5T4 (trophoblast glycoprotein encoded by TPBG ) is a cancer/testis antigen highly expressed in renal cell carcinoma (RCC) and many other cancers but rarely in normal tissues. Interest in developing 5T4 as a prognostic biomarker and direct targeting of 5T4 by emerging receptor-engineered cellular immunotherapies has been hampered by the lack of validated 5T4-specific reagents for immunohistochemistry (IHC). We tested 4 commercially available monoclonal antibodies (mAbs) for the detection of 5T4 in formalin-fixed, paraffin-embedded RCC and normal tissues. Using parental and TPBG -edited A498 cells, 3 mAbs showed 5T4 specificity. Further analyses focused on 2 mAbs with the most robust staining (MBS1750093, Ab134162). IHC on tissue microarrays incorporating 263 renal tumors showed high staining concordance of these 2 mAbs ranging from 0.80 in chromophobe RCC to 0.89 in advanced clear cell RCC (ccRCC). MBS1750093, the most sensitive, exhibited 2+/3+ staining in papillary RCC (92.2%) > advanced ccRCC (60.0%) > chromophobe RCC (43.6%) > localized ccRCC (39.6%) > oncocytoma (22.7%). RNA in situ hybridization also revealed high levels of TPBG RNA were present most frequently in papillary and advanced ccRCC. In advanced ccRCC, there was a trend towards higher 5T4 expression and regional or distant metastases. Normal organ controls showed no or weak staining with the exception of focal moderate staining in kidney glomeruli and distal tubules by IHC. These data identify mAbs suitable for detecting 5T4 in formalin-fixed, paraffin-embedded tissues and demonstrate both interpatient and histologic subtype heterogeneity. Our validated 5T4 IHC protocol will facilitate biomarker studies and support the therapeutic targeting of 5T4.
Publications by Year: 2023
2023
BACKGROUND: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction.
PURPOSE: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patient's outcome at 6-year follow-up.
STUDY DESIGN: Cohort study; Level of evidence, 3.
METHODS: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx Activity Rating Scale. Patients were followed up at 6 years and asked to complete the identical set of outcome instruments. Regression analysis assessed the meniscal and articular cartilage pathology risk factors for clinical outcomes 6 years after revision ACL reconstruction.
RESULTS: An overall 1234 patients were enrolled (716 males, 58%; median age, 26 years). Surgeons reported the pathology at the time of revision surgery in the medial meniscus (45%), lateral meniscus (36%), medial femoral condyle (43%), lateral femoral condyle (29%), medial tibial plateau (11%), lateral tibial plateau (17%), patella (30%), and trochlea (21%). Six-year follow-up was obtained on 79% of the sample (980/1234). Meniscal pathology and articular cartilage pathology (medial femoral condyle, lateral femoral condyle, lateral tibial plateau, trochlea, and patella) were significant drivers of poorer patient-reported outcomes at 6 years (IKDC, KOOS, WOMAC, and Marx). The most consistent factors driving outcomes were having a medial meniscal excision (either before or at the time of revision surgery) and patellofemoral articular cartilage pathology. Six-year Marx activity levels were negatively affected by having either a repair/excision of the medial meniscus (odds ratio range, 1.45-1.72; P≤ .04) or grade 3-4 patellar chondrosis (odds ratio, 1.72; P = .04). Meniscal pathology occurring before the index revision surgery negatively affected scores on all KOOS subscales except for sports/recreation (P < .05). Articular cartilage pathology significantly impaired all KOOS subscale scores (P < .05). Lower baseline outcome scores, higher body mass index, being a smoker, and incurring subsequent surgery all significantly increased the odds of reporting poorer clinical outcomes at 6 years.
CONCLUSION: Meniscal and chondral pathology at the time of revision ACL reconstruction has continued significant detrimental effects on patient-reported outcomes at 6 years after revision surgery.
UNLABELLED: International observerships are one of many efforts aimed at addressing disparities in orthopaedic trauma care globally. However, their impact on visiting surgeons and their home countries, as well as the challenges faced by participating surgeons, are not well-documented.
