Search

The 2020 to 2021 application cycle was marked by structural changes due to the COVID-19 pandemic. Adaptations included the American Orthopaedic Association Council of Residency Program Directors recommendations for a universal interview offer day (UIOD), synchronizing applicant interview offer release. As a novel process within orthopaedics, there are limited data on the execution and effect of a UIOD. Study goals include determining (1) residency program adherence to the Council of Residency Program Directors UIOD guidelines during the 2020 to 2021 cycle, (2) how quickly programs filled available interviews, and (3) any difference in time from release to booking between applicants using edu and com e-mail domains.Orthopaedic residency programs and applicants using the Thalamus interview management software platform during the 2020 to 2021 residency application cycle were analyzed, representing 46 residency programs and 993 interviewees (22% and 77% of the national total, respectively).Of the programs included in this study, 19 (41%) were strictly adherent to the UIOD and time, 14 (30%) were weakly adherent and sent out offers outside of the assigned time, and 13 (28%) were nonadherent and sent out offers on dates other than the UIOD. The average time to fill to 80% capacity was 26 ± 14 minutes (range 3 to 77 minutes) for the 33 programs that released on the UIOD. Applicants with edu e-mail domains scheduled their first interview an average of 1.8 minutes after those with com e-mail domains (14.8 versus 13.0 minutes, P0.05).Despite more than 60% of the residency programs committing to participate, less than half of the programs that initially agreed to participate were strictly adherent to guidelines during the first UIOD in orthopaedic surgery. Although additional research is needed to analyze the unique, fully virtual 2020 to 2021 recruitment season, a phased or waved approach to the UIOD may improve the process for all stakeholders in future cycles.Level V.

Background: External beam radiation therapy is an important aspect of multidisciplinary care for patients with metastatic bone disease. Referral to radiation oncology is within the control of the orthopaedic surgeon and has the potential to serve as a quality benchmark. Methods: This is a retrospective cohort study. Patients with metastatic disease of the femur who underwent prophylactic femoral stabilization or fixation of a pathologic femur fracture from 2010-2015 at a single academic medical center or within the Veterans Health Administration (VHA) were included. A total of 950 VHA patients and 130 academic medical center patients were enrolled. The main outcome was the proportion of patients receiving a referral to radiation oncology by six weeks after the date of surgery. Results are presented for each institution and are stratified by type of procedure (prophylactic stabilization versus pathologic fixation). The study further evaluates regional differences within the VHA. Results: The majority of patients received a referral for radiation after prophylactic stabilization (VHA: 290/361 patients [80% 95% CI: 76% - 84%]; academic medical center: 81/89 patients [91%, 95% CI: 85%, 97%]). The proportion referred was higher at the academic medical center (odds ratio [OR]: 2.5, 95% CI: [1.15, 5.36], P =0.027). After fracture fixation, 428/589 (73%, 95% CI: [69%, 77%]) of VHA patients and 30/41 (73%, 95% CI [59%, 87%]) of patients at the academic medical center received a referral to radiation. Receiving a referral was not associated with healthcare system (OR: 1.0; 95% CI: [0.50, 2.10])). Within the VHA, the proportion of patients referred varied by geographic location (Pearson’s chi-squared test, P =0.004 for prophylactic stabilization and P

Table of microinjected drugs

Microinjection of olaratumab does not inhibit PDGFRα, ERK, or S6 phosphorylation.

All adverse events reported on the study

Supplementary Legend

Distinct drug induced phenotypes and apoptotic responses specific to drug mechanism of action are seen at sites of CIVO microinjection.

Purpose:A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS).Patients and Methods:We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.Results:The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.Conclusions:These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.See related commentary by Sleijfer and Lolkema, p. 3897

Representative images of tumors from patients who received radiation treatment.

Device performance

Clinical Trial Design

Increased phosphorylation of PDGFR� and downstream effectors in an undifferentiated pleomorphic sarcoma displaying a lack of apoptotic response to microdosed doxorubicin.

BACKGROUND: The deleterious effect of diabetes mellitus on surgical outcomes is well documented for joint replacement surgery. We analyzed the large national US Department of Veterans Affairs (VA) database for patients who had undergone elective spinal surgery. METHODS: We retrospectively searched the VA database and identified 174 520 spine cases. RESULTS: There were 7766 (4.5%) wound infections and 49 271 (28%) had hemoglobin A1c (HbA1c) testing (range: 3.0–17.8) prior to surgery. In the preoperative HbA1c–checked group, there were 2941 (6.0% of 49 271) infections and in the without–preoperative HbA1c group, there were 4825 (3.9% of 125 249) infections. The distribution of infections was significantly different (χ(2) = 372.577, P < .0001) and suggests a 2.12% increase in the absolute risk of infection based on the presence of preoperative HbA1c testing, regardless of the result. Logistic regression revealed a preoperative HbA1c test was associated with an odds ratio of 1.435 for infection (confidence interval 1.367–1.505, P < .0001). In a separate model based on HbA1c levels, we found that HbA1c is a significant predictor of infection with an odds ratio of 1.042 (confidence interval 1.017–1.068, P = .0009) for each 1% increase in the test result. This analysis differs from using a strict cutoff value of HbA1c of 6.5%. Similar testing for body mass index and age yielded an odds ratio of 1.027 for each increase of 1 kg/m(2) and an odds ratio of 1.009 for each 1-year increase in age respectively. CONCLUSIONS: Hemoglobin A1c testing, HgA1c value, body mass index, and age all contribute to the risk of wound infection after elective spine surgery in a large national VA population. These data can be used to estimate surgical risks and to aid in patient counseling about proposed spine surgery. LEVEL OF EVIDENCE: 4.

Expandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre-Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported.We conducted a multi-institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan-Meier survival technique and competing risk analysis.Thirty-six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7-93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty-two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1-9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6-31.5) at 5 years. Twenty-nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years.There is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery.Level IV, therapeutic study.

In this retrospective study, we investigated the influence of chemotherapy and immunotherapy on thromboembolic risk among United States Veterans with lung cancer during their first 6 months (180 days) following initiation of systemic therapy. Included patients received treatment with common front-line agents that were divided into four groups: chemotherapy alone, immunotherapy alone, combination of chemo- and immunotherapies, and molecularly targeted therapies (control group). The cohort experienced a 74% overall incidence of thrombosis, but the analysis demonstrated significantly different rates among the different groups. We explored models incorporating multiple confounding variables as well as the competing risk of death, and these results indicated that both chemo- and immunotherapies were associated with an increased incidence of thrombosis, either alone or combined, compared with the control group (756%, P = 2.2 × 10(−16); 10·2%, P = 2.2 × 10(−16); and 7·87%, P = 2.4 × 10(−14) respectively vs. 41·0%). The Khorana score was found to be associated with increased risk, as were vascular disease and metastases. We found an association between risk of thrombosis and the use of anticoagulation, accounting for several confounders, including history of thrombosis. Further study is warranted to better determine the drivers of thromboembolic risk and to identify ways to mitigate this risk for patients.

Purpose: A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS). Patients and Methods: We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue. Results: The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity. Conclusions: These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials. See related commentary by Sleijfer and Lolkema, p. 3897

Background and purpose — Compressive osseointegration fixation is an alternative to intramedullary fixation for endoprosthetic reconstruction. Mechanical failure of compressive osseointegration presents differently on radiographs than stemmed implants, therefore we aimed to develop a reliable radiographic method to determine stable integration. Patients and methods — 8 reviewers evaluated 11 radiographic parameters from 29 patients twice, 2 months apart. Interclass correlation coefficients (ICCs) were used to assess test–retest and inter-rater reliability. We constructed a fast and frugal decision tree using radiographic parameters with substantial test–retest agreement, and then tested using radiographs from a new cohort of 49 patients. The model’s predictions were compared with clinical outcomes and a confusion matrix was generated. Results — 6 of 8 reviewers had non-significant intra-rater ICCs for ≥ one parameter; all inter-rater ICCs were highly reliable (p < 0.001). Change in length between the top of the spindle sleeve and bottom of the anchor plug (ICC 0.98), bone cortex hypertrophy (ICC 0.86), and bone pin hypertrophy (ICC 0.81) were used to create the decision tree. The sensitivity and specificity of the training cohort were 100% (95% CI 52–100) and 87% (CI 74–94) respectively. The decision tree demonstrated 100% (CI 40–100) sensitivity and 89% (CI 75–96) specificity with the test cohort. Interpretation — A stable spindle length and at least 3 cortices with bone hypertrophy at the implant interface predicts stable osseointegration; failure is predicted in the absence of bone hypertrophy at the implant interface if the pin sites show hypertrophy. Thus, our decision tree can guide clinicians as they follow patients with compressive osseo­integration implants.

Transtibial below-knee amputation (BKA) is associated with considerable morbidity, particularly in the vasculopathic population. The purpose of this study was to determine the cumulative probability of undergoing transfemoral above-knee amputation (AKA) conversion within 5 years of BKA and associated risk factors while accounting for the competing risk of death.This is a retrospective, national database study with structured query of the Veterans Affairs (VA) database for patients who underwent BKA from 1999 to 2020, identified by Current Procedural Terminology codes. Above-knee amputation conversion was identified using Current Procedural Terminology codes in combination with natural language processing to match procedure laterality. After internally validating our patient identification method, risk factors were collected. Competing risk analysis estimated the cumulative incidence rate of AKA conversion and associated risk factors with death as a competing risk.Our query yielded 19,875 patients (19,640 men, 98.8%) who underwent BKA with a median age of 66 years (interquartile range, 60 to 73). The median follow-up was 951 days (interquartile range, 275 to 2,026). The crude cumulative probabilities of AKA conversion and death at 5 years were 15.4% (95% confidence interval [CI], 14.9% to 16.0%) and 47.7% (95% CI, 46.9% to 48.4%), respectively. In the Fine and Gray subdistribution hazard model, peripheral vascular disease had the highest AKA conversion risk (hazard ratio [HR] 2.66; 95% CI, 2.22 to 3.20; P0.001). Other factors independently associated with AKA conversion included urgent operation (HR 1.32; 95% CI, 1.23 to 1.42), cerebrovascular disease (HR 1.19; 95% CI, 1.11 to 1.28), chronic obstructive pulmonary disease (HR 1.15; 95% CI, 1.07 to 1.24), and previous myocardial infarction (HR 1.10; 95% CI, 1.02 to 1.19) (All P0.02).Within this predominantly male, VA population, BKA carries a high risk of conversion to AKA within 5 years, without reaching a steady risk of AKA conversion within 5 years. Peripheral vascular disease, chronic obstructive pulmonary disease, cerebrovascular disease, previous myocardial infarction, and urgent BKA increase the risk of AKA conversion.Level III.

