization and AI-assisted analysis, we detected osteocytes with senescence-associated distension of satellites, telomere dysfunction, and p16Ink4a expression in mice and patients with breast cancer bone metastasis. In vitro and ex vivo organ cultures showed that breast cancer cells promote osteocyte senescence and enhance their osteoclastogenic potential. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that osteocytes undergo pathological reprogramming by breast cancer cells and identify osteocyte senescence as an initiating event triggering bone destruction in breast cancer metastases.