METHODS: A survey was distributed to overseas surgeons who participated in an orthopaedic trauma observership from 2009 to 2020. Surgeons were identified through North American institutions previously recognized by the authors as having hosted international observerships. Information gathered included participant demographics, details of and perceived impact of the observership, and barriers faced before, during, and after the program. Responses from 148 international surgeons (ISs) from 49 countries were analyzed.
RESULTS: Sixty percent of observerships were at academic programs, 57% lasted 1-3 months, and 60% were self-funded. Participants identified cost and housing as primary barriers. After completing their observership, lack of funding, equipment and support staff, and excessive workload prevented participants from implementing changes at their clinical practice. Most observers believed that they gained relevant clinical (89%) and surgical knowledge (67%) and developed a professional network of North American hosts (63%). The most common suggested changes to the observership were greater hands-on experience in the operating room and structured goal setting relevant to the visiting surgeon.
CONCLUSIONS: Visiting surgeons find North American orthopaedic trauma observerships helpful in improving their surgical and clinical skills. However, financial constraints and resource limitations at their clinical practice and limited operative experience during the observership present barriers to maximizing this clinical experience. To enhance the relevance of clinical observerships for ISs and impact global orthopaedic trauma care, the unique needs and challenges facing ISs must be addressed.
LEVEL OF EVIDENCE: IV-Cross-Sectional Study.
BACKGROUND: Biologic healing after rotator cuff repair remains a significant challenge. Injectable biologic augmentation may improve tissue quality at the suture-tendon interface.
PURPOSE: To investigate the effect of injectable biologic supplementation in rotator cuff repair and to assess the quality and adherence to evolving reporting standards.
STUDY DESIGN: Systematic review; Level of evidence, 3.
METHODS: A systematic review was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Included were 40 studies: 29 preclinical (in vivo animal models) and 11 clinical. Each clinical study was assessed for quality, risk of bias, and adherence to relevant MIBO (Minimum Information for Studies Evaluating Biologics in Orthopaedics) guidelines. The outcomes of interest were reported load to failure, load to gap, gap size, and stiffness in the preclinical studies, and healing rate and any patient-reported outcome measures in the clinical studies.
RESULTS: Injectables reported included growth factors (eg, transforming growth factor-beta 3, erythropoietin), bone marrow-derived mesenchymal stem cells and adipose-derived mesenchymal stem cells (ADSCs), and other agents such as platelet-rich plasma (PRP) and hyaluronic acid. The most common findings for preclinical injectables were increased load to failure (16/29 studies; 55.2%) and improved collagen histological quality (11/29 studies; 37.9%). All 11 clinical studies (10 PRP, 1 ADSC) indicated no adverse events, with similar or improved patient-reported outcomes compared with repairs in the control groups. In 1 study utilizing an innovative delivery technique, a concentrated PRP globule with fibrin matrix was shuttled over a suture to maintain concentrated PRP at the repair site and demonstrated a significant decrease in retears (P = .03) at a 31-month follow-up. A matched-cohort study investigating augmentation with ADSCs demonstrated a significantly lower retear rate in the ADSC-augmented group than the control group at a 28-month follow-up (P < .001). On average, the clinical studies adhered to 66% of relevant MIBO reporting guidelines and had a low risk of bias.
CONCLUSION: Approximately 83% of preclinical studies found a positive biomechanical or histological effect, with no studies showing an overall negative effect. Clinically, utilization of innovative delivery techniques may reduce the risk of arthroscopic washout of PRP and improve retear rates. ADSCs were shown to reduce retear rates at a 28-month follow-up.
BACKGROUND: Insurance status is important as medical expenses may decrease the likelihood of follow-up after musculoskeletal trauma, especially for low-income populations. However, it is unknown what insurance factors are associated with follow-up care. In this study, we assessed the association between insurance plan benefits, the end of the post-surgical global period, and follow-up after musculoskeletal injury.