Background Iliopsoas impingement after total hip arthroplasty (THA) occurs in up to 4.3% of patients resulting in functional groin pain. Operative treatment historically has included open iliopsoas tenotomy or acetabulum revision. We present a large single surgeon series of patients treated with endoscopic iliopsoas tenotomy for iliopsoas impingement after THA to evaluate the effectiveness and risks. Methods A consecutive series of 60 patients with iliopsoas impingement after THA treated with endoscopic iliopsoas tenotomy was retrospectively evaluated. Outcomes assessed were resolution of pain, change in Hip Outcome Score (HOS), and complications. Radiographs were reviewed by a musculoskeletal radiologist to evaluate component positioning and to compare with a control cohort. Results At last follow-up (mean 5.5 months), 93.3% of patients had resolution of pain. The HOS activities of daily living (ADL) subscale mean was 57.5 (range 10.9-89.3, standard deviation [SD] 18.8) preoperatively and 71.6 (range 14.1-100, SD 26.1) postoperatively (P = .005). The HOS sports subscale mean was 37.3 (range 0-83.3, SD 24.0) preoperatively and 58.1 (range 0-100, SD 33.2) postoperatively (P = .002). One complication was reported, a postoperative hematoma managed conservatively. Body mass index and increased offset were associated with iliopsoas symptoms after THA in this series. Conclusion Endoscopic iliopsoas tenotomy after THA had a 93.3% resolution of pain, clinically important improvements in HOS, and low rate of complications. Endoscopic tenotomy should be considered as a treatment option in patients with iliopsoas impingement after THA.

The Goutallier and Warner Classification systems are useful in determining rotator cuff reparability. Data are limited on how accurately the scapular-Y view used in both systems reflects the 3-dimensional (3-D) changes in fatty infiltration (FI) and muscle atrophy (MA). Tendon retraction in the setting of a cuff tear may also influence the perception of these changes. This study's objectives were to (1) measure the 3-D volume of the supraspinatus muscle in intact rotator cuffs, and with varying magnitudes of retraction; (2) measure the 3-D volume of FI in the supraspinatus muscle in these conditions; and (3) determine the influence of tendon retraction on measured FI and MA using the Goutallier and Warner Classification Systems.Between August 2015 and February 2016, all shoulder magnetic resonance images (MRIs) at the Portland VA Medical Center were standardized to include the medial scapular border. MRIs and charts were reviewed for inclusion/exclusion criteria. Included MRIs were categorized into 4 groups based on rotator cuff retraction. Supraspinatus muscle and fossa were traced to create 3-D volumes. FI and MA were measured within the supraspinatus. The supraspinatus muscle was graded among 6 physicians using the Goutallier and Warner classification systems. These grades were compared to 3-D measured FI and MA. The influence of tendon retraction on the measured grades were also evaluated.One hundred nine patients met inclusion/exclusion criteria. Ten MRIs for each group (N = 40) were included for image analysis. Supraspinatus volume tracings were highly reproducible and consistent between tracers. Supraspinatus muscle volumes decreased while global FI and MA increased with greater degrees of tendon retraction. In muscles with less than 10% global fat, fat concentrated in the lateral third of the muscle. In muscle with more than 10% global fat content, it distributed more diffusely throughout the muscle from medial to lateral. In comparing the scapular-Y to a medial cut, there was no consistent trend in FI whereas MA was more accurate at the medial cut.Parasagittal imaging location did not significantly influence the Goutallier score; however, assessment of MA using the Warner score leads readers to perceive less MA medially regardless of the magnitude of tendon retraction. The pattern of FI within the supraspinatus muscle changes from a laterally based location around the muscle-tendon junction to a more diffuse, global infiltration pattern when the whole muscle fat content exceeds 10%.

BACKGROUND: For decades, opioids have been the mainstay in pain management after total joint arthroplasty despite evidence that their use should be curtailed. To limit unnecessary prescribing of opioids, the US Department of Veterans Affairs (VA) Portland Health Care System Total Joints Service implemented the Minimizing Opioids After Joint Operation (MOJO) postoperative pain protocol in 2018 to reduce opioid use following total knee arthroplasty (TKA). This protocol included reductions of inpatient and outpatient opioid prescribing, preoperative optimization, use of perioperative nerve blocks, and surgery without a tourniquet. METHODS: We performed a retrospective chart review that compared the first 20 consecutive patients undergoing TKA using the MOJO protocol with the last 20 patients using the prior routine. Outcomes included total inpatient opioid use, daily opioid use, emergency department (ED) visits or readmissions within 90 days, phone calls for pain or medication refills, length of stay (LOS), and pain during inpatient hospital stay. RESULTS: There were significant differences between the pre-MOJO and the MOJO groups with regard to daily inpatient morphine equivalent dose (MED) (82 mg vs 31 mg, P < .01) and total inpatient MEDs (306 mg vs 33 mg, P < .01). There was less self-reported pain on postoperative day 1 in the MOJO group (5.5 vs 4.1, P = .01), decreased LOS (4.4 days vs 1.1 days, P < .01), fewer total ED visits (6 vs 2, P < .07), and fewer discharges to skilled nursing facilities (12 vs 0, P < .01). CONCLUSIONS: The MOJO protocol reduced postoperative opioid use after TKA in the VA setting without compromising pain control or increasing ED visits. The framework and routines described are potentially applicable to other institutions and surgical specialties.

