Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma.

PURPOSE: Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. METHODS: Oral cabozantinib (25 mg/m2 ) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75 mg/m2 ) and cyclophosphamide (250 mg/m2 ) were administered intravenously (IV) on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. RESULTS: Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (seven with Ewing sarcoma; five with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis, grade 3 transaminitis, and prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. CONCLUSIONS: The recommended phase 2 doses and schedules for this combination are topotecan 0.75 mg/m2 IV days 1-5, cyclophosphamide 250 mg/m2 IV days 1-5, and cabozantinib 25 mg/m2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity, while allowing for potential disease control.

Resolution of donor non-alcoholic fatty liver disease following liver transplantation.

INTRODUCTION: Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non-function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes. METHODS: Twenty-nine cases were identified with liver biopsies available from both the donor and the corresponding liver transplant recipient. Donor liver biopsies displayed either MaS or MiS ≥15%, while all recipients received postoperative liver biopsies for cause. RESULTS: The mean donor MaS and MiS were 15.6% (range 0%-60%) and 41.3% (7.5%-97.5%), respectively. MaS decreased significantly from donor (M=15.6%) to recipient postoperative biopsies (M=0.86%), P<.001. Similarly, MiS decreased significantly from donor biopsies (M=41.3%) to recipient postoperative biopsies (M=1.8%), P<.001. At a median of 68 days postoperatively (range 4-384), full resolution of MaS and MiS was observed in 27 of 29 recipients. CONCLUSIONS: High degrees of MaS and MiS in donor livers resolve in recipients following liver transplantation. Further insight into the mechanisms responsible for treating fatty liver diseases could translate into therapeutic targets.

Techniques to Address Humeral Bone Insufficiency During Total Shoulder Arthroplasty With a Nonspherical Humeral Head and Inlay Glenoid.

Total shoulder arthroplasty with a humeral head resurfacing (HHR) component and an inlay glenoid (OVOMotion; Arthrosurface) is a successful treatment option for patients with advanced glenohumeral arthritis, an intact rotator cuff, and adequate proximal humeral bone stock. In patients with poor proximal humeral bone, historically stemmed humeral components have been used instead of HHR. However, strategies can be used to successfully optimize HHR implant fixation in suboptimal bone without converting to stemmed implants or in surgical centers where stemmed prostheses are not available. This Technical Note describes 3 techniques-upsizing the humeral taper post, using humeral autograft, and cementation-to improve humeral implant fixation in patients with suboptimal bone stock when using the Arthrosurface OVOMotion implant.

A 7-year perspective on femoral neck fracture management in New York State-Do Level 1 trauma centers provide better care?

INTRODUCTION: Patients with femoral neck fractures are at a substantial risk for medical complications and all-cause mortality. Given this trend, our study aims to evaluate postoperative outcomes and the economic profile associated with femoral neck fractures managed at level-1 (L1TC) and non-level-1-trauma centers (nL1TC). METHODS: The SPARCS database was queried for all geriatric patients sustaining atraumatic femoral neck fractures within New York State between 2011 and 2017. Patients were then divided into two cohorts depending on the treating facility's trauma center designation: L1TC versus nL1TC. Patient samples were evaluated for trends and relationships using descriptive analysis, Student's t-tests, and Chi-squared. Multivariable linear-regressions were utilized to assess the effect of trauma center designation and potential confounders on patient mortality and inpatient healthcare expenses. RESULTS: In total, 44,085 femoral neck fractures operatively managed at 161 medical centers throughout New York during a 7-year period. 4,974 fractures were managed at L1TC while 39,111 were treated at nL1TC. Following multivariate regression analysis, management at L1TC was the most significant cost driver, resulting in an average increased cost of $6,330.74 per fracture. CONCLUSION: Our results suggest that femoral neck fractures treated at L1TC have more comorbidities, higher in-hospital mortality, longer LOS, and greater hospital costs.

Cross-platform dataset of multiplex fluorescent cellular object image annotations.

Defining cellular and subcellular structures in images, referred to as cell segmentation, is an outstanding obstacle to scalable single-cell analysis of multiplex imaging data. While advances in machine learning-based segmentation have led to potentially robust solutions, such algorithms typically rely on large amounts of example annotations, known as training data. Datasets consisting of annotations which are thoroughly assessed for quality are rarely released to the public. As a result, there is a lack of widely available, annotated data suitable for benchmarking and algorithm development. To address this unmet need, we release 105,774 primarily oncological cellular annotations concentrating on tumor and immune cells using over 40 antibody markers spanning three fluorescent imaging platforms, over a dozen tissue types and across various cellular morphologies. We use readily available annotation techniques to provide a modifiable community data set with the goal of advancing cellular segmentation for the greater imaging community.