METHODS: This is a retrospective cohort study of 394 patients with isolated extremity fractures who were treated at three level-I trauma centers over four months in 2018. Paired t-tests were utilized to assess the likelihood of follow-up in relation to the 90-day post-surgical global period. Regression analysis was used to assess factors associated with the likelihood of follow-up. Supervised machine learning algorithms were used to develop predictive models of follow-up after the post-surgical global period.
RESULTS: Our final analysis included 328 patients. Likelihood of follow-up did not significantly change while within the post-surgical global period. When comparing follow-up within and outside of the post-surgical global period, there was a 20.1% decrease in follow-up between the 6-weeks and 6-month time points (68.3% versus 48.2%, respectively; p < 0.0001). Medicaid insurance compared to Medicare (OR 0.27, 95% confidence interval (CI) = [0.09, 0.84], p = 0.02) was a predictor of decreased likelihood of follow-up at 6-months post-operatively.
CONCLUSIONS: Our study demonstrates a statistically significant decrease in follow-up for orthopaedic trauma patients after the post-surgical global period, particularly for patients with Medicaid or Private insurance.
BACKGROUND: Multidisciplinary orthopaedic oncology conferences are important in developing the treatment plan for patients with suspected orthopaedic bone and soft tissue tumors, involving physicians from several services. Past studies have shown the clinical value of these conferences; however, the impact of radiology input on the management plan and time cost for radiology to staff these conferences has not been fully studied.
QUESTIONS/PURPOSES: (1) Does radiology input at multidisciplinary conference help guide clinical management and improve clinician confidence? (2) What is the time cost of radiology input for a multidisciplinary conference?
METHODS: This prospective study was conducted from October 2020 to March 2022 at a tertiary academic center with a sarcoma center. A single data questionnaire for each patient was sent to one of three treating orthopaedic oncologists with 41, 19, and 5 years of experience after radiology discussion at a weekly multidisciplinary conference. A data questionnaire was completed by the treating orthopaedic oncologist for 48% (322 of 672) of patients, which refers to the proportion of those three oncologists' patients for which survey data were captured. A musculoskeletal radiology fellow and musculoskeletal fellowship-trained radiology attending physician provided radiology input at each multidisciplinary conference. The clinical plan (leave alone, follow-up imaging, follow-up clinically, recommend different imaging test, core needle biopsy, surgical excision or biopsy or fixation, or other) and change in clinical confidence before and after radiology input were documented. A second weekly data questionnaire was sent to the radiology fellow to estimate the time cost of radiology input for the multidisciplinary conference.
RESULTS: In 29% (93 of 322) of patients, there was a change in the clinical plan after radiology input. Biopsy was canceled in 30% (24 of 80) of patients for whom biopsy was initially planned, and surgical excision was canceled in 24% (17 of 72) of patients in whom surgical excision was initially planned. In 21% (68 of 322) of patients, there were unreported imaging findings that affected clinical management; 13% (43 of 322) of patients had a missed finding, and 8% (25 of 322) of patients had imaging findings that were interpreted incorrectly. For confidence in the final treatment plan, 78% (251 of 322) of patients had an increase in clinical confidence by their treating orthopaedic oncologist after the multidisciplinary conference. Radiology fellows and attendings spent a mean of 4.2 and 1.5 hours, respectively, reviewing and presenting at a multidisciplinary conference each week. The annual combined prorated time cost for the radiology attending and fellow was estimated at USD 24,310 based on national median salary data for attendings and internal salary data for fellows.
CONCLUSION: In a study taken at one tertiary-care oncology program, input from radiology attendings and fellows in the setting of a multidisciplinary conference helped to guide the final treatment plan, reduce procedures, and improve clinician confidence in the final treatment plan, at an annual time cost of USD 24,310.
CLINICAL RELEVANCE: Multidisciplinary orthopaedic oncology conferences can lead to changes in management plans, and the time cost to the radiologists should be budgeted for by the radiology department or parent institution.