ObjectivesTo determine the proportion of patients with extremity sarcoma who would be willing to participate in a clinical trial in which they would be randomised to one of four different postoperative sarcoma surveillance regimens. Additionally, we assessed patients’ perspectives on the burden of cancer care, factors that influence comfort with randomisation and the importance of cancer research.DesignProspective, cross-sectional patient survey.SettingOutpatient sarcoma clinics in Canada, the USA and Spain between May 2017 and April 2020. Survey data were entered into a study-specific database.ParticipantsPatients with extremity sarcoma who had completed definitive treatment from seven clinics across Canada, the USA and Spain.Main outcome measuresThe proportion of patients with extremity sarcoma who would be willing to participate in a randomised controlled trial (RCT) that evaluates varying postoperative cancer surveillance regimens.ResultsOne hundred thirty complete surveys were obtained. Respondents reported a wide range of burdens related to clinical care and surveillance. The majority of patients (85.5%) responded that they would agree to participate in a cancer surveillance RCT if eligible. The most common reason to participate was that they wanted to help future patients. Those that would decline to participate most commonly reported that participating in research would be too much of a burden for them at a time when they are already feeling overwhelmed. However, most patients agreed that cancer research will help doctors better understand and treat cancer.ConclusionsThese results demonstrate that most participants would be willing to participate in an RCT that evaluates varying postoperative cancer surveillance regimens. Participants’ motivation for trial participation included altruistic reasons to help future patients and deterrents to trial participation included the overwhelming burden of a cancer diagnosis. These results will help inform the development of patient-centred RCT protocols in sarcoma surveillance research.Level of evidenceV.

CASE A 68-year-old woman with a history of stage IIIC (T3bN1bM0) melanoma with metastases to her right axilla status after 10 cycles of nivolumab presented with right shoulder pain. Radiographs showed a progressive erosive glenohumeral joint lesion. The workup was negative for metastasis and infection. Her clinical and radiographic findings were consistent with erosive arthritis. The patient underwent shoulder hemiarthroplasty and experienced substantial improvements. CONCLUSION This is an unusual case of inflammatory arthritis associated with nivolumab, an antiprogrammed cell death protein 1, and is an important reminder of the musculoskeletal toxicities associated with immunotherapies.

Purpose/Objectives: Tumor responses to cancer treatments are highly context-specific and often involve complex interactions between the anti-cancer therapy, genetically diverse tumor cells, and a heterogeneous tumor microenvironment (TME). All preclinical models fall short in capturing this complexity. CIVO (Comparative In Vivo Oncology) is an intratumoral microdose injection research tool intended to bridge the translational gap between preclinical and clinical studies by enabling in situ assessment of up to 8 oncology drugs or drug combinations simultaneously within a patient’s tumor. The CIVO Phase 0 model was established under FDA’s exploratory IND guidelines for microdosing. A Master Protocol was then developed, enabling ongoing evaluation of multiple investigational drugs and combinations without a need for stand-alone new protocols. Each investigational drug or combination is specified as a substudy of the Master Protocol, thus reducing administrative burden to clinical site staff and creating an infrastructure to ensure quality data and oversight of patient safety. This is a multi-center, open-label Phase 0 Master Protocol designed to study the localized pharmacodynamics (PD) of anti-cancer therapies within the TME when administered intratumorally in microdose quantities via the CIVO device. The safety of intratumoral microdose administration via the CIVO device will also be evaluated. Materials/Methods: Approximately 12 subjects are expected to be enrolled per substudy. All substudies will evaluate subjects ≥18 years with a diagnosis of solid tumors with scheduled surgical intervention. Eligible subjects have at least one lesion (primary or recurrent tumor or effaced metastatic lymph node) ≥2 cm in the shortest diameter that is surface accessible for CIVO injection. Each substudy will define the tumor type and specific eligibility criteria for enrollment. The study visits consist of screening, CIVO injection, surgical intervention, and two follow-up visits. All patients will be injected by the CIVO device containing microdose quantities of drugs specified in respective substudies. The CIVO device can be configured with 3, 5, or 8 needles and the device configuration will be assigned on a per-patient basis, dependent upon lesion size. Following surgical resection, the injected portion of the tumor will undergo central PD biomarker analysis. At the time of submission, the study is open for enrollment with 1 substudy enrolling Head and Neck Squamous Cell Carcinoma (HNSCC) patients and 1 substudy enrolling HNSCC or soft tissue sarcoma patients. The Master Protocol was established to efficiently add substudies and accommodate evaluation of a wider repertoire of new agents in order to continually inform and de-risk drug development via the CIVO platform. Clinical trial information: NCT04541108. Citation Format: Karthik Rajasekaran, Jason G. Newman, Robert G. Maki, Thomas J. Ow, Vikas Mehta, Kenneth R. Gundle, Daniel R. Clayburgh, Ryan J. Li, Mercedes Porosnicu, Cherie-Ann O. Nathan, Alice Tang, Beryl A. Hatton, Kimberly H. Sottero, Gloria Kung, Marc O. Grenley, Kirsten Anderson, Richard A. Klinghoffer. A phase 0 master protocol utilizing a novel intratumoral microdosing approach for simultaneously evaluating multiple drugs and drug combinations in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT216.