Anatomic total shoulder arthroplasty with a nonspherical humeral head and inlay glenoid: 90-day complication profile in the inpatient versus outpatient setting.

BACKGROUND: Total shoulder arthroplasty (TSA) with a nonspherical humeral head component and inlay glenoid is a successful bone-preserving treatment for glenohumeral arthritis. This study aimed to describe the 90-day complication profile of TSA with this prosthesis and compare major and minor complication and readmission rates between inpatient- and outpatient-procedure patients. METHODS: A retrospective review was performed of a consecutive cohort of patients undergoing TSA with a nonspherical humeral head and inlay glenoid in the inpatient and outpatient settings by a single surgeon between 2017 and 2022. Age, sex, body mass index, American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index (CCI), and 90-day complication and readmission rates were compared between inpatient and outpatient groups. RESULTS: One hundred eighteen TSAs in 111 patients were identified. Mean age was 64.9 years (range, 39-90) and 65% of patients were male. Ninety-four (80%) and 24 (20%) patients underwent outpatient and inpatient procedures, respectively. Four complications (3.4%) were recorded: axillary nerve stretch injury, isolated ipsilateral arm deep venous thrombosis (DVT), ipsilateral arm DVT with pulmonary embolism requiring readmission, and gastrointestinal bleed requiring readmission. There were no reoperations or other complications. Outpatients were younger with lower ASA and CCI scores than inpatients; however, there was no difference in complications (1/24 vs. 3/94, P=1.00) or readmissions (1/24 vs. 1/94, P=0.37) between these two groups. CONCLUSIONS: TSA with a nonspherical humeral head and inlay glenoid can be performed safely in both inpatient and outpatient settings. Rates of early complications and readmissions were low with no difference according to surgical setting. Level of evidence: IV.

Measurement of the gluteal compartment pressures: A cadaveric study describing safety and reproducibility of two methods.

INTRODUCTION: Gluteal compartment syndrome is an uncommon entity and physicians may use intracompartmental pressure measurements for confirmation of the clinical diagnosis, or in cases where the physical exam is indeterminate. However, there is a paucity of literature describing a safe and reproducible technique to measure gluteal intracompartmental pressures during the diagnosis of gluteal compartment syndrome. The purpose of this cadaveric study is to evaluate the sole previous technique described in the literature to measure gluteal intracompartmental pressures and provide a modified technique which can be safely and reliably utilized clinically. METHODS: A cadaveric study with three phases was performed in 16 gluteal regions in 8 cadavers. In the first phase, the previously described technique was assessed. In the second phase, a modified set of techniques was created and evaluated. In the third phase, inter-user reliability of the modified set of techniques was assessed and calculated using Cohen's ĸ coefficient. In all three phases, methylene blue was injected through pressure monitoring needles into the gluteus maximus (GMax), gluteus medius/minimus (GMM), and the tensor fascia lata (TFL) compartments. Following dissection, rate of successful penetration into each targeted compartment and distance from the neurovascular structures was recorded. RESULTS: The previously described set of techniques was found to be variable. The modified set of techniques was effective, successfully reaching the GMax, GMM, and TFL compartments in 100%, 100%, and 81% of attempts, respectively. Inter-user reliability was excellent (ĸ = 1) for the techniques to reach both the GMax and GMM compartments, and moderate (ĸ = 0.54) for the technique to reach the TFL compartment. Within the GMax, the pressure monitoring needle was at a mean of 5.4±0.6 cm, 4.1±0.7 cm, 6.4±0.5 cm from the sciatic nerve (SN), superior gluteal nerve (SGN), and inferior gluteal nerve (IGN), respectively. Within the GMM, the pressure monitoring needle was at a mean of 9.7±1.4 cm, 7.4±1.3 cm, 11.1±1.7 cm from the SN, SGN, and IGN, respectively. CONCLUSION: The modified set of techniques presented allows the three gluteal compartments to be safely and reproducibly reached to measure intracompartmental pressures during the diagnosis of gluteal compartment syndrome.

Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma.