Through an accepted seven-step process outlined by the International Association for Medical Education, we created a high-quality questionnaire that will provide objective evaluation of prospective hand surgery fellows' goals and desires. Utilizing qualitative methodology via semistructured interviews with prospective and current hand surgery fellows from across the United States, we developed a codebook that represented desired themes within a one-year hand surgery fellowship, focusing on numerous topics including the importance of exposure to a specific pathology, curriculum, fellowship size, and location, etc. We then generated a survey, validated it among experts including current program directors, and performed cognitive interviews with the same prospective and current fellows to ensure content validity. The result was the creation of a survey, which can be employed to monitor trends in the goals and desires of prospective hand surgery applicants to ensure that fellowships remain adaptable and current.
BACKGROUND: Recurrent tears of the rotator cuff pose a substantial problem despite advances in repair technique. Biologic augmentation via marrow stimulation or vented anchors may strengthen the suture-tendon junction and improve healing rates of native tissue, thereby enhancing outcomes of primary surgical repair.
PURPOSE: To provide a focused systematic review and meta-analysis of local, intraoperative marrow-derived augmentation techniques in clinical primary rotator cuff repair.
STUDY DESIGN: Systematic review; Level of evidence, 4.
METHODS: A systematic review of PubMed, Embase, and Cochrane was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 2131 studies from 2010 to 2022, focused on either marrow stimulation or vented anchors, were isolated and classified as either preclinical or clinical. Meta-analysis was performed for comparative marrow stimulation and vented anchor studies. Heterogeneity was tested through calculation of I 2.
RESULTS: A total of 13 clinical studies were included in the review. All 9 comparative studies included in the meta-analysis demonstrated high methodologic quality or a low risk of bias. The pooled retear rate across all 9 clinical studies for patients undergoing marrow stimulation was 11%. For the 5 studies in the meta-analysis, the pooled retear rates were 15% for marrow stimulation and 30% for controls. Meta-analysis demonstrated a significant difference in the overall retear rate that favored marrow stimulation (odds ratio [OR], 0.41; 95% CI, 0.25-0.66; P = .0003; I 2 = 0%). Similarly, meta-analysis of the Constant score at final follow-up demonstrated a statistically significant difference between the 2 groups that favored a higher Constant score in the marrow stimulation group (mean difference, 2.84; 95% CI, 1.02-4.66; P = .002; I 2 = 29%). Vented anchors demonstrated improved ossification and bone density at the anchor site, but no difference in outcomes or retear. Pooled retear rates were 22.5% for vented anchors and 27.8% for controls.
CONCLUSION: Current evidence demonstrates that marrow-stimulation techniques may have a positive impact on healing and retear rate, while vented anchors have a muted impact relative to nonvented anchors. Although available evidence is limited and more research is needed, findings to date suggest that marrow stimulation techniques may be an inexpensive, straightforward technique to consider in qualifying patients to prevent rotator cuff retears.
BACKGROUND: The incidence of periprosthetic femur fracture (PPFF) in the setting of total hip arthroplasty (THA) is steadily increasing. We seek to address whether there is a difference in outcomes between Vancouver B fracture types managed with ORIF when the original stem was a press-fit stem versus a cemented stem.
METHODS: In this retrospective cohort study at a level 1 trauma center, we identified 136 patients over 65 years-of-age with Vancouver B-type fractures sustained between 2005 and 2019. Patients were treated by ORIF and had either cemented or press-fit stems prior to their injury. Outcomes were subsidence of the femoral implant, time to full weight bearing, rate of the hip implant revision, estimated blood loss (EBL), postoperative complications, and the one-year mortality rate.
RESULTS: A total of 103 (75.7%) press-fit and 33 (24.3%) cemented patients were reviewed. Patient baseline characteristics, Vancouver fracture sub-types, and implant characteristics were not found to be significantly different between groups. The difference in subsidence rates, postoperative complications, and time to weight bearing were not significantly different between groups. EBL and one-year mortality rate were significantly higher in the cemented group.
CONCLUSIONS: In geriatric patients with Vancouver B type periprosthetic fractures managed with ORIF, patients with an originally press fit stem may have lower mortality, lower estimated blood loss, and similar subsidence and hospital length of stays when compared to those with a cemented stem.