Despite over four thousand clinical trials investigating combinations of various anti-cancer agents with immune checkpoint inhibitors (CPI), few have demonstrated significant clinical improvement over CPI alone. This indicates a need for approaches that can guide development of complex (≥ 3 drug) I-O combination treatments by enabling far greater mechanistic understanding of response to drug exposure by components of the authentic tumor microenvironment (TME). Here we show how an approach based on two technologies, the Presage Comparative In Vivo Oncology (CIVO) Platform and the NanoString GeoMx Digital Spatial Profiler (GeoMx DSP), highlights drug synergies as well as mechanisms of resistance to drug exposure in the native and intact TME of cancer patients, providing a path to rapid identification of effective drug combinations. The CIVO platform enables trackable multiplexed intratumoral delivery of microdosed drugs, either as single agents or in combinations, allowing evaluation of the localized tumor response to drug candidates in the TME while capturing tumor heterogeneity and patient diversity. GeoMx DSP is a method for high-plex spatial profiling of mRNAs with rare-cell sensitivity. Combining these technologies in Phase 0 clinical studies in human soft tissue sarcoma patients we evaluated distinct tumor sites microdosed with either nivolumab (anti-PD1), aldesleukin (recombinant IL-2), the combination of nivolumab and aldesleukin, vehicle (no drug), or chemotherapy controls. Using the Nanostring Cancer Transcriptome Atlas we evaluated the effect of drug exposure on expression of over 1,800 genes simultaneously with spatial resolution across individual patient tumors. Synergistic elevation of multiple transcripts was observed at tumor sites exposed to the combination of aldesleukin and nivolumab. This included T-cell specific elevation of granzyme B, a classic biomarker of T-cell activation. Importantly, we show how events such as T-cell activation may be dampened by feedback loops involving immune suppressive responses including, but not limited to, elevation of IDO-1 in non-T-cell components of the TME. Results were observed across multiple patient tumors and were verified by conventional immuno-histochemistry or in situ hybridization. Performing these studies across different patients allows us to explore the inter-individual variation in drug responses. We believe this is an efficient and biologically relevant approach to better understanding feedback loops activated within the authentic TME and ultimately prioritizing drug combinations for clinical development. Citation Format: Jason P. Frazier, Kenneth R. Gundle, Marc Grenley, Gloria Kung, Kimberly Sottero, Kirsten Anderson, Richard Klinghoffer, Jonathan M. Derry. Deep mechanistic profiling of immune oncology (I-O) drug combinations in cancer patients with CIVO® intratumoral microdosing and NanoString GeoMx DSP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3424.

In this retrospective study, we investigated the influence of chemotherapy and immunotherapy on thromboembolic risk among US Veterans with lung cancer during their first six months of systemic therapy. Patients in the study cohort received treatment with common frontline agents that were divided into four groups: chemotherapy alone, immunotherapy alone, combination of chemo- and immunotherapies, and molecularly targeted therapies. The latter served as a control group of systemically treated lung cancer patients who received neither chemotherapy nor immunotherapy. The cohort experienced a 6.8% overall incidence of thromboembolic events with a median time to event of 49 days, but the analysis demonstrated significantly different rates among the different treatment groups. We explored models incorporating multiple confounding variables as well as the competing risk of death, and these results indicated that both chemotherapy and immunotherapy were associated with an increased incidence of thrombosis, either when given alone or combined, compared with the control group (6.91%, 9.09%, and 7.47% respectively versus 3.68%, p < 0.024). Both the Khorana score assessing thrombosis risk for cancer patients and the Charlson comorbidity score were found to be associated with increased risk of thrombosis in our analyses. Paradoxically, we found an association between risk of thrombosis and the use of prophylactic anticoagulation or aspirin during the first month of systemic treatment, accounting for several confounding variables including a patient’s prior history of thrombosis. Additionally, our data suggest that thromboembolic events may occur more commonly in lung cancer patients treated with immunotherapy compared with chemotherapy. Further study is warranted to better determine the drivers of thromboembolic risk and to identify ways to mitigate this risk for patients.

This review summarizes the biomechanical concepts, clinical outcomes and limitations of compressive osseointegration fixation for endoprosthetic reconstruction. Compressive osseointe - gration establishes stable fixation and integration through a novel mechanism; a Belleville washer system within the spindle applies 400-800 PSI force at the boneimplant interface. Compressive osseointegration can be used whenever standard endoprosthetic reconstruction is indicated. However, its mode of fixation allows for a shorter spindle that is less limited by the length of remaining cortical bone. Most often compressive osseointegration is used in the distal femur, proximal femur, proximal tibia, and humerus but these devices have been customized for use in less traditional locations. Aseptic mechanical failure occurs earlier than with standard endoprosthetic reconstruction, most often within the first two years. Compressive osseointegration has repeatedly been proven to be non-inferior to standard endoprosthetic reconstruction in terms of aseptic mechanical failure. No demographic, device specific, oncologic variables have been found to be associated with increased risk of aseptic mechanical failure. While multiple radiographic parameters are used to assess for aseptic mechanical failure, no suitable method of evaluation exists. The underlying pathology associated with aseptic mechanical failure demonstrates avascular bone necrosis. This is in comparison to the bone hypertrophy and ingrowth at the boneprosthetic interface that seals the endosteal canal, preventing aseptic loosening.

Study Design: Cross-sectional cohort study. Objectives: Cauda equina syndrome (CES) is a neurologic emergency, and delay in diagnosis can result in irreversible impairment. Our purpose was to determine the value of physical examination in diagnosis of CES in patients complaining of bladder and/or bowel complications in the emergency department. Methods: Adult patients at one tertiary academic medical center that endorsed bowel/bladder dysfunction, underwent a lumbar magnetic resonance imaging (MRI), and received an orthopedic spine surgery consultation from 2008 to 2017 were included. Patients consulted for trauma or tumor were excluded. A chart and imaging review was performed to collect demographic, physical examination, and treatment data. Sensitivity, specificity, and negative and positive predictive values were calculated, and fast-and-frugal decision trees (FFTs) were generated using R. Results: Of 142 eligible patients, 10 were diagnosed with CES. The sensitivity and specificity of the exam findings were highest for bulbocavernosus reflex (BCR) (100% and 100%), followed by rectal tone (80% and 86%), postvoid residual bladder (80% and 59%), and perianal sensation (60% and 68%). The positive predictive value was high for BCR (100%), but low for other findings (13% to 31%). However, negative predictive values were consistently high for all examinations (96% to 100%). Two FFTs utilizing combinations of voluntary rectal tone, perianal sensation, and BCR resulted in no false negatives. Conclusions: A combination of physical examination findings of lower sacral function is an effective means of ruling out CES and, with further study, may eliminate the need for MRI in many patients reporting back pain and bowel or bladder dysfunction.