BACKGROUND: Ewing sarcoma (EWS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. Cyclin-dependent kinase 4 (CDK4) is a genomic vulnerability in EWS that is synergistic with IGF-1R inhibition in preclinical studies. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF-1R monoclonal antibody) for patients with relapsed EWS. PATIENTS AND METHODS: This open-label, non-randomized, phase 2 trial enrolled patients ≥12 years with relapsed EWS. All patients had molecular confirmation of EWS and RECIST measurable disease. Patients initially received palbociclib 125 mg orally on Days 1-21 and ganitumab 18 mg/kg intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. An exact one-stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. The study was closed following enrollment of the 10th patient due to discontinuation of ganitumab supply. RESULTS: Ten evaluable patients enrolled [median age 25.7 years (range 12.3-40.1)]. The median duration of therapy was 2.5 months (range 0.9-10.8). There were no complete or partial responders. Three of 10 patients had stable disease for >4 cycles and 2 had stable disease at completion of planned therapy or study closure. Six-month progression-free survival was 30% (95% CI 1.6%-58.4%). Two patients had cycle 1 hematologic dose-limiting toxicities (DLTs) triggering palbociclib dose reduction to 100 mg daily for 21 days. Two subsequent patients had cycle 1 hematologic DLTs at the reduced dose. Eighty percent of patients had grade 3/4 AEs, including neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Serum total IGF-1 significantly increased (p = 0.013) and ctDNA decreased during the first cycle. CONCLUSIONS: This combination lacks adequate therapeutic activity for further study, though a subset of patients had prolonged stable disease.

CT Scan versus Saline Load Test for Detection of Traumatic Wrist Arthrotomy.

Background Traumatic arthrotomy of the wrist is most commonly detected using the saline load test (SLT); however, little data exists on the effectiveness of the SLT to this specific joint. The use of computed tomography (CT) scan has been validated as an alternative method to detect traumatic arthrotomy of the knee, as the presence of intra-articular air can be seen when there is violation of the joint capsule. Question/Purpose The purpose of this study was to determine the ability of CT scan to identify arthrotomy of the wrist capsule and compare the diagnostic performance of CT versus traditional SLT. Materials and Methods Ten fresh frozen cadavers which had undergone transhumeral amputation were initially used in this study. A baseline CT scan was performed to ensure no intra-articular air existed prior to intervention. After baseline CT, an arthrotomy was created at the 6R radiocarpal portal site. The wrists then underwent a postarthrotomy CT to identify the presence or absence of intra-articular air. Following CT, the wrists were subjected to the SLT to detect the presence of extravasation from the arthrotomy. Results Nine cadavers were included following baseline CT scan. Following arthrotomy, intra-articular air was visualized in eight of the nine cadavers in the postarthrotomy CT scan. Air was seen in the radiocarpal joint in eight of the nine wrists; midcarpal joint in seven of the nine wrists; and distal radioulnar joint in six of the nine wrists. All wrists (nine of the nine) demonstrated extravasation during the SLT. The mean volume of extravasation occurred at 3.7 mL (standard deviation = 2.6 mL), with a range of 1 to 7 mL. Conclusion CT scan correctly identified eight of the nine simulated traumatic arthrotomies. Injection of 7 mL during the SLT was necessary to identify 100% of the arthrotomies. Clinical Relevance CT scan is a sensitive modality for detection of traumatic arthrotomy of the wrist in a cadaveric model.

Gluteal compartment syndrome: A systematic review and meta-analysis.

INTRODUCTION: Gluteal compartment syndrome is a rare but devastating condition with limited characterization in the literature. The purpose of our systematic review, case series, and meta-analysis is to synthesize the current literature and provide recommendations on how to prevent gluteal compartment syndrome, identify at-risk patients, and avoid delays in diagnosis and treatment. METHODS: International Classification of Disease codes were used to identify patients at our institution. PubMed, MEDLINE, and the Cochrane Library were searched to identify case reports between 1972 and March 1st, 2018. Cases were analyzed based on demographics, etiology, presentation, symptoms, diagnosis, treatment, and outcomes. RESULTS: 139 cases - 13 from our institution and 126 previously published - were included. The most common etiologies were postoperative (41%), prolonged immobilization secondary to substance abuse or loss of consciousness (35%) and trauma (19%). 89% were male, mean age was 45 years (range, 16-74), and mean body mass index was 41 kg/m2. Rhabdomyolysis and sciatic neuropathy were identified in 94% and 74% of patients, respectively. Fasciotomy was performed in 80% of patients. Overall, 93% of patients survived. However, 41% of patients suffered prolonged neurologic dysfunction. In patients with an initial neurologic deficit, there was a higher rate of permanent neurological deficit in patients treated medically than those treated surgically (12/14 vs 29/61, p=0.0153), but no statistical difference in mortality (0/14 vs 4/61, p=1). In patients without initial neurologic deficit, there were no statistical differences in rates of permanent neurological deficit (0/7 vs 2/20, p=1) or mortality (0/7 vs 3/20, p=0.545) between those receiving medical or surgical treatment. DISCUSSION: Gluteal compartment syndrome is an orthopaedic emergency that may be more prevalent and associated with higher morbidity and mortality than previously recognized. Risk factors may include prolonged surgical duration, immobilization secondary to substance abuse, and pelvic trauma. Intraoperative precautions and postoperative surveillance are recommended in obese patients undergoing prolonged procedures. Fasciotomies improve neurologic outcomes in patients presenting with an initial neurologic deficit. In patients who are neurologically intact on presentation, medical management with neurologic function surveillance may be the optimal initial treatment. Fasciotomies do not impact mortality. Additionally, a treatment algorithm is provided.