Introduction A retrospective review was performed for patients in the Veterans Administration Healthcare System who underwent prophylactic stabilization of the femur for metastatic disease. The goal was to evaluate indications for prophylactic stabilization through Mirels criteria. Methods All veterans who underwent inpatient prophylactic femoral stabilization between October 2010 and September 2015 were identified. Procedure and demographic variables were collected by using chart review. Provider notes and radiographs were reviewed to calculate Mirels scores. Results Ninety-two patients underwent confirmed prophylactic stabilization for metastatic bone disease. Lung cancer and multiple myeloma accounted for most lesions. The mean Mirels score was 10.3 (range 7 to 12). 3.2% of patients had a score of 7, and 6.5% had a score of 8. Most lesions were peritrochanteric (66%) and lytic (85%). There was more variability in size (mean 2.3), with 15% being under one third of bony width and 38% between one and two-thirds. The mean pain score was 2.5; 73% reported functional pain. Of lytic and peritrochanteric lesions (53% of all cases), 55% were less than two-thirds the cortical width and 31% lacked functional pain. Conclusion This retrospective study of prophylactically stabilized metastatic lesions revealed that more than 90% of patients had Mirels scores greater than 8, suggesting a substantial risk of pathologic fracture. Over half of all stabilized lesions were peritrochanteric and lytic. These criteria alone achieve a minimum Mirels score of 8; however, one-third of these lacked functional pain. Notably, Mirels' original paper found location and type criteria to be the least predictive of impending fracture. Contrariwise, functional pain was the most accurate predictor. Multiple studies have found poor specificity of the Mirels criteria. The high scores achievable by the location and type criteria may represent an overrepresentation of their contribution to fracture risk. Reconsideration of the relative weights of each criterion warrants further examination.

Introduction: Cohorts from the electronic health record are often defined by the Current Procedural Terminology (CPT) codes. The error prevalence of CPT codes for patients receiving surgical treatment of metastatic disease of the femur has not been investigated, and the predictive value of coding ontologies to identify patients with metastatic disease of the femur has not been adequately discussed. Methods: All surgical cases at a single academic tertiary institution from 2010 through 2015 involving prophylactic stabilization of the femur or fixation of a pathologic fracture of the femur were identified using the CPT and International Classification of Disease (ICD) codes. A detailed chart review was conducted to determine the procedure performed as documented in the surgical note and the patient diagnosis as documented in the pathology report, surgical note, and/or office visit notes. Results: We identified 7 CPT code errors of 171 prophylactic operations (4.1%) and one error of 71 pathologic fracture fixation s(1.4%). Of the 164 prophylactic operations that were coded correctly, 87 (53.0%) had metastatic disease. Of the 70 pathologic operations that were coded correctly, 41 (58%) had metastatic disease. Discussion: The error prevalence was low in both prophylactic stabilization and pathologic fixation groups (4.1% and 1%, respectively). The structured data (CPT and ICD-9 codes) had a positive predictive value for patients having metastatic disease of 53% for patients in the prophylactic stabilization group and 58% for patients in the pathologic fixation group. The CPT codes and ICD codes assessed in this analysis do provide a useful tool for defining a population in which a moderate proportion of individuals have metastatic disease in the femur at an academic medical center. However, verification is necessary.

Functional assessment of patients with osteosarcoma may yield unique insights into the guide and advance treatment. A range of patient-reported outcomes has been validated, including general health and condition-specific measures as well as computer adaptive testing. Health state utility measures, which facilitate comparative-effectiveness research, are also available. Beyond these surveys, and laboratory-dependent gait analyses, is the potential for real-world evaluation through research-oriented and consumer-oriented accelerometers. Initial studies have shown promising validity of these activity trackers and may also have implications for traditional oncologic outcomes.

Background Below-the-knee amputation (BKA) is relatively common among patients with vascular disease, infection, trauma, or neoplastic disease. Many BKAs are performed in patients with incompletely treated medical comorbidities, and some are performed in patients with acute high-energy trauma or crush injuries, malignant neoplasm undergoing time-sensitive limb removal, and diabetes with active infection or sepsis. Consequently, revision is common. Prior studies of outcomes after BKA, including several based on the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database, have follow-up periods that do not cover the entire at-risk period. Questions/purposes (1) What is the survivorship free from unplanned reoperation within 1 year of BKA? (2) What patient characteristics are associated with reoperation within 1 year of BKA? Methods We retrospectively studied all BKAs performed by the orthopaedic surgery service at a Level 1 trauma center from 2008 to 2018, as identified by Current Procedural Terminology (CPT) codes. Twenty-eight percent (38 of 138) underwent amputation as treatment for traumatic injury, 57% (79 of 138) for infection, and 15% (21 of 138) for malignancy. A total of 17% (23 of 138) had a final follow-up encounter before the 1-year study minimum, without differential loss to follow-up by surgical indication (p = 0.43) or hemoglobin A1c (p = 0.71). Median (range) follow-up was 570 days (6 to 3375). The primary outcome was survivorship from unplanned reoperation within 1 year of BKA index surgery or last planned reoperation, as determined by Kaplan-Meier estimation. Secondarily, we identified patient characteristics independently associated with reoperation within 1 year of BKA. Collected data included age, indication, BMI, diabetes, hemoglobin A1c level, closure method, and substance use. Unplanned reoperation was defined as irrigation and debridement, stump revision, or revision to a higher-level amputation; this did not include planned reoperations for BKAs closed in a staged manner. Factors associated with reoperation were determined using multivariate logistic regression analyses. All endpoints and variables related to patients and their surgical procedures were extracted from electronic medical records by someone other than the operating surgeon. Results Using Kaplan-Meier estimation, 38% of patients (95% confidence interval 29 to 46) who underwent BKA had an unplanned reoperation within 1 year of their index surgery. Twelve percent of patients (95% CI 7 to 17) who underwent BKA did not reach 30 days with the limb survivorship free from unplanned reoperation. The median (range) time between the initial surgery and reoperation was 54 days (6 to 315). After controlling for potential confounding variables like age, gender, platelet count, albumin, and the reason for undergoing amputation, a hemoglobin A1c level greater than 8.1% (relative to A1c ≤ 8.1%) was the only variable independently associated with increased odds of reoperation (odds ratio 4.6 [95% CI 1.3 to 18.1]; p = 0.02). Conclusions BKA carries a higher risk for reoperation than currently reported in studies that use 30-day postoperative follow-up periods. Clinicians should critically assess whether BKA is necessary, especially in patients with uncontrolled diabetes assessed by hyperglycemia. Before planned BKA, patients should have documented glycemic control to minimize the odds of reoperation. Because many of this study's limitations were due to its retrospective single center design, we recommend that future work cover a clinically appropriate surveillance period using a larger cohort such as a national database and/or employ a prospective design. Level of evidence Level III, therapeutic study.