Patellar Fracture Fixation With Cannulated Compression Screws and FiberTape Cerclage.

Transverse patella fractures with loss of knee extensor mechanism function are a common orthopaedic injury requiring operative fixation. Current accepted surgical options for noncomminuted transverse fractures include open reduction with tension band wiring. Although these procedures result in good clinical outcomes and fracture healing, symptomatic hardware from the historically used metal implants is very common. The purpose of this Technical Note is to describe a technique for treatment of transverse patellar fractures using cannulated compression screws with tensioned high-resistance suture tape functioning as the tension band. This technique provides effective, reproducible fracture fixation while minimizing symptomatic hardware, failure, and reoperation.

Surgical Management of a Pediatric Cuboid Nutcracker Fracture: A Case Report.

CASE: Cuboid impaction fractures (nutcracker fractures) result from high-energy trauma and are exceedingly rare in children. We present a case of an 8-year-old boy who sustained a comminuted cuboid nutcracker fracture after a fall from height. The patient underwent open reduction and internal fixation with a locking plate. At 1 year postoperatively, lateral column length and articular congruency were maintained, and the patient return to full function and activity. CONCLUSION: Cuboid nutcracker fractures in children are rare and can be successfully treated with open reduction and internal fixation with locking plates, with excellent radiographic and functional outcomes.

Late Anterior Prosthetic Hip Dislocation Due to Yoga.

The popularity of yoga and the prevalence of total hip arthroplasty (THA) have simultaneously increased in the United States. Accordingly, one can assume that the number of THA patients practicing yoga has increased. Certain yoga poses reach the extremes of hip range of motion, potentially leaving patients vulnerable to dislocation. To date, 2 cases of late posterior prosthetic hip dislocations during yoga have been reported; however, there have been no reports of anterior prosthetic hip dislocations. We present one case of late anterior prosthetic hip dislocation during yoga in a patient who underwent THA via the direct anterior approach. Prosthetic hip dislocation during yoga may be a growing concern. We provide additional evidence in support of recommendations for THA patients to safely practice yoga.

Oral health implications in total hip and knee arthroplasty patients: A review.

Over the past two decades, oral health has emerged as a health care priority. Historically, patients greater than 65 years of age, the economically disadvantaged, members of racial or ethnic minority groups, or the disabled or home bound have experienced significant barriers to routine dental care. The connection between oral health care and periprosthetic joint infections (PJI) continues to be of importance to the orthopedic surgeon, as such infections are significantly morbid and costly. This review aims to introduce the importance of oral health as a small but crucial portion of an arthroplasty patient's overall perioperative management.

The Correlation of Skeletal and Cardiac Muscle Dysfunction in Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle and cardiac dysfunction. While skeletal muscle dysfunction precedes cardiomyopathy, the relationship between the progressive decline in skeletal and cardiac muscle function is unclear. This relationship is especially important given that the myocardial effects of many developing DMD therapies are largely unknown. OBJECTIVE: Our objective was to assess the relationship between progression of skeletal muscle weakness and onset of cardiac dysfunction in DMD. METHODS: A total of 77 DMD subjects treated at a single referral center were included. Demographic information, quantitative muscle testing (QMT), subjective muscle strength, cardiac function, and current and retrospective medications were collected. A Spearman rank correlation was used to evaluate for an association between subjective strength and fractional shortening. The effects of total QMT and arm QMT on fractional shortening were examined in generalized least square with and without adjustments for age, ambulatory status, and duration of corticosteroids and cardiac specific medications. RESULTS: We found a significant correlation between maintained subjective skeletal muscle arm and leg strength and maintained cardiac function as defined by fractional shortening (rho=0.47, p=0.004 and rho=0.48, p=0.003, respectively). We also found a significant association between QMT and fractional shortening among non-ambulatory DMD subjects (p=0.03), while this association was not significant in ambulatory subjects. CONCLUSIONS: Our findings allow us to conclude that in this population, there exists a significant relationship between skeletal muscle and cardiac function in non-ambulatory DMD patients. While this does not imply a causal relationship, a possible association between skeletal and cardiac muscle function suggests that researchers should carefully monitor cardiac function, even when the primary outcome measures are not cardiac in nature.