A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed ComparativeWe conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.

Functional assessment of patients with osteosarcoma may yield unique insights into the guide and advance treatment. A range of patient-reported outcomes has been validated, including general health and condition-specific measures as well as computer adaptive testing. Health state utility measures, which facilitate comparative-effectiveness research, are also available. Beyond these surveys, and laboratory-dependent gait analyses, is the potential for real-world evaluation through research-oriented and consumer-oriented accelerometers. Initial studies have shown promising validity of these activity trackers and may also have implications for traditional oncologic outcomes.

BACKGROUND: Ten years ago, we reported the results of a procedure in which we translocated the ipsilateral ulna as a vascularized autograft to reconstruct defects of the distal radius after tumor resection, with excellent functional results. At that time, wrist arthrodesis was achieved by aligning the translocated ulna with the scapholunate area of the carpus and usually the third metacarpal. This resulted in wrist narrowing. We then wondered if aligning the translocated ulna with the scaphoid and the second metacarpal would result in ulnar deviation and thereby improve grip strength. We believed lateralization would reduce the wrist narrowing that occurs with fusion to the third metacarpal and would make the cosmesis more acceptable. We also modified the incision to dororadial to make the scar less visible and thus improve the cosmesis. QUESTIONS/PURPOSES: (1) Is there an objective improvement in grip strength and functional scores (Musculoskeletal Tumor Society [MSTS] and Mayo wrist) when the translocated ulna is lateralized and the wrist is fused with the translocated ulna and aligned with the second metacarpal versus when the translocated ulna is aligned with the third metacarpal? (2) Did lateralization caused by the wrist fusion aligned with the second metacarpal minimize wrist narrowing as measured by the circumference compared with the fusion aligned with the third metacarpal? METHODS: From 2010 and 2018, we treated 40 patients with distal radius tumors at our institution, 30 of whom had a distal radius enbloc resection. Twenty-eight patients had an ipsilateral ulna translocation and wrist arthrodesis in which the radius and translocated ulna were aligned with either the second (n = 15) or the third (n = 13) metacarpals. Two patients in the second metacarpal group and three patients in the third metacarpal group were lost to follow-up before 24 months after surgery and were excluded. A retrospective analysis of 23 patients (20 with giant cell tumors and three with malignant bone tumors) included a review of radiographs and institutional tumor database for surgical and follow-up records to study oncologic (local disease recurrence), reconstruction (union of osteotomy junctions, implant breakage or graft fracture, and wrist circumference), and functional outcomes (MSTS and Mayo wrist scores and objective grip strength assessment compared with the contralateral side). The results were compared for each study group (second metacarpal versus third metacarpal). There was no difference in the incidence of local recurrence or the time to union between the two groups. There were no implant breakages or graft fractures noted in either group. RESULTS: Patients in the second metacarpal group lost less grip strength compared with the unoperated side in the third metacarpal group (median 12% [range -30% to 35%] versus median 28% [15% to 42%], difference of medians 16%; p = 0.006). There were no between-group differences in terms of MSTS (median 30 [24 to 30] versus median 26.5 [22 to 30], difference of medians 3.5; p = 0.21) or Mayo wrist scores (median 83 [65 to 100] versus median 72 [50 to 90], difference of medians 11; p = 0.10). The second metacarpal group also had less wrist narrowing as seen from the median difference in circumference between the operated and unoperated wrists (median narrowing 10 mm [3 to 35 mm] in the second metacarpal group versus median 30 mm [15 to 35 mm] in the third metacarpal group, difference of medians 20 mm; p = 0.04). CONCLUSION: Wrist arthrodesis after ulna translocation with alignment of the translocated ulna and the second metacarpal provides a functional position with ulnar deviation that offers some improvement in grip strength but no improvement in the MSTS or Mayo scores. Radialization/lateralization of the translocated ulna achieved from the alignment with the second metacarpal decreases the reduction in the wrist circumference and therefore reduces wrist narrowing. LEVEL OF EVIDENCE: Level III, therapeutic study.

Angiosarcomas are rare vascular connective tissue tumors originating from the tunica intima, media, or adventitia and may arise in large vessels. Here two cases of primary angiosarcoma of the aorta are described that highlight initial manifestations and unique complications from diffuse arterial tumor emboli, which led to delayed cancer diagnosis. In patients with aortic lesions, imaging characteristics must be thoughtfully reconciled with clinical scenarios, particularly in patients with no additional evidence of atherosclerosis or vasculitis. Keywords: Oncology, Neoplasms-Primary, MR-Angiography, Aorta © RSNA, 2021.

To determine the validity, feasibility, and responsiveness of a new web-based platform for rapid milestone-based evaluations of orthopedic surgery residents.Single academic medical center, including a trauma center and pediatrics tertiary hospital.Forty residents (PG1-5) in an orthopedic residency program and their faculty evaluators.Residents and faculty were trained and supported in the use of a novel trainee-initiated web-based evaluation system. Residents were encouraged to use the system to track progress on patient care subcompetencies. Two years of prospectively collected data were reviewed from residents at an academic program. The primary outcome was Spearman's rank correlation between postgraduate year (PGY) and competency level achieved as a measure of validity. Secondary outcomes assessed feasibility, resident self-evaluation versus faculty evaluation, the distributions among subcompetencies, and responsiveness over time.Between February 2014 and February 2016, 856 orthopedic surgery patient care subcompetency evaluations were completed (1.2 evaluations per day). Residents promptly requested feedback after a procedure (median = 0 days, interquartile range: 0-2), and faculty responded within 2 days in 51% (median = 2 days, interquartile range: 0-13). Primary outcome showed a correlation between PGY and competency level (r = 0.78, p0.001), with significant differences in competency among PGYs (p0.001 by Kruskal-Wallis rank sum test). Self-evaluations by residents substantially agreed with faculty-assigned competency level (weighted Cohen's κ = 0.72, p0.001). Resident classes beginning the study as PGY1, 2, and 3 separately demonstrated gains in competency over time (Spearman's rank correlation 0.39, 0.60, 0.59, respectively, each p0.001). There was significant variance in the number of evaluations submitted per subcompetency (median = 43, range: 6-113) and competency level assigned (p0.01).Rapid tracking of trainee competency with milestone-based evaluations in a learner-centered mobile platform demonstrated validity, feasibility, and responsiveness. Next Accreditation System-mandated data may be efficiently collected and used for trainee and program self-study.

Dayne T Mickelson,1 Philip K Louie,2 Kenneth R Gundle,3 Alex W Farnand,4 Douglas P Hanel5 1Department of Orthopedic Surgery and Sports Medicine, Duke University, Durham, NC, USA; 2Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA; 3Department of Orthopedics and Rehabilitation, Oregon Health and Science University, Portland, OR, USA; 4Department of General Surgery, Presence Saint Joseph Hospital – Chicago, Chicago, IL, USA; 5Department of Orthopedic Surgery and Sports Medicine, University of Washington, Harborview Medical Center, Seattle, WA, USA Purpose: To investigate the impact of the Orthopaedic Surgery and Sports Medicine Interest Group (OSSMIG) on medical student interest and confidence in core musculoskeletal (MSK) concepts through supplemental education and experiences at a single tertiary, academic institution.Methods: Medical student OSSMIG members at various levels of training were anonymously surveyed at the beginning and end of the 2014–2015 academic year.Results: Eighteen (N=18) medical student interest group members completed the survey. Significant improvement in their level of training was observed with regard to respondents’ self-assessed competence and confidence in MSK medicine (p

Introduction: Surgical navigation systems are increasingly used to aid resection and reconstruction of osseous malignancies. In the process of implementing image-based surgical navigation systems, there are numerous opportunities for error that may impact surgical outcome. This study aimed to examine modifiable sources of error in an idealized scenario, when using a bidirectional infrared surgical navigation system. Materials and Methods: Accuracy and precision were assessed using a computerized-numerical-controlled (CNC) machined grid with known distances between indentations while varying: 1) the distance from the grid to the navigation camera (range 150 to 247cm), 2) the distance from the grid to the patient tracker device (range 20 to 40cm), and 3) whether the minimum or maximum number of bidirectional infrared markers were actively functioning. For each scenario, distances between grid points were measured at 10-mm increments between 10 and 120mm, with twelve measurements made at each distance. The accuracy outcome was the root mean square (RMS) error between the navigation system distance and the actual grid distance. To assess precision, four indentations were recorded six times for each scenario while also varying the angle of the navigation system pointer. The outcome for precision testing was the standard deviation of the distance between each measured point to the mean three-dimensional coordinate of the six points for each cluster. Results: Univariate and multiple linear regression revealed that as the distance from the navigation camera to the grid increased, the RMS error increased (p Conclusion: In our model laboratory test environment, the infrared bidirectional navigation system was more accurate and precise when the distance from the navigation camera to the physical (working) space was minimized and all bidirectional markers were active. These findings may require alterations in operating room setup and software changes to improve the performance of this system.

Background:Many treatment options exist for unicameral bone cysts (UBC), without clear evidence of superiority. Meta-analyses have been limited by small numbers of patients in specific anatomic and treatment subgroups. The purpose of this study was to report the outcomes of injecting bone marrow aspirate and demineralized bone matrix (BMA/DBM) for the treatment of proximal humerus UBC.Methods:Fifty-one patients with proximal humerus lesions treated by BMA/DBM injection were retrospectively reviewed from a single academic medical center.Results:The mean number of injections performed per patient was 2.14 (range 1-5). Eleven patients underwent only one injection (22%), an additional 19 patients completed treatment after two injections (37%), four patients healed after three injections (8%), and one patient healed after four injections (2%). The cumulative success rate of serial BMA/DBM injections was 22% (11/51), 58% (30/51), 67% (34/51), and 69% (35/51). Eleven patients (22%) ultimately underwent open curettage and bone grafting, and five patients (10%) were treated with injection of calcium phosphate bone substitute.Conclusion:A BMA/DBM injection strategy avoided an open procedure in 78% of patients with a proximal humerus UBC. The majority of patients underwent at least 2 injection treatments.Level of Evidence:Level IV retrospective cohort study.